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Thymus is the important immune organ, responsible for T cell development and differentiation. The lower circulating T counts have been observed in patients who died from COVID-19 compared with survivors. Azvudine, also known as FNC, is a thymus-homing anti-SARS-CoV-2 drug in treating COVID-19 patients. In this study, single-cell transcriptome, proteomics, and parallel reaction monitoring (PRM) were applied to insight into the activation process of FNC in rat and SARS-CoV-2 rhesus monkey thymus. The results indicated that thymic immune cells possess a robust metabolic capacity for cytidine-analogue drugs such as FNC. Key enzymes involved in the FNC phosphorylation process, such as Dck, Cmpk1, and Nme2, were highly expressed in CD4+ T cells, CD8+ T cells, and DP (CD4+ CD8+) cells. Additionally, FNC could upregulate multiple phosphorylated kinases in various cell types while downregulating the phosphatases, phosphoribosyl transferases, and deaminases, respectively. The robust phosphorylation capacity of the thymus for cytidine analogue drug FNC, and the activation effect of FNC on the NAs metabolism system potentially contribute to its enrichment in the thymus and immune protection effect. This suggests that it is crucial to consider the expression level of phosphorylation kinases when evaluating NA drug properties, as an important factor during antiviral drug design. The activation effect of FNC on the nucleoside metabolism system potentially contribute to its enrichment in the thymus and immune protection effect. [Display omitted] [ABSTRACT FROM AUTHOR]

In our retrospective cohort study, we aim to explore whether Azvudine modifies the risk of death in COVID-19 patients. It was conducted on the medical records of patients, consecutively admitted for COVID-19 pneumonia to two hospitals in Chongqing, China. Based on Azvudine treatment exposure, the patients were divided into Azvudine group and non-Azvudine group. We used 1:2 ratio propensity score matching (PSM) in our study to adjust for confounding factors and differences between Azvudine and non-Azvudine groups. There were 1072 patients included in our original cohort. With 1:2 ratio PSM, the Azvudine group included 195 patients and non-Azvudine group included 390 patients. The results showed that Azvudine treatment was associated with improved in-hospital mortality in overall population (OR 0.375, 95% CI 0.225–0.623, P < 0.001), severe subgroup (OR 0.239, 95% CI 0.107–0.535, P = 0.001), critical subgroup (OR 0.091, 95% CI 0.011–0.769, P = 0.028) in matched cohort with univariate analysis. And there was a significantly lower in-hospital mortality in overall population (11% vs. 24%, P ＜0.001), severe sub-group (10% vs. 32%, P < 0.001) and critical sub-group (5% vs. 34%, P = 0.017) in matched cohort. These results suggest Azvudine can reduce in-hospital mortality in overall COVID-19 patients, severe, and critical subgroup population. Whether Azvudine can reduce the in-hospital mortality of COVID-19 patients is an interesting question. In this manuscript, Azvudine's positive effect has been proved. [Display omitted] [ABSTRACT FROM AUTHOR]

Azvudine has been designated as a priority treatment for patients infected with SARS-CoV-2, however, clinical evidence in hospitalized cases remains insufficient. We performed a multi-center, retrospective cohort study to evaluate the effectiveness and safety of azvudine in hospitalized patients with SARS-CoV-2 in China (NCT06349655). Kaplan-Meier method, Cox regression model, subgroup analysis, and seven sensitive analyses were employed. A total of 32864 hospitalized patients with SARS-CoV-2 were enrolled, in which 5735 azvudine recipients and 5735 controls were selected using 1:1 propensity score matching. Based on Kaplan-Meier analysis, azvudine significantly reduced rates of all-cause death (P < 0.0001) and composite disease progression (P = 0.00019). Cox regression analysis demonstrated that hazard ratios of all-cause death and composite disease progression were 0.68 (95%CI: 0.598–0.775, P < 0.001) and 0.88 (95% CI: 0.795–0.976, P = 0.016), respectively. Subgroup analysis showed preference of azvudine for patients receiving antibiotics in reducing all-cause death and composite disease progression. Seven sensitivity analyses verified the robustness of our results. Safety analysis on adverse events showed no significant difference between both groups. This study suggested that azvudine may reduce all-cause death and composite disease progression in hospitalized patients with SARS-CoV-2 infection without serious adverse events. However, the findings are susceptible to some potential biases, and further studies still need to identify the efficacy of azvudine. • Azvudine recipients may potentially experience a reduced mortality and composite disease progression. • Azvudine exhibited acceptable safety in patients with SARS-CoV-2 infection. • Azvudine may be a promising antiviral agent for treating COVID-19. [ABSTRACT FROM AUTHOR]

