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Background: Pregnant people with coronavirus disease 2019 (COVID-19) experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy., Methods: IMPAACT 2032 was a phase 4 prospective, open-label, nonrandomized opportunistic study of hospitalized pregnant and nonpregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks after last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and nonpregnant women were calculated., Results: Fifty-three participants initiated remdesivir (25 pregnant; median gestational age, 27.6 weeks; interquartile range, 24.9-31.0 weeks). Plasma exposures of remdesivir, its 2 major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and nonpregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI, 1.35-3.03) with each additional infusion in nonpregnant versus pregnant participants. Three adverse events in nonpregnant participants were related to treatment (1 grade 3; 2 grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected., Conclusions: Plasma remdesivir PK parameters were comparable between pregnant and nonpregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy., Clinical Trials Registration: NCT04582266., Competing Interests: Potential conflicts of interest. K. M. B. has received consulting fees from ViiV Healthcare. K. B. has received research support from Gilead Sciences, Inc and ViiV Healthcare paid to her institution. D. S. has received research support from Gilead Sciences, Inc, Merck, and ViiV Healthcare paid to his institution. A. A. serves on scientific advisory boards for Gilead Sciences, Inc and ViiV Healthcare; is a site principal investigator for a multisite and investigator-initiated studies with Gilead Sciences, Inc; and is a consultant for Merck. E. V. C. is serving on a data and safety monitoring board for Melinta Pharmaceuticals. D. E. Y. was previously an unpaid technical advisor for the nonprofit Cover the Globe and Maipelo Trust. M. M. has received research support from Gilead Sciences, Inc, Merck, and ViiV Healthcare paid to his institution. R. H. and K. K. are employees of Gilead Sciences, Inc and hold stock in the company. J. D. M. has received research support from Gilead Sciences, Inc paid to his institution. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Cyclodextrin (CD) derivatives have gained significant attention in biomedical applications due to their remarkable biocompatibility, unique inclusion capabilities, and potential for functionalization. This review focuses on recent advancements in CD-based assemblies, specifically their role in improving drug delivery, emphasizing remdesivir (RMD). The review introduces CD materials and their versatile applications in self-assembly and supramolecular assembly. CD materials offer immense potential for designing drug delivery systems with enhanced activity. Their inherent inclusion capabilities enable the encapsulation of diverse therapeutic agents, including RMD, resulting in improved solubility, stability, and bioavailability. The recent advances in CD-based assemblies, focusing on their integration with RMD have been concentrated here. Various strategies for constructing these assemblies are discussed, including physical encapsulation, covalent conjugation, and surface functionalization techniques. Furthermore, exploring future directions in these fields has also been provided. Ongoing research efforts are directed toward developing novel CD derivatives with enhanced properties, such as increased encapsulation efficiency and improved release kinetics. Moreover, the integration of CD-based assemblies with advanced technologies such as nanomedicine and gene therapy holds tremendous promise for personalized medicine and precision therapeutics.

Oral broad-spectrum antivirals are urgently needed for the treatment of many emerging and contemporary RNA viruses. We previously synthesized 1- O -octadecyl-2- O -benzyl- sn -glyceryl-P-RVn (ODBG-P-RVn, V2043), a phospholipid prodrug of GS-441524 (remdesivir nucleoside, RVn), and demonstrated its in vivo efficacy in a SARS-CoV-2 mouse model. Structure-activity relationship studies focusing on the prodrug scaffold identified two modifications, 3-fluoro-4-methoxy-benzyl (V2053) and 4-cyano-benzyl (V2067), that significantly enhanced the in vitro broad-spectrum antiviral activity against multiple RNA viruses when compared to V2043. Here, we demonstrate that V2043, V2053, and V2067 are all orally bioavailable, well-tolerated, and achieve high sustained plasma levels after single oral daily dosing. All three phospholipid prodrugs are significantly more active than RVn in vitro and significantly reduce SARS-CoV-2 lung titers in prophylaxis and treatment mouse models of SARS-CoV-2 B.1.351 infection. On a molar basis, V2043 and V2067 are substantially more active than obeldesivir/GS-5245 and molnupiravir in vivo . Together, these data support the continued development of phospholipid RVn prodrugs for the treatment of SARS-CoV-2 and other RNA viruses of clinical concern., Competing Interests: K.Y.H., J.R.B., N.V., and R.T.S. are named as inventors of PCT/US2021/040394 and US 2023/0287029 (Antiviral Prodrugs, Pharmaceutical Formulations and Methods) and PCT/US2023/011693 (Antiviral Prodrugs, Intermediate and Long-Acting Formulations and Methods).

Purpose: Clinicians consider polypharmacy, comorbidities, and other factors including the potential for drug-drug interactions (DDIs) when evaluating therapeutic options for specific clinical diagnoses. Contemporary treatment for coronavirus disease 2019 (COVID-19) includes direct-acting antivirals (DAAs). We sought to characterize patients' characteristics, comorbidities, and medications received during their hospitalization for COVID-19 and quantify potential DDIs that clinicians consider in selecting appropriate DAAs., Methods: Patients hospitalized with a primary diagnosis of COVID-19 between May 2020 and December 2022 from the PINC AI Healthcare Database were identified. Medications administered during the hospitalization with the potential to cause DDIs with nirmatrelvir/ritonavir, remdesivir, or molnupiravir (per the Emergency Use Authorization factsheet or package insert) were assessed. For DDIs with nirmatrelvir/ritonavir, medications are categorized as "Contraindicated," "Avoid Concomitant Use," or "Other DDIs" (includes recommendation for dose modification or clinical and laboratory monitoring). For remdesivir, coadministration with chloroquine phosphate and hydroxychloroquine sulfate was not recommended. For molnupiravir, no drugs are listed as having potential DDIs. In a subset of patients, a multivariable logistic regression model was used to examine the association between documented patient/hospital characteristics and the likelihood of being "Contraindicated" to receive nirmatrelvir/ritonavir., Findings: Of the 788,238 patients hospitalized for COVID-19 in 920 hospitals, 53% were ≥ 65 years old, and 31% had Charlson Comorbidity Index (CCI) ≥ 3. During the study period, about half of the patients received medications categorized as "Contraindicated" (11%) and/or "Avoid Concomitant Use" (41%) with nirmatrelvir/ritonavir. The frequency of administered drugs was higher in those aged ≥ 65 years (68%), CCI ≥ 3 (78%), with high-risk underlying conditions (55%). About 1% of patients received medications that were not recommended to be coadmistered with remdesivir. Among a subset of patients hospitalized for COVID-19 in 2022, those who were older, had higher CCI, high-risk underlying conditions, severe hepatic impairment, Medicare insurance, and hospitalized in larger hospitals were significantly more likely to be categorized as "Contraindicated" when considering nirmatrelvir/ritonavir as a therapeutic option to manage COVID-19., Implications: A significant proportion of patients hospitalized for COVID-19 receive medications for other conditions that have the potential to result in DDIs with DAAs; most predominantly with nirmatrelvir/ritonavir, a strong CYP3A enzyme inhibitor, fewer with remdesivir, and none with molnupiravir. Higher age and comorbidity burden were significantly associated with a higher likelihood of receiving medications that are "Contraindicated" with nirmatrelvir/ritonavir. In the evolving COVID-19 era, these findings provide insights into patients hospitalized for COVID-19, and the polypharmacy evaluations that clinicians may encounter when selecting among DAAs to manage COVID-19., Competing Interests: Declaration of competing interest Summary of ICMJE forms: Essy Mozaffari is an employee of Gilead Sciences, Inc. and holds stock or stock options. Aastha Chandak is an employee of Certara and declares support provided by Gilead Sciences, Inc. to her institution. Andrew Ustianowski declares consulting fees provided by Generate Biomedicines, Gilead Sciences, Inc., Merck/MSD, and Pfizer Inc. and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events, and/or participation on a Data Safety Monitoring Board or Advisory Board from Astra Zeneca, Gilead Sciences, Inc., and GSK. Christina G. Rivera declares the receipt of grant or contracts from Gilead Science, Inc. as payment to PI colleague, consulting fees and participation on a Data Safety Monitoring Board or Advisory Board from Gilead Science, Inc., and payment of honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Jobson Health, Continuing Education Network, CE Impact, Insmed, Gilead Sciences, Inc., Annenberg Center for Health Science, American College of Clinical Pharmacy, and PharmCon Healthcare Education. Neera Ahuja declares payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Gilead Sciences, Inc. Heng Jiang is an employee of Certara and declares support provided by Gilead Sciences, Inc. to his institution. Mark Berry is an employee of Gilead Sciences, Inc. and holds stock or stock options. Jason F. Okulicz is an employee of Gilead Sciences, Inc. and holds stock or stock options. Alpesh N. Amin is a PI or co-PI of clinical trials sponsored by NIH/NIAID, NeuroRx Pharma, Pulmotect, Blade Therapeutics, Novartis, Takeda, Humanigen, Eli Lilly, PTC Therapeutics, OctaPharma, Fulcrum Therapeutics, Alexion unrelated to this manuscript; speaker and/or consultant fees for Pfizer, Salix, Alexion, AstraZeneca, Bayer, Ferring, Seres, Spero, Eli Lilly, Nova Nordisk, Gilead, Renibus, GSK, Dexcom, Reprieve, HeartRite, and Aseptiscope; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events for Pfizer, Salix, Alexion, AstraZeneca, Bayer, Ferring, Seres, Spero, Eli Lilly, Nova Nordisk, Gilead, Renibus, GSK, Dexcom, Reprieve, HeartRite, and Aseptiscope., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The extent of the SARS-CoV-2 short-term evolution under Remdesivir (RDV) exposure and whether it varies across different upper respiratory compartments are not fully understood., Methods: Patients hospitalized for COVID-19, with or without RDV therapy, were enrolled and completed up to three visits, in which they provided specimens from four respiratory compartments. Near full-length genome SARS-CoV-2 sequences were obtained from viral RNA, standard lineage and variant assignments were performed, and viral mutations in the RNA-dependent RNA polymerase (RdRp) region-the RDV target gene-were detected and compared between participants with and without RDV, across the four compartments, within participants across visits, and versus a larger sequence dataset. The statistical analysis used a generalized linear mixed-effects model., Results: A total of 139 sequences were obtained from 37 out of the 44 (84%) enrolled participants. The genotyping success varied across respiratory compartments, which ranged from 42% with oropharyngeal specimens to 67% with nasopharyngeal specimens and showed improvement with higher viral loads. No RdRp mutations known to be associated with RDV resistance were identified, and for 34 detected mutations at 32 amino acid positions that are not known as RDV-associated, there was no evidence of any associations with the RDV exposure, respiratory compartment, or time. At least 1 of these 34 mutations were detected in all participants, and some differed from the larger sequence dataset., Conclusions: This study highlighted the SARS-CoV-2 short-term genomic stability within hosts and across upper respiratory compartments, which suggests a lack of evolution of RDV resistance over time. This contributes to our understanding of SARS-CoV-2 genomic dynamics.

