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While research has identified several inhibitors of the main protease (Mpro) of SARS-CoV-2, a significant portion of these compounds exhibit reduced activity in the presence of reducing agents, raising concerns about their effectiveness in vivo. Furthermore, the conventional biosafety level 3 (BSL-3) for cellular assays using viral particles poses a limitation for the widespread evaluation of Mpro inhibitor efficacy in a cell-based assay. Here, we established a BSL-1 compatible cellular assay to evaluate the in vivo potential of Mpro inhibitors. This assay utilizes mammalian cells expressing a tagged Mpro construct containing N-terminal glutathione S-transferase (GST) and C-terminal hemagglutinin (HA) tags and monitors Mpro autodigestion. Using this method, GC376 and boceprevir effectively inhibited Mpro autodigestion, suggesting their potential in vivo activity. Conversely, carmofur and ebselen did not exhibit significant inhibitory effects in this assay. We further investigated the inhibitory potential of selenoneine on Mpro using this approach. Computational analyses of binding energies suggest that noncovalent interactions play a critical role in facilitating the covalent modification of the C145 residue, leading to Mpro inhibition. Our method is straightforward, cost-effective, and readily applicable in standard laboratories, making it accessible to researchers with varying levels of expertise in infectious diseases. [ABSTRACT FROM AUTHOR]

Aim: Utilizing the therapeutic potentials of previously approved medications against a new target or pharmacological response is known as drug repurposing. The health and scientific communities are under continual pressure to discover new compounds with antiviral potential due to the rising reports of viral resistance and the occurrence and re-emergence of viral outbreaks. The use of antiviral peptides has emerged as an intriguing option in this search. Here, this article includes the current United States Food and Drug Administration (FDA)-approved antiviral peptides that might be enforced for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and carried out docking study of the viral protease inhibitors. Methods: In silico techniques like molecular docking was carried out using Autodock Vina software. Results: The molecular docking studies of peptide-based antiviral agents against SARS-CoV-2 [Protein Data Bank (PDB) ID: 7P35] using docking software AutoDockTools 1.5.6. Among all the docked ligands, compound velpatasvir showed interaction with residues ILE213, GLN256, LEU141, GLN189, GLU166, HIS41, CYS145, and ASN142, and displayed the highest docking score of –8.2 kcal/mol. This medication could be a novel treatment lead or candidate for treating SARS-CoV-2. Conclusions: To conclude, a docking study of peptide based antiviral compounds for their binding mode in the catalytic domain of SARS-CoV-2 receptor is reported. On molecular docking, the compounds have showed remarkable binding affinity with the amino acids of receptor chain A. The compounds occupied the same binding cavity as the reference compound maintaining the interactions with conserved amino acid residues essential for significant inhibitory potential, especially for compound velpatasvir with binding score of –8.2 kcal/mol.

Nirmatrelvir, which targets the SARS-CoV-2 main protease (Mpro), is the first-in-line drug for prevention and treatment of severe COVID-19, and additional Mpro inhibitors are in development. However, the risk of resistance development threatens the future efficacy of such direct-acting antivirals. To gain knowledge on viral correlates of resistance to Mpro inhibitors, we selected resistant SARS-CoV-2 under treatment with the nirmatrelvir-related protease inhibitor boceprevir. SARS-CoV-2 selected during five escape experiments in VeroE6 cells showed cross-resistance to nirmatrelvir with up to 7.3-fold increased half-maximal effective concentration compared to original SARS-CoV-2, determined in concentration–response experiments. Sequence analysis revealed that escape viruses harbored Mpro substitutions L50F and A173V. For reverse genetic studies, these substitutions were introduced into a cell-culture-infectious SARS-CoV-2 clone. Infectivity titration and analysis of genetic stability of cell-culture-derived engineered SARS-CoV-2 mutants showed that L50F rescued the fitness cost conferred by A173V. In the concentration–response experiments, A173V was the main driver of resistance to boceprevir and nirmatrelvir. Structural analysis of Mpro suggested that A173V can cause resistance by making boceprevir and nirmatrelvir binding less favorable. This study contributes to a comprehensive overview of the resistance profile of the first-in-line COVID-19 treatment nirmatrelvir and can thus inform population monitoring and contribute to pandemic preparedness. [ABSTRACT FROM AUTHOR]