COVID-19 pneumonia has spread across China and globally since late 2019, becoming a pandemic. Its extremely contagious nature as well as high morbidity and mortality rates have attracted widespread attention globally. For the treatment of SARS-CoV-2 pneumonia, two commonly used antiviral drugs in the clinic are nirmatrelvir/ritonavir(Paxlovid) and Azvudine, while the therapeutic efficacy of the two drugs and their impact on patient prognosis remain inconclusive. Therefore, the aim of this study is to investigate the effects of two antiviral drugs, Azvudine and Paxlovid, on the disease development and prognosis of patients with COVID-19. This study collected and analyzed in Inner Mongolia hospital treated 267 cases of COVID - 19 patients. According to the use of antiviral medications, the participants in this experiment were split into the Azvudine and Paxlovid groups. The effectiveness of the medications was evaluated using the length of hospitalization, Nucleic acid into negative time for the first time, and laboratory indices such as total protein, lymphocytes, leukocytes, albumin, creatinine, and platelets. Compared with the Azvudine group, patients in the Paxlovid group had a shorter recovery time, a higher degree of rise in lymphocytes, a faster recovery of the immune system, a lower rise in creatinine, and a lesser renal burden, but patients in the Paxlovid group had a greater decrease in total protein. In assessing patient conditions for treatment selection, Paxlovid may be preferable for individuals with renal insufficiency or those exhibiting compromised immune responses. Conversely, for patients experiencing malnutrition or cirrhotic hypoproteinemia, Azvudine could be considered to mitigate the reduction in protein levels. [ABSTRACT FROM AUTHOR]

In this retrospective cohort study, we aimed to assess clinical effectiveness and viral clearance following the use of molnupiravir, azvudine and paxlovid in hospitalized patients with COVID-19 in China dominated by the omicron BA.5.2 and BF.7 subvariant of SARS-CoV-2. Enrolled patients were assigned to the molnupiravir group or the azvudine group or the paxlovid group or the control group (not taking any antiviral drugs). The primary outcome of the cohort study was viral clearance and viral burden rebound after treatment and the secondary outcome was 28-day all-cause mortality. The four groups were propensity score-matched (1:1). We plotted viral load trends for each antiviral drug intervention using locally weighted regression (LOWESS) smoothed data. Multivariate logistic regression (stepwise algorithm) models were used to determine any risk factors for 28-day mortality. Of the 1537 patients receiving any treatment, 886 (57.6 %) received molnupiravir, 390 (25.4 %) received azvudine, 94 (6.1 %) received paxlovid, and 167 (10.9 %) did not use any antiviral drugs. Our data analysis showed that age (OR = 1.05, 95 % CI: 1.03-1.07, P < 0.001), Charlson comorbidty index (OR = 1.32, 95 % CI: 1.18-1.48, P < 0.001), severity of COVID-19 (P < 0.001), gamma globulin (OR = 2.04, 95 % CI: 1.03-3.99, P = 0.039) and corticosteroids use (OR = 2.3, 95 % CI: 1.19-4.69, P = 0.017) were independent prognostic factors for 28-day mortality in COVID-19 patients. After propensity score matching (PSM), the paxlovid recipients (OR = 0.22, 95 % CI: 0.05–0.83, P = 0.036) or azvudine recipients (OR = 0.27, 95 % CI: 0.07-0.91, P = 0.046) had lower 28-day mortality compared to their matched controls. Viral rebound occurred in the control group around days 9-16, while no viral rebound was found in any of the three oral antiviral groups. We found that molnupiravir group performed comparably in terms of the rate of nucleic acid conversion negative compared with the paxlovid group, while azvudine group performed slightly worse compared with the paxlovid group or molnupiravir group. In our retrospective cohort of hospitalized patients with COVID-19 during the wave of omicron strain, the molnupiravir, paxlovid and azvudine recipients showed a faster and more stable decrease in viral load and rare virus rebound in response to antiviral treatments when compared to the controls. The study supported that initiation treatment with paxlovid and azvudine was associated with significantly lower risk of all-cause death within 28 days. [ABSTRACT FROM AUTHOR]