Background: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo., Methods: Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed., Results: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40-2.71) for levels >245 pg/mL vs 1.04 (95% CI, .76-1.42) for levels <245 pg/mL. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive., Conclusions: Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy., Clinical Trial Registration: NCT04280705 (ClinicalTrials.gov)., Competing Interests: Potential conflicts of interest . A. L. G. reports contract testing to his institution from Abbott, Cepheid, Novavax, Pfizer, Janssen, and Hologic and research support to his institution from Gilead Sciences, Inc, and Merck outside of the described work. D. P. is an employee and shareholder of Gilead Sciences, Inc. K. J. is a shareholder of and was employed by Gilead Sciences, Inc, at the time of manuscript development. C. A. B. has received grants/contracts to her institution from Gilead Sciences, Inc, and consultant fees from NDA Partners, LLC, related to drug development. C. A. B. served as the president of the CROI Foundation Board of Directors, vice president of the Zimbabwe AIDS Treatment Assistance Project Board of Directors, and secretary/treasurer of the IAS-USA Board of Directors (all nonprofit organizations). C. A. B. recently served as deputy editor for Clinical Infectious Diseases for the Infectious Diseases Society of America. N. J. reports salary support by Sagent Pharmaceuticals to his institution. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Transaminase and creatinine elevations have been well described in adults treated with remdesivir for COVID-19. It is hypothesized that a similar safety profile exists in children with COVID-19 treated with remdesivir, but available data are limited, especially in children < 12 months. The primary aim of this study was to determine the prevalence and timing of elevations in transaminases and creatinine in children with COVID-19 who were treated with remdesivir., Methods: This was a retrospective, observational cohort study including all pediatric patients admitted to a single, freestanding children's hospital who were positive for COVID-19 and received at least 1 dose of remdesivir between 1/1/2020 and 5/31/2022. Available baseline and peak transaminase and creatinine concentrations were evaluated. Multivariable logistic regression analysis was performed to identify risk factors for transaminase elevation., Results: A total of 180 patients met inclusion criteria. Creatinine elevation of any grade was noted in 16% and remained elevated only in those with underlying chronic kidney disease. Transaminase elevation of any grade was noted in 58% of patients and remained elevated in only 1%. Older age and critical respiratory disease were associated with higher risk of significant transaminase elevation, whereas non-Hispanic ethnicity was strongly associated with protection against significant transaminase elevation., Conclusions: In our cohort of hospitalized children with COVID-19 who were treated with remdesivir, most patients experienced only mild transaminitis and normal creatinine concentrations. A limited number of patients experienced laboratory abnormalities which were transient, suggesting a favorable safety profile for remdesivir use in pediatrics., (© 2024. The Author(s).)

Remdesivir therapy has been declared as efficient in the early stages of Covid-19. Of the 339 patients (males 55.8%, age 71(59;77) years) with a detectable viral load, 140 were treated with remdesivir (of those 103 in the ICU and 57 immunosuppressed) and retrospectively compared with 199 patients (of those 82 in the ICU and 28 immunosuppressed) who were denied therapy due to advanced Covid-19. The viral load was estimated by detecting nucleocapsid antigen in serum (n = 155, median 217(28;1524)pg/ml), antigen in sputum (n = 18, COI 18(4.6;32)), nasopharyngeal antigen (n = 44, COI 17(8;35)) and the real-time PCR (n = 122, Ct 21(18;27)). After adjustment for confounders, patients on remdesivir had better 12-month survival (HR 0.66 (0.44;0.98), p = 0.039), particularly when admitted to the ICU (HR 0.49 (0.29;0.81), p = 0.006). For the immunocompromised patients, the difference did not reach statistical significance (HR 0.55 (0.18;1.69), p = 0.3). The other most significant confounders were age, ICU admission, mechanical ventilation, leukocyte/lymphocyte ratio, admission creatinine and immunosuppression. The impact of monoclonal antibodies or previous vaccinations was not significant. Despite frequent immune suppression including haemato-oncology diseases, lymphopenia, and higher inflammatory markers in the remdesivir group, the results support remdesivir administration with respect to widely available estimates of viral load in patients with high illness severity., (© 2024. The Author(s).)

GS-441524 is an adenosine nucleoside antiviral demonstrating significant efficacy in the treatment of feline infectious peritonitis (FIP), an otherwise fatal illness, resulting from infection with feline coronavirus. However, following the emergence of COVID-19, veterinary development was halted, and Gilead pursued clinical development of a GS-441524 pro-drug, resulting in the approval of Remdesivir under an FDA emergency use authorization. Despite lack of regulatory approval, GS-441524 is available without a prescription through various unlicensed online distributors and is commonly purchased by pet owners for the treatment of FIP. Herein, we report data obtained from the analytical characterization of two feline renal calculi, demonstrating the propensity for GS-441524 to cause renal toxicity through drug-induced crystal nephropathy in vivo. As definitive diagnosis of drug-induced crystal nephropathy requires confirmation of the lithogenic material to accurately attribute a mechanism of toxicity, renal stone composition and crystalline matrix were characterized using ultra-performance liquid chromatography photodiode array detection (UPLC-PDA), ultra-performance liquid chromatography mass spectrometry (LCMS), nuclear magnetic resonance (NMR) spectroscopy, X-ray powder diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR). This work serves to provide the first analytical confirmation of GS-441524-induced crystal nephropathy in an effort to support toxicologic identification of adverse renal effects caused by administration of GS-441524 or any pro-drug thereof., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Literature on the safety of remdesivir in hospitalized COVID-19 patients with severe renal impairment is limited. We aimed to investigate the safety and effectiveness of remdesivir in this population., Methods: We conducted a retrospective cohort study of adult hospitalized COVID-19 patients who received remdesivir between April 2022 and October 2022. Outcomes were compared between estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m 2 and ≥30 mL/min/1.73 m 2 groups. The primary safety outcomes were acute kidney injury (AKI) and bradycardia, while the primary effectiveness outcomes included mortality in COVID-19-dedicated wards and hospital mortality. Secondary outcomes included laboratory changes, disease progression, and recovery time., Results: A total of 1,343 patients were recruited, with 307 (22.9%) in the eGFR <30 group and 1,036 (77.1%) in the eGFR ≥30 group. Patients with an eGFR <30 had higher risks of AKI (adjusted hazard ratio [aHR] 2.92, 95% CI 1.93-4.44) and hospital mortality (aHR 1.47, 95% CI 1.06-2.05) but had comparable risks of bradycardia (aHR 1.15, 95% CI 0.85-1.56) and mortality in dedicated wards (aHR 1.43, 95% CI 0.90-2.28) than patients with an eGFR ≥30. Risk of disease progression was higher in the eGFR <30 group (adjusted odds ratio 1.62, 95% CI 1.16-2.26). No difference between the two groups in laboratory changes and recovery time., Conclusions: Hospitalized COVID-19 patients receiving remdesivir with severe renal impairment had an increased risk of AKI, hospital mortality, and COVID-19 disease progression compared to patients without severe renal impairment.