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a prominent drug target as it plays a key role in viral replication and is greatly conserved in the coronaviruses with no homologues in the human genome. Ma et al. reported boceprevir, an FDA‐approved hepatitis C virus (HCV) drug, for inhibiting SARS‐CoV‐2 Mpro activity (IC50=4.13±0.61 μM). However, how boceprevir inhibits Mpro activity remains unexplored. The molecular dynamics (MD) simulations have been utilized in the present study to examine the mechanistic basis of the high‐affinity binding of boceprevir with SARS‐CoV‐2 Mpro. The molecular docking analysis depicted a strong binding (−7.5 kcal/mol) of boceprevir to Mpro due to its hydrogen bond interactions with catalytic dyad (Cys145) and oxyanion hole residues (Asn142, Gly143) of Mpro. MD simulations revealed the structural stability of the Mpro‐boceprevir complex during the whole simulation. The MD simulations illuminated key interactions of boceprevir with the residues lining the subpockets of the active site of Mpro, which is consistent with its high‐affinity binding with Mpro observed in the in vitro studies. The results from the current investigation will offer direction and valuable insights for developing novel Mpro inhibitors. [ABSTRACT FROM AUTHOR]

In recent years, more than 200 countries of the world have faced a health crisis due to the epidemiological disease of COVID-19 caused by the SARS-CoV-2 virus. It had a huge impact on the world economy and the global health sector. Researchers are studying the design and discovery of drugs that can inhibit SARS‐CoV‐2. The main protease of SARS‐CoV‐2 is an attractive target for the study of antiviral drugs against coronavirus diseases. According to the docking results, binding energy for boceprevir, masitinib and rupintrivir with CMP are −10.80, −9.39, and −9.51 kcal/mol respectively. Also, for all investigated systems, van der Waals and electrostatic interactions are quite favorable for binding the drugs to SARS-CoV-2 coronavirus main protease, indicating confirmation of the complex stability.

Context: The unavailability of target-specific antiviral drugs for SARS-CoV-2 viral infection kindled the motivation to virtually design derivatives of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide as potential antiviral inhibitors against the concerned virus. The molecular docking and molecular dynamic results revealed that the reported derivatives have a potential to act as antiviral drug against SARS-CoV-2. The reported hit compounds can be considered for in vitro and in vivo analyses. Methods: Fragment-based drug designing was used to model the derivatives. Furthermore, DFT simulations were carried out using B3LYP/6-311G** basis set. Docking simulations were performed by using a combination of empirical free energy force field with a Lamarckian genetic algorithm under AutoDock 4.2. By the application of AMBER14 force field and SPCE water model, molecular dynamic simulations and MM-PBSA were calculated for 100 ns. [ABSTRACT FROM AUTHOR]

The main protease (Mpro) of SARS-CoV-2 is an attractive drug target for antivirals, as this enzyme plays a key role in virus replication. Drug repurposing is a promising option for the treatment of coronavirus disease 2019 (COVID-19). Recently, a number of FDA-approved drugs have been identified as Mpro inhibitors, but stringent hit validation is lacking. In this study, we rigorously reevaluated the in vitro inhibition of the Mpro enzyme by repurposed drugs via combined experiments, including the fluorescence resonance energy transfer (FRET) assay, fluorescence polarization (FP) assay, and protease biosensor cleavage assay. Our results from a set of in vitro assays revealed that boceprevir is a potential Mpro inhibitor, but other repurposed drugs, including atazanavir, dipyridamole, entrectinib, ethacridine, glecaprevir, hydroxychloroquine, ivermectin, meisoindigo, pelitinib, raloxifene, roxatidine acetate, saquinavir, teicoplanin, thonzonium bromide, and valacyclovir, are not. Our research highlights that the use of candidate Mpro inhibitors from primary screening warrants further comprehensive studies before the reporting of new findings., (© 2025 Wiley Periodicals LLC.)