Azvudine (FNC) is a new drug conditionally approved in 2022 for the treatment of coronavirus disease 2019 (COVID-19) in China. However, the exposure level of FNC in COVID-19 patients in clinical practice is still obscure, and there is no liquid chromatography-tandem mass spectrometry (LC-MS/MS) or LC method reported for quantifying the FNC. In this study, a simple, fast, and reliable LC-MS/MS method using L -phenylalanine-D5 (Phe-D5) as the internal standard (IS) was developed for the quantification of FNC in plasma from COVID-19 patients. After simple protein precipitation with methanol, the analyte in the supernatant was separated on Waters Atlantis® T3 (2.1 ×100 mm, 3.0 µm) column with the mobile phase consisting of acetonitrile (ACN) - aqueous solution (containing 0.03% heptafluorobutyric acid and 0.2% formic acid). The mobile phase was delivered at 0.3 mL/min in an isocratic elution program (15:85, V: V). The linear relationship of FNC was good within the calibration range of 2.0 – 2000.0 ng/mL, with the recovery of FNC ranging from 81.37% to 103.31% and the matrix effect was 94.77%− 109.83%. The short-term, long-term, and freeze-thaw stability of the FNC assessed in method was acceptable, and all other items met the requirements of validation of the biological analytical method. Finally, the method was applied to detect the exposure level of FNC in plasma samples from patients diagnosed with COVID-19, and the results, which are within the linear range of the method, showed huge inter-individual variation, supporting the significance of therapeutic drug monitoring of FNC. • First reported a LC-MSMS method for quantifying of FNC. • A simple protein precipitation method was utilized for FNC extraction. • Application to determine concentration of FNC in plasma from COVID-19 patients. • Provided a reference for investigating the efficacy-exposure relationship of FNC. [ABSTRACT FROM AUTHOR]

The ongoing COVID-19 pandemic has resulted in millions of deaths globally, highlighting the need to develop potent prophylactic and therapeutic strategies against SARS-CoV-2. Small molecule inhibitors (remdesivir, Paxlovid, and molnupiravir) are essential complements to vaccines and play important roles in clinical treatment of SARS-CoV-2. Many advances have been made in development of anti-SARS-CoV-2 inhibitors in China, but progress in discovery and characterization of pharmacological activity, antiviral mechanisms, and clinical efficacy are limited. We review development of small molecule anti-SARS-CoV-2 drugs (azvudine [approved by the NMPA of China on July 25, 2022], VV116 [approved by the NMPA of China on January 29, 2023], FB2001, WPV01, pentarlandir, and cepharanthine) in China and summarize their pharmacological activity, potential mechanisms of action, clinical trials and use, and important milestones in their discovery. The role of structural biology in drug development is also reviewed. Future studies should focus on development of diverse second-generation inhibitors with excellent oral bioavailability, superior plasma half-life, increased antiviral activity against SARS-CoV-2 and its variants, high target specificity, minimal side effects, reduced drug-drug interactions, and improved lung histopathology. [Display omitted] • Azvudine—The first Chinese oral SARS-CoV-2 RdRp inhibitor. • VV116—China's first up-and-coming deuterated oral SARS-CoV-2 RdRp candidate. • FB2001—China's first inhaled aerosolized SARS-CoV-2 Mpro candidate drug. • Cepharanthine—Natural product-derived SARS-CoV-2 receptor binding inhibitor. • Summarize pharmacological activity, potential mechanisms of action, clinical trials, and important milestones in drug discovery. [ABSTRACT FROM AUTHOR]