Background: We aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with coronavirus disease 2019 (COVID-19) who received remdesivir plus standard of care (SoC) compared with SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases., Methods: This post hoc safety analysis is based on data from the multicenter, randomized, open-label, controlled DisCoVeRy trial in hospitalized patients with COVID-19. Any first AE that occurred between randomization and day 29 in the modified intention-to-treat (mITT) population randomized to either remdesivir or control group was considered. Analysis was performed using Kaplan-Meier survival curves, and Kaplan-Meier estimates were calculated for event rates., Results: Cardiac AEs were reported in 46 (11.2%) of 410 and 48 (11.3%) of 423 patients in the mITT population (n = 833) enrolled in the remdesivir and control groups, respectively. The difference between both groups was not significant (hazard ratio [HR], 1.0; 95% confidence interval [CI], .7-1.5; P = .98), even when serious and nonserious cardiac AEs were evaluated separately. The majority of reports in both groups were of arrhythmic nature (remdesivir, 84.8%; control, 83.3%) and were associated with a favorable outcome. There was no significant difference between the two groups in the occurrence of cardiac AE subclasses, including arrhythmic events (HR, 1.1; 95% CI, .7-1.7; P = .68)., Conclusions: Remdesivir treatment was not associated with an increased risk of cardiac AEs compared with control in patients hospitalized with moderate or severe COVID-19. These results are consistent with other randomized, controlled trials and meta-analyses. Clinical Trials Registration. NCT04315948; EudraCT 2020-000936-23., Competing Interests: Potential conflicts of interest. D. C. reports an human immunodeficiency virus grant from Janssen and lecture fees from Pfizer, outside the submitted work. F. M. reports grants and consulting fees from Pharmatheus, grants from Sanofi, and consulting fees from Ipsen, outside the submitted work. M. H. reports grants from the Belgian Center for Knowledge, the Fonds Erasme-COVID-Université Libre de Bruxelles, and the EU-Horizon programme, for the submitted work; support for attending meetings from Pfizer, MSD and Gilead, Pharmamar; support for participation on an advisory board for therapeutics on COVID-19 (DisCoVeRy trial); support for leadership for the Belgian guidelines on therapeutics for COVID-19; acting as president for the Belgian Society of Clinical Microbiology and Infectious Diseases; and payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Gilead, GKS, INSMED, and Shionogi. J. P. reports lecture fees from Gilead and MSD; support for attending meetings from Gilead, Eumedica, and Merck Sharp & Dohme, outside the submitted work. C. B. reports participation on a DSMB for 4Living Biotech and consulting fees from Da Volterra and Mylan Pharmaceuticals, outside the submitted work. R. G. reports consulting fees from Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, Merck Sharp & Dohme, Merck, Gilead, and Daiichi Sankvo; lecture fees from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Sandoz, AbbVie, Gilead, and Daiichi Sankvo; support for attending meetings from Roche, Amgen, Janssen, AstraZeneca, Novartis, Merck Sharp & Dohme, Celgene, Gilead, Bristol Myers Squibb, AbbVie, and Daiichi Sankvo; participation on a DSMB for Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, Merck Sharp & Dohme, Merck, Gilead, and Daiichi Sankyo; research grants from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Sandoz, AbbVie, Gilead, and Daiichi Sankyo; and stock or stock options from Novo Nordisk, Lilly. J.-A. P. reports consulting fees from Pfizer, Merck Sharp & Dohme, Janssen-Cilag, and AOP Orphan Pharmaceuticals; lecture fees from Cepheid, Pfizer, and Gilead; and support for attending meetings from Pfizer and Gilead. C. A. reports lecture fees from Insmed, GSK, Moderna, AstraZeneca, and Chiesi; grants or contracts from FEDER funding; support for attending meetings from Home perf; a leadership or fiduciary role as president of the Scientific Council of the French Respiratory Society; and serving as a member of the French ANRS-MIE for COVID and member of the COVID Group of the French Public Health High Council. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: A trial performed among unvaccinated, high-risk outpatients with COVID-19 during the delta period showed remdesivir reduced hospitalization. We used our real-world data platform to determine the effectiveness of remdesivir on reducing 28-day hospitalization among outpatients with mild-moderate COVID-19 during an Omicron period including BQ.1/BQ.1.1/XBB.1.5., Methods: We did a propensity-matched, retrospective cohort study of non-hospitalized adults with SARS-CoV-2 infection between April 7, 2022, and February 7, 2023. Electronic healthcare record data from a large health system in Colorado were linked to statewide vaccination and mortality data. We included patients with a positive SARS-CoV-2 test or outpatient remdesivir administration. Exclusion criteria were other SARS-CoV-2 treatments or positive SARS-CoV-2 test more than seven days before remdesivir. The primary outcome was all-cause hospitalization up to day 28. Secondary outcomes included 28-day COVID-related hospitalization and 28-day all-cause mortality., Results: Among 29,270 patients with SARS-CoV-2 infection, 1,252 remdesivir-treated patients were matched to 2,499 untreated patients. Remdesivir was associated with lower 28-day all-cause hospitalization (1.3% vs. 3.3%, adjusted hazard ratio (aHR) 0.39 [95% CI 0.23-0.67], p < 0.001) than no treatment. All-cause mortality at 28 days was numerically lower among remdesivir-treated patients (0.1% vs. 0.4%; aOR 0.32 [95% CI 0.03-1.40]). Similar benefit of RDV treatment on 28-day all-cause hospitalization was observed across Omicron periods, aOR (95% CI): BA.2/BA2.12.1 (0.77[0.19-2.41]), BA.4/5 (0.50[95% CI 0.50-1.01]), BQ.1/BQ.1.1/XBB.1.5 (0.21[95% CI 0.08-0.57]., Conclusion: Among outpatients with SARS-CoV-2 during recent Omicron surges, remdesivir was associated with lower hospitalization than no treatment, supporting current National Institutes of Health Guidelines., (© 2024. The Author(s).)

Background: Antiviral drugs have become crucial in managing COVID-19, reducing complications and mortality. Remdesivir has emerged as an effective therapeutic drug for hospitalized patients at risk of disease progression, especially when alternative treatments are infeasible. While the recommended treatment duration of remdesivir extends up to 7 days post-symptom onset, this study examines how early remdesivir administration impacts clinical outcomes., Methods: We conducted a retrospective analysis using clinical data from consecutively PCR confirmed SARS-CoV‑2 adult patients (≥ 18 years) who received remdesivir during their hospitalization at the department of infectious diseases, Klinik Favoriten in Vienna. The data covered the period from July 1, 2021, to April 31, 2022. Patients were divided into two groups based on the timing of remdesivir administration: an early group (0-3 days since symptom onset) and a late group (≥ 4 days since symptom onset). The primary outcome was in-hospital disease progression, assessed using the WHO COVID-19 Clinical Progression Scale (≥ 1 point increase). Multivariable logistic regression, adjusted for age, sex, SARS-CoV‑2 variant, and COVID-19 vaccination status, was used to assess clinical outcomes., Results: In total 219 patients were included of whom 148 (67.6%) were in the early group and 71 (32.4%) were in the late group. The average age was 66.5 (SD: 18.0) years, 68.9% of the patients were vaccinated, and 72.6% had the Omicron virus variant. Late remdesivir administration was associated with a significantly higher probability of needing high-flow oxygen therapy (OR 2.52, 95% CI 1.40-4.52, p = 0.002) and ICU admission (OR 4.34, 95% CI 1.38-13.67, p = 0.012) after adjusting for confounders. In the late group there was a trend towards a higher risk of clinical worsening (OR 2.13, 95% CI 0.98-4.64, p = 0.056) and need for any oxygen therapy (OR 1.85, 95% CI 0.94-3.64, p = 0.074)., Conclusion: Compared to patients who received remdesivir within the first 3 days after symptom onset, administering remdesivir after day 3 in hospitalized COVID-19 patients is associated with higher risk for complications, such as the need for high-flow oxygen therapy and ICU admission., (© 2024. The Author(s).)