The main protease (Mpro) of the betacoronavirus SARS-CoV-2 is an attractive target for the development of treatments for COVID-19. Structure-based design is a successful approach to discovering new inhibitors of the Mpro. Starting from crystal structures of the Mpro in complexes with the Hepatitis C virus NS3/4A protease inhibitors boceprevir and telaprevir, we optimized the potency of the alpha-ketoamide boceprevir against the Mpro by replacing its P1 cyclobutyl moiety by a γ-lactam as a glutamine surrogate. The resulting compound, MG-78, exhibited an IC50 of 13 nM versus the recombinant Mpro, and similar potency was observed for its P1′ N-methyl derivative MG-131. Crystal structures confirmed the validity of our design concept. In addition to SARS-CoV-2 Mpro inhibition, we also explored the activity of MG-78 against the Mpro of the alphacoronavirus HCoV NL63 and against enterovirus 3C proteases. The activities were good (0.33 µM, HCoV-NL63 Mpro), moderate (1.45 µM, Coxsackievirus 3Cpro), and relatively poor (6.7 µM, enterovirus A71 3Cpro), respectively. The structural basis for the differences in activities was revealed by X-ray crystallo-graphy. We conclude that the modified boceprevir scaffold is suitable for obtaining high-potency inhibitors of the coronavirus Mpros but further optimization would be needed to target enterovirus 3Cpros efficiently. [ABSTRACT FROM AUTHOR]

The novel coronavirus disease (COVID-19) has spread throughout the globe, affecting millions of people. The World Health Organization (WHO) has declared this infectious disease a pandemic. At present, several clinical trials are going on to identify possible drugs for treating this infection. SARS-CoV-2 Mpro is one of the most critical drug targets for the blockage of viral replication. The aim of this study was to identify potential natural anthraquinones that could bind to the active site of SARS-CoV-2 main protease and stop the viral replication. Blind molecular docking studies of 13 anthraquinones and one control drug (Boceprevir) with SARS-CoV-2 Mpro were carried out using the SwissDOCK server, and alterporriol-Q that showed the highest binding affinity towards Mpro were subjected to molecular dynamics simulation studies. This study indicated that several antiviral anthraquinones could prove to be effective inhibitors for SARS-CoV-2 Mpro of COVID-19 as they bind near the active site having the catalytic dyad, HIS41 and CYS145 through non-covalent forces. The anthraquinones showed less inhibitory potential as compared to the FDA-approved drug, boceprevir. Among the anthraquinones studied, alterporriol-Q was found to be the most potent inhibitor of SARS-CoV-2 Mpro. Further, MD simulation studies for Mpro- alterporriol-Q system suggested that alterporriol-Q does not alter the structure of Mpro to a significant extent. Considering the impact of COVID-19, identification of alternate compounds like alterporriol-Q that could inhibit the viral infection will help in accelerating the process of drug discovery. [ABSTRACT FROM AUTHOR]

Because of the scale of the novel coronavirus (COVID-19) pandemic and the swift transmission of this highly contagious respiratory virus, repurposing existing drugs has become an urgent treatment approach. The objective of our study is to unravel the binding mechanism of the Food and Drug Administration (FDA)-approved dexamethasone (Dex) and boceprevir (Boc) drugs with selected COVID-19 protein targets SARS-CoV-2 spike protein C-terminal domain (spike-CTD), main protease (Mpro), and interleukin-6 (IL-6). Another objective is to analyze the effects of binding Dex and Boc drugs on the interactions of viral spike protein to human angiotensin-converting enzyme 2 (hACE2). Molecular docking and one-microsecond-long molecular dynamics simulations of each of the six protein–drug complexes along with steered molecular dynamics (SMD) and umbrella sampling (US) methods have revealed the binding mode interactions and the physicochemical stability of the three targeted proteins with two drugs. Results have shown that both drugs bind strongly with the three protein targets through hydrogen bonding and hydrophobic interactions. A major finding from this study is how the binding of the drugs with viral spike protein affects its interactions at the binding interface with hACE2 protein. Simulations of drug-bound spike-CTD with hACE2 show that due to the presence of a drug at the binding interface of spike-CTD, hACE2 is being blocked from making putative interactions with viral protein at such interface. These important findings regarding the binding affinity and stability of the two FDA-approved drugs with the main targets of COVID-19 along with the effect of drugs on hACE2 interactions would contribute to COVID-19 drug discovery and development. [ABSTRACT FROM AUTHOR]