The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRps) of prototypic respiratory viruses. GS-646939 is the active 5'-triphosphate metabolite of a 4'-cyano modified C-adenosine analog phosphoramidate prodrug GS-7682. Enzyme kinetics show that the RdRps of human rhinovirus type 16 (HRV-16) and enterovirus 71 incorporate GS-646939 with unprecedented selectivity; GS-646939 is incorporated 20-50-fold more efficiently than its natural ATP counterpart. The RdRp complex of respiratory syncytial virus and human metapneumovirus incorporate GS-646939 and ATP with similar efficiency. In contrast, influenza B RdRp shows a clear preference for ATP and human mitochondrial RNA polymerase does not show significant incorporation of GS-646939. Once incorporated into the nascent RNA strand, GS-646939 acts as a chain terminator although higher NTP concentrations can partially overcome inhibition for some polymerases. Modeling and biochemical data suggest that the 4'-modification inhibits RdRp translocation. Comparative studies with GS-443902, the active triphosphate form of the 1'-cyano modified prodrugs remdesivir and obeldesivir, reveal not only different mechanisms of inhibition, but also differences in the spectrum of inhibition of viral polymerases. In conclusion, 1'-cyano and 4'-cyano modifications of nucleotide analogs provide complementary strategies to target the polymerase of several families of respiratory RNA viruses., Competing Interests: Conflict of interest M. G. received funding from Gilead Sciences in support for studies on the mechanism of action of nucleotide analog polymerase inhibitors. J. P., D. S. S., J. K. P., J. Y. F., and J. P. B. are current or former Gilead employees., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Efficacy of remdesivir for COVID-19 remains unclear. We updated our published systematic review to better inform on the use of remdesivir for COVID-19., Methods: We searched for randomized controlled trials (RCTs) among hospitalized COVID-19 patients. Meta-analysis was conducted using an inverse variance, random-effects model, presenting relative risk (RR) or mean difference (MD) and their associated 95% confidence intervals (CIs). Statistical heterogeneity was calculated using the I 2 statistic. In addition, we conducted trial sequential analysis (TSA). Outcomes with additional data were clinical progression, hospitalization days, and all-cause mortality., Results: We included nine RCTs (12,876 individuals). Three trials each were of a low, unclear, and a high risk of bias. Compared with no treatment/placebo, remdesivir (100 mg daily, over 10 days) significantly improved clinical progression (RR 1.06, CI 1.02-1.11), but did not significantly reduce hospitalization days (MD -0.48, CI -2.18-1.21) and all-cause mortality (RR 0.92, CI 0.84-1.01). TSA suggested that further information is not required to conclude on the efficacy of remdesivir in improving clinical progression, and that, while more information is required for hospitalization days and all-cause mortality, further RCTs to prove fewer hospitalization days may be futile, as efficacy of remdesivir for this outcome is unlikely., Conclusions: Remdesivir appeared promising for COVID-19, but there is insufficient evidence of its efficacy. High quality RCTs are needed for a stronger evidence base.

The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case of remdesivir, we here show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics., (© 2024. The Author(s).)

The progress of viral infection involves numerous transcriptional regulatory events. The identification of the newly synthesized transcripts helps us to understand the replication mechanisms and pathogenesis of the virus. Here, we utilized a time-resolved technique called metabolic RNA labeling approach called thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) to differentially elucidate the levels of steady-state and newly synthesized RNAs of BHK21 cell line in response to human coronavirus OC43 (HCoV-OC43) infection. Our results showed that the Wnt/β-catenin signaling pathway was significantly enriched with the newly synthesized transcripts of BHK21 cell line in response to HCoV-OC43 infection. Moreover, inhibition of the Wnt pathway promoted viral replication in the early stage of infection, but inhibited it in the later stage of infection. Furthermore, remdesivir inhibits the upregulation of the Wnt/β-catenin signaling pathway induced by early infection with HCoV-OC43. Collectively, our study showed the diverse roles of Wnt/β-catenin pathway at different stages of HCoV-OC43 infection, suggesting a potential target for the antiviral treatment. In addition, although infection with HCoV-OC43 induces cytopathic effects in BHK21 cells, inhibiting apoptosis does not affect the intracellular replication of the virus. Monitoring newly synthesized RNA based on such time-resolved approach is a highly promising method for studying the mechanism of viral infections., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests in the present work., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: The use of remdesivir in patients with coronavirus disease 2019 (COVID-19) and severe renal impairment has been approved; however, limited clinical data exist. Accordingly, we aimed to compare outcomes and adverse events associated with remdesivir in hospitalized patients with COVID-19, with and without severe renal impairment., Methods: Hospitalized patients with COVID-19 undergoing a 5-day remdesivir course at Taipei Veterans General Hospital from April 1 to July 31, 2022, were enrolled. Comparative analysis of outcomes and safety between patients with or without severe renal impairment (estimated glomerular filtration rate of < 30 mL/min per 1.73 m 2 ) were conducted. Prognostic factors associated with 28-day mortality in patients with severe renal impairment were investigated using logistic regression analysis., Results: A total of 671 hospitalized patients, including 132 patients with severe renal impairment, who received a 5-day course of remdesivir were analyzed. The 28-day mortality was higher in patients with severe renal impairment than in patients without severe renal impairment (15.2% vs. 7.8%). The proportion of patients with acute kidney injury (AKI) and deteriorated liver function after completing remdesivir therapy was similar between the patients with and without severe renal impairment, and the recovery rate of AKI was similar in both groups. The sequential organ failure assessment score was an independent factor associated with 28-day mortality in patients with severe renal impairment., Conclusions: Remdesivir was well-tolerated in hospitalized patients with COVID-19, regardless of renal function. Our findings support the recent recommendation to administer remdesivir in patients with severe renal impairment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: Remdesivir (RDV) causes liver enzyme elevation in adults; however, the frequency of this elevation in children and the associated risk factors are largely unknown. Therefore, we aimed to examine risk factors for liver enzyme elevation in hospitalised paediatric patients who received RDV., Methods: This was a retrospective case-control study of all patients aged <18 years who were diagnosed with coronavirus disease 2019 and received RDV at a tertiary care hospital between February 2022 and September 2023. Demographic and clinical data were retrieved from the medical records and analysed. Patients with liver enzyme elevation were defined as cases, while those with no liver enzyme elevation were defined as controls. The two groups were compared and analysed for possible risk factors for liver enzyme elevation with RDV use., Results: Sixty-six patients were treated with RDV, 12 (18.2%) of whom developed liver enzyme elevation. Liver enzyme elevation was associated with the median duration of RDV administration (7.5 days vs. 3 days, P = 0.012), median total RDV dose (17.7 mg/kg vs. 10.3 mg/kg, P = 0.017) and acetaminophen use (67% vs. 22%) (odds ratio = 4.34; 95% confidence interval, 1.05-19.97, P = 0.023). All patients showed improvement, except three who had no liver enzyme measurements after having the highest aspartate aminotransferase and alanine aminotransferase values during the observation period., Conclusion: Liver enzyme elevation was reversible after discontinuing RDV use. Overall, RDV can be considered safe in children with careful monitoring., (© 2024 The Author(s). Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Antiviral therapies for treatment of COVID-19 may be associated with significant proarrhythmic potential. In the present study, the potential cardiotoxic side effects of these therapies were evaluated using a Langendorff model of the isolated rabbit heart. 51 hearts of female rabbits were retrogradely perfused, employing a Langendorff-setup. Eight catheters were placed endo- and epicardially to perform an electrophysiology study, thus obtaining cycle length-dependent action potential duration at 90% of repolarization (APD 90 ), QT intervals and dispersion of repolarization. After generating baseline data, the hearts were assigned to four groups: In group 1 (HXC), hearts were treated with 1 µM hydroxychloroquine. Thereafter, 3 µM hydroxychloroquine were infused additionally. Group 2 (HXC + AZI) was perfused with 3 µM hydroxychloroquine followed by 150 µM azithromycin. In group 3 (LOP) the hearts were perfused with 3 µM lopinavir followed by 5 µM and 10 µM lopinavir. Group 4 (REM) was perfused with 1 µM remdesivir followed by 5 µM and 10 µM remdesivir. Hydroxychloroquine- and azithromycin-based therapies have a significant proarrhythmic potential mediated by action potential prolongation and an increase in dispersion. Lopinavir and remdesivir showed overall significantly less pronounced changes in electrophysiology. In accordance with the reported bradycardic events under remdesivir, it significantly reduced the rate of the ventricular escape rhythm., (© 2024. The Author(s).)

The aim of this study was to investigate the effects of administrating Remdesivir at the acute COVID-19 phase on developing post-COVID symptoms in previously hospitalized COVID-19 survivors by controlling factors such as age, sex, body mass index, and vaccination status. A case-control study was performed. Hospitalized COVID-19 survivors who had received intravenous Remdesivir during the acute phase (n = 216) were matched by age, sex, body mass index, and vaccination status with survivors who did not receive antiviral treatment (n = 216). Participants were asked to self-report the presence of any post-COVID symptom (defined as a symptom that started no later than three months after infection) and whether the symptom persisted at the time of study (mean: 18.4, SD: 0.8 months). Anxiety levels (HADS-A), depressive symptoms (HADS-D), sleep quality (PSQI), and severity/disability (FIC) were also compared. The multivariate analysis revealed that administration of Remdesivir at the acute COVID-19 phase was a protective factor for long-term COVID development (OR0.401, 95%CI 0.256-0.628) and specifically for the following post-COVID symptoms: fatigue (OR0.399, 95%CI 0.270-0.590), pain (OR0.368, 95% CI 0.248-0.548), dyspnea at rest (OR0.580, 95%CI 0.361-0.933), concentration loss (OR0.368, 95%CI 0.151-0.901), memory loss (OR0.399, 95%CI 0.270-0.590), hair loss (OR0.103, 95%CI 0.052-0.207), and skin rashes (OR0.037, 95%CI 0.005-0.278). This study supports the potential protective role of intravenous administration of Remdesivir during the COVID-19 acute phase for long-lasting post-COVID symptoms in previously hospitalized COVID-19 survivors.

Lung transplant (LTx) recipients face a significant risk from coronavirus disease 2019 (COVID-19), with elevated hospitalization mortality rates even post-vaccination. While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) typically induces pneumonia in even healthy individuals, it can also infect the transplanted lungs of LTx recipients, potentially leading to graft dysfunction. Despite the prevalence of COVID-19 pneumonia in LTx recipients, data on its characteristics and associated risk factors remain limited. This retrospective study analyzed data from LTx recipients at Tohoku University Hospital between January 2001 and November 2023. COVID-19 cases were identified, and patient records, including thoracic computed tomography (CT) evaluations, were reviewed. Patient characteristics, vaccination history, immunosuppressant use, and comorbidities were assessed. Descriptive analysis was utilized for data presentation. Among 172 LTx recipients, 39 (22.7%) contracted COVID-19, with 9 (23%) developing COVID-19 pneumonia. COVID-19 incidence in LTx recipients aligned with national rates, but pneumonia risk was elevated. Delayed antiviral therapy initiation was noted in pneumonia cases. Remdesivir was uniformly administered and remained the primary treatment choice. LTx recipients are susceptible to COVID-19 pneumonia, warranting vigilance and tailored management strategies. Pre-transplant vaccination and prompt COVID-19 diagnosis and treatment are imperative for optimizing outcomes in this population., (© 2024. The Author(s).)

Summary: COVID-19 continues to pose a significant threat: mortality stands at nearly twice that of influenza, and the incidence rate is growing as the population's vaccination rate decreases, particularly in Spain and other areas of Europe. Given this situation, it is vitally important know whether medical protocols are consistent and appropriately implemented by health care staff in the interest of preventing possible inefficiency or inequity. Physicians from hospital emergency departments met to study their hospitals' usual clinical practices for managing SARS-CoV-2 infection and to determine their expert opinions on the use of antiviral agents. The participating physicians then reached consensus on evidencebased recommendations for strategies that would optimize emergency treatment.

Remdesivir (RDV) is the mainstay antiviral therapy for moderate to severe COVID-19. Although remdesivir was the first drug approved for COVID-19, information about its efficacy and safety profile is limited in a significant segment of the population, such as people with underlying diseases, the elderly, children, and pregnant and lactating women. The efficacy and safety profile of RDV in disease progression, renal impairment, liver impairment, immunosuppression, geriatrics, pediatrics, pregnancy, and breastfeeding in COVID-19 patients was evaluated. The databases searched included Embase, Scopus, and PubMed. Only English language studies enrolling specific subpopulations with COVID-19 and treated with RDV were included. Thirty-nine clinical trials, cohorts, cross-sectional studies, and case series/reports were included. Most supported the benefits of RDV therapy for COVID-19 patients, such as lessening the duration of hospitalization, alleviating respiratory complications, and reducing mortality. Adverse effects of RDV, including liver and kidney impairment, were, for the most part, moderate to mild, supporting the safety profile of RDV therapy. RDV therapy was well tolerated, no new safety signals were detected, and liver function test abnormalities were the most common adverse events. Moreover, RDV, for the most part, was effective in managing the complications of COVID-19 and reducing mortality in these patients, except for patients with kidney impairment. Future studies, including RCTs, should include these subpopulations of patients to avoid delays associated with receiving proper medication through compassionate use programs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

(1) Background: Geriatric patients are at high risk of complications of Coronavirus disease-2019 (COVID-19) and are good candidates for antiviral drugs. (2) Methods: A retrospective study of electronic health records (EHRs) aiming to describe antiviral (nirmatrelvir and ritonavir (nirmatrelvir/r) or remdesivir) use, drug-drug interactions (DDIs) and adverse drug reactions (ADRs) in elderly patients (75 and over), hospitalized with mild-to-moderate COVID-19 between July 2022 and June 2023. (3) Results: Out of 491 patients (mean age: 86.9 years), 180 (36.7%) received nirmatrelvir/r, 78 (15.9%) received remdesivir, and 233 (47.4%) received no antiviral therapy. No association was found between the choice of antiviral and the demographic or medical data. No serious ADR was observed. Nirmatrelvir/r dosage adjustment was inadequate in 65% of patients with renal impairment. In total, 128 patients (71%) on nirmatrelvir/r had potential pharmacokinetic DDIs, with 43 resulting in a possibly related ADR. In the remdesivir group, pharmacodynamic DDIs were more frequent, with QTc prolongation risk in 56 patients (72%). Only 20 patients underwent follow-up ECG, revealing QTc prolongation in 4. (4) Conclusions: There is an underutilization of antivirals despite their justified indications. Nirmatrelvir/r dosage was rarely adjusted to renal function. Dose adjustments and closer monitoring are needed due to the high risk of drug interactions.

The coronavirus-2 has led to a global pandemic of COVID-19 with an outbreak of severe acute respiratory syndrome leading to worldwide quarantine measures and a rise in death rates. The objective of this study is to propose a green, sensitive, and selective densitometric method to simultaneously quantify remdesivir (REM) in the presence of the co-administered drug linezolid (LNZ) and rivaroxaban (RIV) in spiked human plasma. TLC silica gel aluminum plates 60 F254 were used as the stationary phase, and the mobile phase was composed of dichloromethane (DCM): acetone (8.5:1.5, v/v) with densitometric detection at 254 nm. Well-resolved peaks have been observed with retardation factors (R f ) of 0.23, 0.53, and 0.72 for REM, LNZ, and RIV, respectively. A validation study was conducted according to ICH Q2 (R1) Guidelines. The method was rectilinear over the concentration ranges of 0.2-5.5 μg/band, 0.2-4.5 μg/band and 0.1-3.0 μg/band for REM, LNZ and RIV, respectively. The sensitivities of REM, LIN, and RIV were outstanding, with quantitation limits of 128.8, 50.5, and 55.8 ng/band, respectively. The approach has shown outstanding recoveries ranging from 98.3 to 101.2% when applied to pharmaceutical formulations and spiked human plasma. The method's greenness was assessed using Analytical Eco-scale, GAPI, and AGREE metrics., (© 2024. The Author(s).)

Since 2019 the SARS-CoV-2 and its variants caused COVID-19, such incidents brought the world in pandemic situation. This happened due to furious mutations in SARS-CoV-2, in which some variants had high transmissibility and infective, this led the virus emerged as virulent and worsened the COVID-19 situation. Among the variants, P323L is one of the important mutants of RdRp in SARS-CoV-2. To inhibit the erroneous function of this mutated RdRp, we have screened 943 molecules against the P323L mutated RdRp with the criteria that the molecules with 90% similar to the structure of remdesivir (control drug) resulted nine molecules. Further, these molecules were evaluated by induced fit docking (IFD) identified two molecules (M2 & M4) which are forming strong intermolecular interactions with the key residues of mutated RdRp and has high binding affinity. Docking score of the M2 and M4 molecules with mutated RdRp are -9.24 and -11.87 kcal/mol, respectively. Further, to understand the intermolecular interactions, conformational stability, the molecular dynamics simulation and binding free energy calculations were performed. The binding free energy values of M2 and M4 molecules with the P323L mutated RdRp complexes are -81.60 and -83.07 kcal/mol, respectively. The results of this in silico study confirm that M4 is a potential molecule; hence, it may be considered as the potential inhibitor of P323L mutated RdRp to treat COVID-19 after clinical investigation.Communicated by Ramaswamy H. Sarma.

Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC 50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients.

Severe acute respiratory syndrome 2 (SARS-CoV-2) caused the emergence of the COVID-19 pandemic all over the world. Several studies have suggested that antiviral drugs such as favipiravir (FAV), remdesivir (RDV), and lopinavir (LPV) may potentially prevent the spread of the virus in the host cells and person-to-person transmission. Simultaneously with the widespread use of these drugs, their stability and action mechanism studies have also attracted the attention of many researchers. This review focuses on the action mechanism, metabolites and degradation products of these antiviral drugs (FAV, RDV and LPV) and demonstrates various methods for their quantification and discrimination in the different biological samples. Herein, the instrumental methods for analysis of the main form of drugs or their metabolite and degradation products are classified into two types: optical and chromatography methods which the last one in combination with various detectors provides a powerful method for routine and stability analyses. Some representative studies are reported in this review and the details of them are carefully explained. It is hoped that this review will be a good guideline study and provide a better understanding of these drugs from the aspects investigated in this study.