BackgroundIn 2011, the FDA approved telaprevir (TVR) and boceprevir (BOC) for use with pegylated interferon and ribavirin to treat hepatitis C virus (HCV) genotype 1. We aimed to evaluate the real-world application, tolerability, and effectiveness of TVR- and BOC-based HCV treatment in a large integrated care setting.MethodsWe utilized Northern California Kaiser Permanente Medical Care Program (KPNC) electronic databases and medical records to study the experience of all KPNC patients who initiated TVR or BOC from June 2011 to March 2012.ResultsCompared with the pool of 5,194 treatment-eligible patients, the 352 treatment initiators were more likely to be cirrhotic (24 vs. 10%, p < 0.001) and treatment-experienced (44 vs. 22%, p < 0.001). Among the treatment initiators, 211 received TVR and 141 BOC. Overall, 31% discontinued treatment prematurely; 16% of patients stopped treatment early because of side effects. One patient with cirrhosis died of sepsis during treatment. Premature discontinuation was highest among TVR-treated cirrhotic patients (58%). Sustained virologic response (SVR) was achieved in 55% overall and was similar comparing the TVR (56%)- and BOC (53%)-treated groups. The only independent predictors of treatment failure were cirrhosis at baseline [odds ratio (OR) for SVR 0.44, p = 0.004] and prior partial or null response (OR for SVR 0.57, p = 0.02).ConclusionsIn the initial application of TVR and BOC, patients with cirrhosis and prior treatment failure were prioritized for treatment. In this real-world experience, most patients successfully completed a full treatment course. However, side effect-related premature discontinuations were common, and SVR rates were lower than reported in clinical trials.

Background & aimsNS3/4A protease inhibitors, boceprevir or telaprevir, combined with peginterferon and ribavirin was the standard treatment for HCV genotype 1 and remains the only available direct antiviral drug based therapy in some countries. Efficacy and safety data in liver transplant recipients are limited.MethodsThis was a retrospective cohort study of 81 patients with genotype 1 HCV treated with boceprevir (10%) or telaprevir (90%) plus peginterferon and ribavirin at 6 US transplant centers (53% stage 3-4/4 fibrosis, 57% treatment experienced). The primary end point was undetectable HCV RNA 12 weeks after treatment completion (SVR12).ResultsThe intent-to-treat SVR12 rate was 63% (51/81). Patients with an extended rapid virologic response, (undetectable HCV RNA at 4 and 12 weeks after starting boceprevir or telaprevir), had a higher rate of SVR12 than all other patients (85% vs. 15%, p

Αbstract: Remdesivir (GS-5734), a drug initially developed to treat hepatitis C and Ebola virus disease, was the first approved treatment for severe coronavirus disease 2019 (COVID-19). However, apart from remdesivir, there is a paucity of other specific anti-viral agents against SARS-CoV-2 infection. In 2017, researchers had documented the anti-coronavirus potential of remdesivir in animal models. At the same time, trials performed during two Ebola outbreaks in Africa showed that the drug was safe. Although vaccines against SARS-CoV-2 infection have emerged at an enormously high speed, equivalent results from efforts towards the development of anti-viral drugs, which could have played a truly life-saving role in the current stage of the pandemic, have been stagnating. In this review, we will focus on the current treatment options for COVID-19 which mainly consist of repurposed agents or treatments conferring passive immunity (convalescent plasma or monoclonal antibodies). Additionally, potential specific anti-viral therapies under development will be reviewed, such as the decoy miniprotein CTC-445.2d, protease inhibitors, mainly against the Main protein Mpro, nucleoside analogs, such as molnupiravir and compounds blocking the replication transcription complex proteins, such as zotatifin and plitidepsin. These anti-viral agents seem to be very promising but still require meticulous clinical trial testing in order to establish their efficacy and safety. The continuous emergence of viral variants may pose a real challenge to the scientific community towards that end. In this context, the advent of nanobodies together with the potential administration of a combination of anti-viral drugs could serve as useful tools in the armamentarium against COVID-19.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats. [ABSTRACT FROM AUTHOR]

Emerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets. Here, the authors identify potential drugs that target 3-chymotrypsin like protease (3CLpro), which is a pivotal protease for the replication of SARS-CoV-2. They found that off-target inhibitors such as ivermectin and micafungin inhibit 3CLpro enzyme activity, suggesting that these molecules could constitute useful therapies to inhibit SARS-CoV-2 replication. [ABSTRACT FROM AUTHOR]