The global pandemic known as coronavirus disease (COVID-19) is causing morbidity and mortality on a daily basis. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV- -2) virus has been around since December 2019 and has infected a high number of patients due to its idiopathic pathophysiology and rapid transmission. COVID-19 is now deemed a newly identified "syndrome" condition since it causes a variety of unpleasant symptoms and systemic side effects following the pandemic. Simultaneously, it always becomes potentially hazardous when new variants develop during evolution. Its random viral etiology prevents accurate and suitable therapy. Despite the fact that multiple preclinical and research studies have been conducted to combat this lethal virus, and various therapeutic targets have been identified, the precise course of therapy remains uncertain. However, just a few drugs have shown efficacy in treating this viral infection in its early stages. Currently, several medicines and vaccinations have been licensed following clinical trial research, and many countries are competing to find the most potent and effective immunizations against this highly transmissible illness. For this narrative review, we used PubMed, Google Scholar, and Scopus to obtain epidemiological data, pre-clinical and clinical trial outcomes, and recent therapeutic alternatives for treating COVID-19 viral infection. In this study, we discussed the disease's origin, etiology, transmission, current advances in clinical diagnostic technologies, different new therapeutic targets, pathophysiology, and future therapy options for this devastating virus. Finally, this review delves further into the hype surrounding the SARS-CoV-2 illness, as well as present and potential COVID-19 therapies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Coronavirus disease 2019 (COVID-19) is considered an infectious disease which is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neonatal COVID-19 had been occurred in many countries which would indicate the need of effective and safe treatment for these vulnerable group. In this study, we showed symptoms of corona virus in neonates, investigation of coronavirus in neonates and radiological features of neonatal COVID-19. In addition, we discussed management of neonates with COVI-19, antiviral treatment, monoclonal antibodies administration, immunomodulatory therapy, antibiotics, vitamins, and minerals in the treatment of neonatal COVID-19, and also telemedicine in neonatal COVID-19 and feeding the newborn of COVID-19 mother. We also discussed multisystem inflammatory syndrome in neonates (MIS-N), management of affected COVID-19 neonates and discussion of the complication of the neonatal COVID-19. We further discussed the methods of dealing with COVID-19 neonates and the research done on the neonatal COVID-19 treatment.

Remdesivir, a competitive inhibitor of viral RNA-dependent RNA polymerase, is the drug of choice for anti-COVID-19 treatment. However, the instability of these substances in plasma raises doubts about their therapeutic potency. Additionally, SARS-CoV-2-infected cells may exhibit a variety of antiviral behaviors due to intricate activation pathways. Therefore, this study aimed to develop a synthesis for the remdesivir derivative. The remdesivir derivative was synthesized using acetyl chloride as a reagent in a ratio of 1:3 in dichloromethane and tetrahydrofuran solvent at 30°C for 6 h. Thin-layer chromatography and spectrophotometers (1H NMR and 13C NMR) were used to identify the produced molecule, which was a brownish-yellow crystalline powder.  The results of the synthesis yielded 0.8 gr (77.34%), and the Rf value of the remdesivir derivate was 0.54. The characterization with 1H NMR at δ2.5 ppm (3H, s) indicated the presence of a proton in the H-C-C=O structure caused by the substitution of the acetyl group in the remdesivir structure. The 13C NMR data indicated the presence of aromatic carbons, alkenes, C≡N, and carbon bonds with electronegative O. This remdesivir derivate chemical can be a potential candidate for an anti-COVID-19 drug that has more potency because it has substitutions of acetyl groups at positions 2' and 3' in the structure of remdesivir., Competing Interests: The authors declare that they have no conflict of interest.

Broad spectrum oral antivirals are urgently needed for the early treatment of many RNA viruses of clinical concern. We previously described the synthesis of 1-O-octadecyl-2-O-benzyl-glycero-3-phospho-RVn (V2043), an orally bioavailable lipid prodrug of remdesivir nucleoside (RVn, GS-441524) with broad spectrum antiviral activity against viruses with pandemic potential. Here we compared the relative activity of V2043 with new RVn lipid prodrugs containing sn-1 alkyl ether or sn-2 glycerol modifications. We found that 3-F-4-MeO-Bn, 3-CN-Bn, and 4-CN-Bn sn-2 glycerol modifications improved antiviral activity compared to V2043 when tested in vitro against clinically important RNA viruses from 5 virus families. These results support the continued development of V2043 and sn-2 glycerol modified RVn lipid prodrugs for the treatment of a broad range of RNA viruses for which there are limited therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purposes: Patients with hematologic malignancies (HM) are among the individuals with highest risk of COVID-19 complications. We report the impact of remdesivir in patients with hematologic malignancies (HM) during Omicron in Mexico City., Methods: All patients with HM and COVID-19 during December 2021-March 2022 were included. Socio-demographic and clinical data were collected. The primary outcome was COVID-19 progression. Variables associated with progression were analyzed., Results: 115 patients were included. Median age was 50 years (IQR 35-63); 36% (N = 41) had at least one comorbidity. Fifty-two percent had non-Hodgkin lymphoma. Fifty patients (44%) had at least two doses of SARS-CoV-2 vaccine. COVID-19 was classified as mild (52.6%), moderate (9.7%), and severe/critical (28%). Twenty-eight patients (24%) received remdesivir. Nine patients received remdesivir at the ambulatory clinic (33%), the rest during hospital admission. Overall, 22(19%) patients progressed to severe/critical COVID-19; nine died due to COVID-19(8%). Hospital admission for non-COVID-19 causes was associated with higher odds of progression. Remdesivir did not reduce the risk of progression in hospitalized patients; none of the patients who received remdesivir in the ambulatory clinic progressed to severe COVID-19 or died., Conclusions: Patients with HM and COVID-19 continue to present with high risk of complications. More prospective studies are needed to define the impact of antivirals in this high-risk group, including the best duration of treatment. Also, better vaccine coverage and access to treatment are mandatory., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Severely immunocompromised patients are at risk for prolonged or relapsed Coronavirus Disease 2019 (COVID-19), leading to increased morbidity and mortality. We aimed to evaluate efficacy and safety of combination treatment in immunocompromised COVID-19 patients., Methods: We included all immunocompromised patients with prolonged/relapsed COVID-19 treated with combination therapy with 2 antivirals (remdesivir plus nirmatrelvir/ritonavir, or molnupiravir in case of renal failure) plus, if available, anti-spike monoclonal antibodies (mAbs), between February and October 2022. The main outcomes were virological response at day 14 (negative Severe Acute Respiratory Syndrome Coronavirus 2 [SARS-CoV-2] swab) and virological and clinical response (alive, asymptomatic, with negative SARS-CoV-2 swab) at day 30 and the last follow-up., Results: Overall, 22 patients (Omicron variant in 17/18) were included: 18 received full combination of 2 antivirals and mAbs and 4 received 2 antivirals only; in 20 of 22 (91%) patients, 2 antivirals were nirmatrelvir/ritonavir plus remdesivir. Nineteen (86%) patients had hematological malignancy, and 15 (68%) had received anti-CD20 therapy. All were symptomatic; 8 (36%) required oxygen. Four patients received a second course of combination treatment. The response rate at day 14, day 30, and last follow-up was 75% (15/20 evaluable), 73% (16/22), and 82% (18/22), respectively. Day 14 and 30 response rates were significantly higher when combination therapy included mAbs. Higher number of vaccine doses was associated with better final outcome. Two patients (9%) developed severe side effects (bradycardia leading to remdesivir discontinuation and myocardial infarction)., Conclusions: Combination therapy including 2 antivirals (mainly remdesivir and nirmatrelvir/ritonavir) and mAbs was associated with high rate of virological and clinical response in immunocompromised patients with prolonged/relapsed COVID-19., Competing Interests: Potential conflicts of interest. E. A. reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Vertex Pharmaceuticals and Celgene (Bristol-Myers Squibb), Vifor Pharma, Novartis, Blue Bird Bio, Menarini Stemline, Glaxo, Regeneron, Gilead, and Novartis. M. B. reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Bayer, bioMérieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, and Shionogi. D. R. G. reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Gilead, Shionogi, Pfizer, and Tillotts Pharma. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To compare clinical characteristics and examine in-hospital length of stay (LOS) differences for COVID-19 patients who received remdesivir, by race or ethnicity., Design: Retrospective descriptive analysis comparing cumulative LOS as a proxy of recovery time., Setting: A large academic medical center serving a minoritized community in Northern Manhattan, New York City., Participants: Inpatients (N=1024) who received remdesivir from March 30, 2020-April 20, 2021., Methods: We conducted descriptive analyses among patients who received remdesivir. Patients were described by proxies of social determinants of health (SDOH): race and ethnicity, residence, insurance coverage, and clinical characteristics. We calculated median hospital LOS as the cumulative incidence of hospitalized patients who were discharged alive, and tested differences between groups by using the Gray test. Patients who died or were discharged to hospice were censored at 29 days., Main Outcome Measures: The primary outcome was hospital LOS. The secondary outcome was in-hospital mortality., Results: Median LOS was 11.9 days (95% CI, 10.8-13.2) overall, with Black patients having the shortest (10.0 days, 95% CI, 8.0-13.2) and Asian patients having the longest (16.2 days, 95% CI, 8.3-27.2) LOS. A total of 214 patients (21%) died or were discharged to hospice, ranging from 16.5% to 23.7% of patients who identified as Black and Other (multiracial, biracial, declined), respectively., Conclusions: COVID-19 has disproportionately burdened communities of color. We observed no difference in median LOS between racial or ethnic groups, which supports the notion that the heterogeneous effect of remdesivir in the literature may be explained in part by underrecruitment or participation of Black, Hispanic, and Asian patients in clinical trials., Competing Interests: Conflict of Interest No conflicts of interest reported by authors.

Background: Early antiviral therapy was effective in the treatment of coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of combined interferon beta-1b and remdesivir treatment in hospitalized COVID-19 patients., Methods: We conducted a multicentre, prospective open-label, randomized-controlled trial involving high-risk adults hospitalized for COVID-19. Patients were randomly assigned to a 5-day interferon beta-1b 16 million units daily and remdesivir 200 mg loading on day 1 followed by 100 mg daily on day 2 to 5 (combination group), or to remdesivir only of similar regimen (control group) (1:1). The primary endpoint was the time to complete alleviation of symptoms (NEWS2 = 0)., Results: Two-hundred and twelve patients were enrolled. The median days of starting treatment from symptom onset was 3 days. The median age was 65 years, and 159 patients (75%) had chronic disease. The baseline demographics were similar. There was no mortality. For the primary endpoint, the combination group was significantly quicker to NEWS2 = 0 (4 vs 6.5 days; hazard ratio [HR], 6.59; 95% confidence interval [CI], 6.1-7.09; P < .0001) when compared to the control group. For the secondary endpoints, the combination group was quicker to negative nasopharyngeal swab (NPS) viral load (VL) (6 vs 8 days; HR, 8.16; 95% CI, 7.79-8.52; P < .0001) and to develop seropositive immunoglobulin G (IgG) (8 vs 10 days; HR, 10.78; 95% CI, 9.98-11.58; P < .0001). All adverse events resolved upon follow-up. Combination group (HR, 4.1 95% CI, 1.9-8.6, P < .0001) was the most significant independent factor associated with NEWS2 = 0 on day 4., Conclusions: Early treatment with interferon beta-1b and remdesivir was safe and better than remdesivir only in alleviating symptoms, and in shortening viral shedding and hospitalization with earlier seropositivity in high-risk COVID-19 patients., Clinical Trials Registration: NCT04647695., Competing Interests: Potential conflicts of interest. I. F. H received honoraria as speaker from MSD for COVID-19 Regional Expert Input Forum 2021 and Herpes Zoster lecture 2021 and was a member of the Advisory Board for Pfizer on COVID-19 Management 2022 and Gilead on Evolving Treatment Landscape in COVID-19 2021. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

SARS-CoV-2 is the causative agent of the immune response-driven disease COVID-19 for which new antiviral and anti-inflammatory treatments are urgently needed to reduce recovery time, risk of death and long COVID development. Here, we demonstrate that the immunoregulatory kinase p38 MAPK is activated during viral entry, mediated by the viral spike protein, and drives the harmful virus-induced inflammatory responses. Using primary human lung explants and lung epithelial organoids, we demonstrate that targeting p38 signal transduction with the selective and clinically pre-evaluated inhibitors PH-797804 and VX-702 markedly reduced the expression of the pro-inflammatory cytokines IL6, CXCL8, CXCL10 and TNF-α during infection, while viral replication and the interferon-mediated antiviral response of the lung epithelial barrier were largely maintained. Furthermore, our results reveal a high level of drug synergism of both p38 inhibitors in co-treatments with the nucleoside analogs Remdesivir and Molnupiravir to suppress viral replication of the SARS-CoV-2 variants of concern, revealing an exciting and novel mode of synergistic action of p38 inhibition. These results open new avenues for the improvement of the current treatment strategies for COVID-19., Competing Interests: Declaration of competing interest LB, SL, SS, AF and UR submitted a patent application for the use of p38 inhibitors with nucleoside analogs for the treatment of COVID-19 (EU patent nr. 21183887.5). SL is a cofounder and member of the advisory board of Atriva Therapeutics GmbH, Tuebingen, Germany., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Liver involvement in COVID-19 is multifactorial, and the three potential mechanisms are direct hepatocyte viral damage, vascular or cellular damage during the cytokine storm of severe COVID-19 and drug-induced liver injury. To date, three antivirals are licensed for the treatment of COVID-19 by most guidelines: remdesivir, molnupiravir, and ritonavir-boosted nirmatrelvir., Areas Covered: We performed a narrative review about the hepatic safety profile of the three antivirals licensed for COVID-19 treatment. We used data about hepatobiliary adverse events from English-language randomized clinical trials (RCTs)., Expert Opinion: Remdesivir was found to be potentially hepatotoxic, and liver biochemistry abnormalities were common (2-34%) but mild and reversible. Molnupiravir exhibits a favorable safety profile and the increase in aminotransferases was usually mild and reversible (up to 11% of patients in one study). Ritonavir-boosted nirmatrelvir is potentially hepatotoxic, but in the only phase 3 RCT there were no safety issues and aspartate aminotransferase/alanine aminotransferase levels increase did not exceed 2.4% of patients. All antivirals have a favorable safety profile, but they are not sufficiently studied in patients with underlying chronic kidney or liver disease. In this special populations, antivirals should be used with caution and careful monitoring during treatment should be pursued on a case-by-case basis.

Background: Pregnant women less frequently receive COVID-19 vaccination and are at increased risk for adverse pregnancy outcomes from COVID-19., Objective: This study aimed to first, describe the vaccination status, treatment, and outcomes of hospitalized, symptomatic pregnant women with COVID-19, and second, estimate whether treatment differs by pregnancy status among treatment-eligible (ie, requiring supplemental oxygen per National Institutes of Health guidelines at the time of the study) women., Study Design: From January to November 2021, the COVID-19-Associated Hospitalization Surveillance Network completed medical chart abstraction for a probability sample of 2715 hospitalized women aged 15 to 49 years with laboratory-confirmed SARS-CoV-2 infection. Of these, 1950 women had symptoms of COVID-19 on admission, and 336 were pregnant. We calculated weighted prevalence estimates of demographic and clinical characteristics, vaccination status, and outcomes among pregnant women with symptoms of COVID-19 on admission. We used propensity score matching to estimate prevalence ratios and 95% confidence intervals of treatment-eligible patients who received remdesivir or systemic steroids by pregnancy status., Results: Among 336 hospitalized pregnant women with symptomatic COVID-19, 39.6% were non-Hispanic Black, 24.8% were Hispanic or Latino, and 61.9% were aged 25 to 34 years. Among those with known COVID-19 vaccination status, 92.9% were unvaccinated. One-third (32.7%) were treatment-eligible. Among treatment-eligible pregnant women, 74.1% received systemic steroids and 61.4% received remdesivir. Among those that were no longer pregnant at discharge (n=180), 5.4% had spontaneous abortions and 3.5% had stillbirths. Of the 159 live births, 29.0% were preterm. Among a propensity score-matched cohort of treatment-eligible hospitalized women of reproductive age, pregnant women were less likely than nonpregnant women to receive remdesivir (prevalence ratio, 0.82; 95% confidence interval, 0.69-0.97) and systemic steroids (prevalence ratio, 0.80; 95% confidence interval, 0.73-0.87)., Conclusion: Most hospitalized pregnant patients with symptomatic COVID-19 were unvaccinated. Hospitalized pregnant patients were less likely to receive recommended remdesivir and systemic steroids compared with similar hospitalized nonpregnant women. Our results underscore the need to identify opportunities for improving COVID-19 vaccination, implementation of treatment of pregnant women, and the inclusion of pregnant women in clinical trials., (Published by Elsevier Inc.)