Background: The clinical experience with protease-inhibitor (PI) triple regimen appears disappointing regarding effect, side effects, high work load, and costs. This real-world study evaluates baseline and emerging resistance-associated substitutions (RASs) and their significance for treatment outcome. Method: Thirty-six genotype 1a/b patients treated according to Swedish recommendations during 2011–2013 with triple therapy including pegylated interferon and ribavirin in combination with a protease-inhibitor, either boceprevir (BOC) or telaprevir (TVR), were retrospectively evaluated. Frozen serum samples from the patients were tested for resistance with pan-genotypic population sequencing. Results: Overall, 56% (20/36) of the patients achieved sustained viral response (SVR). The SVR was comparable between BOC (64%; 9/14) and TVR (50%; 11/22) (p = 0.07), and the IL28B type non-CC (48%; 12/25) and CC (46%; 6/13) (p = 0.77). The SVR was higher in patients without cirrhosis (89.5%; 17/19) (p 800,000 IU/mL) (50%; 12/24). Conclusion: PI triple regimes were highly effective in treatment-naïve patients without cirrhosis, but in this real-world cohort an inferior effect was evident in cirrhotic and treatment-experienced patients. Although tested on a limited sample, the baseline resistance testing seems to have no impact on prediction of therapy outcome. The reason could be that the baseline RASs T54S and V55A have relatively low resistance towards BOC and TVR. Emerging RASs, mainly R155K, with known high resistance to BOC and TVR were frequently found in non-responders.

Abstract Background Observational studies are used to measure the effectiveness of an intervention in non-experimental, real world scenarios at the population level and are recognised as an important component of the evidence pyramid. Such data can be accrued through prospective cohort studies and a patient registry is a proven method for this type of study. The national hepatitis C (HCV) registry was established in Ireland in 2012 with the aim of monitoring the clinical and economic outcomes from new, high cost regimens for the treatment of HCV infection. A sustained virological response (SVR) 24 weeks following completion of therapy with interferon-containing regimens is considered a cure. Non-randomisation in these studies can result in confounding or selection bias. Propensity score (PS) matching is one of a number of statistical tools that can be used to mitigate the effects of confounding in observational studies. Methods We analysed the data of 309 patients who underwent triple therapy treatment with telaprevir (TPV) in combination with pegylated-interferon and ribavirin (PR) or boceprevir (BOC)/PR between June 2012 and December 2014. The decision to initiate treatment and the selection of the treatment regimen was at the discretion of the physician. To adjust for confounding, three approaches to propensity score matching were assessed Adjusted sustained-virological response rates (SVR), odds ratios, p-values and 95% confidence intervals were calculated from the three PS matched dataset. Results Prior to matching, the unadjusted sustained virological response rates 24 weeks after treatment complete (SVR24) were 74% (n = 158/215) and 61% (n = 57/94) for telaprevir/PR and boceprevir/PR, respectively. After matching, adjusted SVR24 rates were between 73–74% and 60–61% for telaprevir/PR and boceprevir/PR, respectively. Conclusion Efficacy rates were comparable with those reported in pivotal clinical trials and real world studies. After adjusting for confounding, we conclude that there was no difference in treatment effect after PS matching. The small sample size limits the conclusions that can be made about the effect of PS matching. Propensity score adjustment remains a tool that can be applied to future analysis, however, we suggest, where possible, using a larger sample size in order to reduce the uncertainty around the outcomes.