Remdesivir (REM) is an antiviral drug, which exercises its effect by targeting specifically RNA-dependent RNA polymerase. The interaction of REM with calf thymus DNA (CT-DNA) was investigated by multi-spectroscopic techniques (UV-Vis, fluorescence, circular dichroism and 31 P NMR) in combination with different biophysical experiments and metadynamics simulation studies. UV-Vis and fluorescence spectroscopic analysis indicated formation of a complex between REM and CT-DNA, whose binding constant is in the order of 10 4 M -1 . Competitive displacement assays with ethidium bromide (EB) and Hoechst 33258 shown that REM binds to CT-DNA via intercalation mode. Significant alteration in the band due to base stacking pairs at 274 nm in the circular dichroism spectrum, appreciable increase in relative viscosity of the biomolecule upon binding with REM and the results of potassium iodide quenching studies confirmed that REM intercalates into the base pairs of CT-DNA. Thermodynamic parameters revealed that the binding of REM to CT-DNA is a spontaneous process (ΔG 0  < 0) and the main force which holds them together in the REM/CT-DNA complex is electrostatic interaction (ΔH 0  < 0 and ΔS 0  > 0). The up-field shift in the 31 P NMR signal of REM on interaction with CT-DNA suggested that phenyl ring adjacent to the phosphate moiety of REM may involve in the intercalation process. This is well supported by the analysis of free energy surface landscape derived from metadynamics simulation studies., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: To perform network meta-analysis for a head-to-head comparison of various interventions used in coronavirus disease 2019 (COVID-19) on mortality, clinical recovery, time to clinical improvement and the occurrence of serious adverse events., Methods: Systematic search was performed using online databases with suitable MeSH terms including coronavirus, COVID-19, randomized controlled trial, hydroxychloroquine, lopinavir/ritonavir, tocilizumab, remdesivir, favipiravir, dexamethasone and interferon-β. Data were independently extracted by 2 study investigators and analysed., Results: Out of 1225 studies screened, 23 were included for qualitative and quantitative analysis. Among the drugs studied, dexamethasone reduces mortality by 10%, with a relative risk of 0.90 (95% confidence interval [0.82-0.97]) and increases clinical recovery by 6% (relative risk 1.06, 95% confidence interval [1.02-1.10]) compared to standard of care. Similarly, remdesivir administered for 10 days increased clinical recovery by 10%, reduced time to clinical improvement by 4 days and lowered the occurrence of serious adverse events by 27% as compared to standard of care., Conclusion: In comparison to standard of care, dexamethasone was found to increase clinical recovery and lower mortality; remdesivir was significantly associated with a lower risk of mortality as compared to tocilizumab and higher clinical recovery and shorter time to clinical improvement as compared to hydroxychloroquine and tocilizumab; remdesivir followed by tocilizumab were found to have lesser occurrence of serious adverse events in patients with moderate to severe COVID-19., (© 2022 British Pharmacological Society.)

RNA-dependent RNA polymerase (RdRp), also called nsp12, is considered a promising but challenging drug target for inhibiting replication and hence, the growth of various RNA-viruses. In this report, a computational study is performed to offer insights on the binding of Remdesivir and Galidesivir with SARS-CoV2 RdRp with natural substrate, ATP, as the control. It was observed that Remdesivir and Galidesivir exhibited similar binding energies for their best docked poses, -6.6 kcal/mole and -6.2 kcal/mole, respectively. ATP also displayed comparative and strong binding free energy of -6.3 kcal/mole in the catalytic site of RdRp. However, their binding locations within the active site are distinct. Further, the interaction of catalytic site residues (Asp760, Asp761, and Asp618) with Remdesivir and Galidesivir is comprehensively examined. Conformational changes of RdRp and bound molecules are demonstrated using 100 ns explicit solvent simulation of the protein-ligand complex. Simulation suggests that Galidesivir binds at the non-catalytic location and its binding strength is relatively weaker than ATP and Remdesivir. Remdesivir also binds at the catalytic site and showed high potency to inhibit the function of RdRp. Binding of co-factor units nsp7 and nsp8 with RdRp (nsp12) complexed with Remdesivir and Galidesivir was also examined. MMPBSA binding energy for all three complexes has been computed across the 100 ns simulation trajectory. Overall, this study suggests, Remdesivir has anti-RdRp activity via binding at a catalytic site. In contrast, Galidesivir may not have direct anti-RdRp activity but it can induce a conformational change in the RNA polymerase.

Remdesivir and molnupiravir have gained considerable interest because of their demonstrated activity against SARS-CoV-2. These antivirals are converted intracellularly to their active triphosphate forms remdesivir-TP and molnupiravir-TP. Cellular hydrolysis of these active metabolites would consequently decrease the efficiency of these drugs; however, whether endogenous enzymes that can catalyze this hydrolysis exist is unknown. Here, we tested remdesivir-TP as a substrate against a panel of human hydrolases and found that only Nudix hydrolase (NUDT) 18 catalyzed the hydrolysis of remdesivir-TP with notable activity. The k cat /K m value of NUDT18 for remdesivir-TP was determined to be 17,700 s -1 M -1 , suggesting that NUDT18-catalyzed hydrolysis of remdesivir-TP may occur in cells. Moreover, we demonstrate that the triphosphates of the antivirals ribavirin and molnupiravir are also hydrolyzed by NUDT18, albeit with lower efficiency than Remdesivir-TP. Low activity was also observed with the triphosphate forms of sofosbuvir and aciclovir. This is the first report showing that NUDT18 hydrolyzes triphosphates of nucleoside analogs of exogenous origin, suggesting that NUDT18 can act as a cellular sanitizer of modified nucleotides and may influence the antiviral efficacy of remdesivir, molnupiravir, and ribavirin. As NUDT18 is expressed in respiratory epithelial cells, it may limit the antiviral efficacy of remdesivir and molnupiravir against SARS-CoV-2 replication by decreasing the intracellular concentration of their active metabolites at their intended site of action., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Remdesivir is a prodrug of a nucleoside analog and the first antiviral therapeutic approved for coronavirus disease. Recent cardiac safety concerns and reports on remdesivir-related acute kidney injury call for a better characterization of remdesivir toxicity and understanding of the underlying mechanisms. Here, we performed an in vitro toxicity assessment of remdesivir around clinically relevant concentrations (C max 9 µM) using H9c2 rat cardiomyoblasts, neonatal mouse cardiomyocytes (NMCM), rat NRK-52E and human RPTEC/TERT1 cells as cell models for the assessment of cardiotoxicity or nephrotoxicity, respectively. Due to the known potential of nucleoside analogs for the induction of mitochondrial toxicity, we assessed mitochondrial function in response to remdesivir treatment, early proteomic changes in NMCM and RPTEC/TERT1 cells and the contractile function of NMCM. Short-term treatments (24 h) of H9c2 and NRK-52E cells with remdesivir adversely affected cell viability by inhibition of proliferation as determined by significantly decreased 3 H-thymidine uptake. Mitochondrial toxicity of remdesivir (1.6-3.1 µM) in cardiac cells was evident by a significant decrease in oxygen consumption, a collapse of mitochondrial membrane potential and an increase in lactate secretion after a 24-48-h treatment. This was supported by early proteomic changes of respiratory chain proteins and intermediate filaments that are typically involved in mitochondrial reorganization. Functionally, an impedance-based analysis showed that remdesivir (6.25 µM) affected the beat rate and contractility of NMCM. In conclusion, we identified adverse effects of remdesivir in cardiac and kidney cells at clinically relevant concentrations, suggesting a careful evaluation of therapeutic use in patients at risk for cardiovascular or kidney disease., (© 2022. The Author(s).)

We extend our established agent-based multiscale computational model of infection of lung tissue by SARS-CoV-2 to include pharmacokinetic and pharmacodynamic models of remdesivir. We model remdesivir treatment for COVID-19; however, our methods are general to other viral infections and antiviral therapies. We investigate the effects of drug potency, drug dosing frequency, treatment initiation delay, antiviral half-life, and variability in cellular uptake and metabolism of remdesivir and its active metabolite on treatment outcomes in a simulated patch of infected epithelial tissue. Non-spatial deterministic population models which treat all cells of a given class as identical can clarify how treatment dosage and timing influence treatment efficacy. However, they do not reveal how cell-to-cell variability affects treatment outcomes. Our simulations suggest that for a given treatment regime, including cell-to-cell variation in drug uptake, permeability and metabolism increase the likelihood of uncontrolled infection as the cells with the lowest internal levels of antiviral act as super-spreaders within the tissue. The model predicts substantial variability in infection outcomes between similar tissue patches for different treatment options. In models with cellular metabolic variability, antiviral doses have to be increased significantly (>50% depending on simulation parameters) to achieve the same treatment results as with the homogeneous cellular metabolism.

Since early 2020, scientists have strived to find an effective solution to fight SARS-CoV-2, in particular by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stages of the infection. However, the current synthetic routes rely on the use of protecting groups, air-sensitive reagents, and cryogenic conditions, thus impeding a cost-efficient supply to patients. We have, therefore, focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium-catalyzed and completely stereoselective C-glycosylation that initially yields the open-chain polyols, which can be selectively cyclized to provide either the kinetic α-furanose or the thermodynamically favored β-anomer. The method significantly expedites the synthesis of Remdesivir precursor GS-441524 after a subsequent Mn-catalyzed C-H oxidation and deoxycyanation., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)