Helena HL Borba,1 Astrid Wiens,1 Laiza M Steimbach,1 Fernanda S Tonin,1 Maria LA Pedroso,2 Cláudia AP Ivantes,3 Fernando Fernandez-Llimos,4 Roberto Pontarolo1 1Pharmaceutical Sciences Postgraduate Research Program, Department of Pharmacy, 2Gastroenterology Service, Hospital de Clínicas, Federal University of Paraná, 3Guidance and Counseling Center, Curitiba City Hall, Curitiba, Paraná, Brazil; 4Department of Social Pharmacy, Faculty of Pharmacy, Research Institute for Medicines, University of Lisboa, Lisbon, Portugal Background: Chronic hepatitis C is a major public health issue, but there is a gap in the literature regarding the effectiveness and safety of direct-acting antiviral agents in the Brazilian population. The main aim of this study was to describe the effectiveness of boceprevir and telaprevir in patients treated at public health care institutions in Brazil.Materials and methods: A prospective longitudinal and multicenter study was conducted in five centers in the State of Paraná between September 2014 and June 2016. Data regarding effectiveness and safety were collected from medical records of patients treated with boceprevir or telaprevir. The effectiveness outcome comprised the rapid virological response (RVR). Multivariate analysis was performed to verify the influence of independent variables (ie, age, gender, baseline viral load) on RVR achievement.Results: Data were collected from 117 patients with chronic hepatitis C virus (HCV) genotype 1 infection. Fifteen patients received treatment with boceprevir and 102 received telaprevir. The mean age was 51.6 years, 64.1% were male, 44.4% were infected with HCV subtype 1a, 62.4% had a high baseline viral load (≥800,000 IU/mL) and 33% were cirrhotic. Furthermore, 79.5% of patients achieved RVR (26.7% in the boceprevir group and 87.3% in the telaprevir group). Multivariate analysis demonstrated that the type of protease inhibitor (boceprevir or telaprevir) and the baseline viral load had an influence on the RVR rate (odds ratio [OR] =0.011; 95% confidence interval [CI]: 0.001–0.119; P

Amaç: Pegile interferon+ribavirin kombinasyonu uzun yıllar kronik hepatit C tedavisinde standart tedavi olmuştur. Son yıllarda proteaz inhibitörleri bu kombinasyona ilave edilmiş ve daha yüksek kalıcı virolojik yanıt oranları elde edilebilmiştir. Biz bu çalışmada kliniğimizde takip edilen ve PEG-İFN+ribavirin+proteaz inhibitörü içeren üçlü tedavi alan hastalarımızın verilerini retrospektif olarak değerlendirmeyi amaçladık.Gereç ve Yöntem: Necmettin Erbakan Üniversitesi Meram Tıp Fakültesi Gastroenteroloji Kliniğine Aralık 2012-Aralık 2015 tarihleri arasında başvuran ve proteaz inhibitörü içeren 3’lü tedavi verilen 23 kronik HCV hastasının verileri retrospektif olarak incelenmiştir.Bulgular: Hastaların 18’i %78,3 kadın ve 5’i %21,7 erkek ve median yaşları 58 yıl Aralık 42-70 yıl idi. Toplam 16 hastada %69,6 kalıcı virolojik yanıt elde edilmişti. Telaprevir kullanan 18 hastanın 13’ünde %72,2 ve boseprevir kullanan 5 hastanın 3’ünde %60 kalıcı virolojik yanıt elde edildi. Daha önce PEG IFN+ribavirin ikili tedavisi alıp nüks olan 11 hastanın 10’unda %90,1 , kısmi yanıt veren 3 hastanın tamamında ve ilk tedavide primer yanıtsız olan 4 hastanın 2’sinde %50 kalıcı virolojik yanıt elde edildi. Sirotik olan 9 hastanın 7’si %77,8 planlanan tedavi süresini tamamladı, 5 hastada %55,6 kalıcı virolojik yanıt elde edildi. Sirozu olmayan 14 hastanın 12’si %85,7 tedaviyi tamamlarken, bu hastaların 11’inde %78,5 kalıcı virolojik yanıt elde edildi. 4 hastada %17,4 çeşitli yan etkiler nedeniyle tedavi süresi tamamlanamadı.Sonuç: İnterferonsuz tedavi rejimlerinin ülkemizde henüz rutin kullanıma girmediği göz önüne alınırsa, seçilmiş vakalarda PEG IFN, ribavirin ve bir proteaz inhibitörü içeren üçlü tedavilerin hala bir seçenek olabileceği kanaatindeyiz

Boceprevir drug is a ketoamide serine protease inhibitor with a linear peptidomimetic structure that exhibits inhibition activity against 2019-nCoV main protease. This paper reports electronic properties of boceprevir and its molecular docking as well as molecular dynamics simulation analysis with protein receptor. For this, the equilibrium structure of boceprevir has been obtained by DFT at B3LYP and ωB97XD levels with 6-311+G(d,p) basis set in gas and water mediums. HOMO-LUMO and absorption spectrum analysis have been used to evaluate the boceprevir's toxicity and photosensitivity, respectively. Molecular docking simulation has been performed to test the binding affinity of boceprevir with 2019-nCoV M PRO ; which rendered a variety of desirable binding locations between the ligand and target protein's residue positions. The optimum binding location has been considered for molecular dynamics simulation. The findings have been addressed to clarify the boceprevir drug efficacy against the 2019-nCoV M PRO ., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection progressing to cirrhosis within five years in 20% to 30% of them. Obtaining a sustained virological response (SVR) greatly improves overall and graft survival. Until 2011, standard antiviral therapy using PEGylated interferon (PEG-IFN) and ribavirin (RBV) was the only effective therapy, with an SVR rate around 30% in this setting. For patients infected with genotype 1, first generation NS3/4A protease inhibitors (PIs), boceprevir (BOC) or telaprevir (TVR), associated with PEG-IFN and RBV for 48 weeks have increased the SVR rates to 60% in non-transplant patients. However, tolerability and drug-drug interactions with calcineurin inhibitors (CNI) are both limiting factors of their use in the liver transplant setting. Over recent years, the efficacy of antiviral C therapy has improved dramatically using new direct-acting antiviral (DAA) agents without PEG-IFN and/or RBV, leading to SVR rates over 90% in non-transplant patients. Results available for transplant patients showed a better efficacy and tolerability and less drug-drug interactions than with first wave PIs. However, some infrequent cases of viral resistance have been reported using PIs or NS5A inhibitors pre- or post-LT that can lead to difficulties in the management of these patients.

Background: According to the EASL and AASLD guidelines, the recommended treatment for patients who failed to achieve a sustained virologic response (SVR) on prior interferon-based triple therapy with protease inhibitors (PI), is a combination of sofosbuvir and NS5A inhibitors. Polish national recommendations also allow the use of paritaprevir/ritonavir/ombitasvir+dasasbuvir±ribavirin (PrODR) in this group of patients. The aim of the study was to evaluate the efficacy and safety of PrODR vs. ledipasvir/sofosbuvir±RBV (LSR) in PI-experienced patients in real-life setting.Methods: Our analysis included patients registered in the nationwide, investigators initiated, multicentre EpiTer-2 database. Among 4530 patients registered, 335 with genotype 1 (93% 1b) were previously treated with IFN-based regimens with PIs: 127 with boceprevir (BOC), 208 with telaprevir (TVR). Patients with advanced fibrosis (F3/F4) were significantly predominant (BOC 28.4%/61.4%, TVR 18.8%/64.4%, respectively). Subjects were assigned to IFN-free retreatment as follows: BOC - 64 (50.4%) PrODR and 63 (49.6%) LSR; TVR- 103 (49.5%) PrODR and 105 (50.5%) LSR.Results: SVR rates were comparable for particular groups: BOC → PrODR- 100%; BOC → LSR - 98%; TVR → PrODR - 97%; TVR → LSR - 96% (intent-to treat analysis-ITT) and BOC → PrODR→100%; BOC → LSR - 99%; TVR → PrODR - 99%; TVR → LSR - 98% (modified intent-to treat analysis-mITT). Both treatment regimens had a favourable safety profile. Adverse events (AEs) were generally mild or moderate in severity. Three deaths were reported. The treatment was stopped due to AEs in five patients (three treated with PrODR and two with LSR).Conclusion: Efficacy and safety of treatment with PrODR and LSR is comparable in BOC or TVR-experienced patients. [ABSTRACT FROM AUTHOR]

Background/purpose: The role of directly-acting antivirals (DAA)-containing regimens in the treatment of patients dually-infected with hepatitis C virus (HCV) and hepatitis B virus (HBV) remains unclear. The pilot study aimed to explore the safety and efficacy of a protease inhibitor, boceprevir, in combination with peginterferon/ribavirin for HCV genotype 1 (HCV-1)/HBV dually-infected patients refractory to prior peginterferon/ribavirin.Methods: Twelve peginterferon-experienced patients dually-infected with HCV-1/HBV were assigned to receive boceprevir 800 mg, twice a day, plus peginterferon-α 2b 1.5 μg/kg/week and ribavirin 800-1400 mg/day for 36 or 48 weeks. The primary endpoint was HCV sustained virological response (SVR, HCV RNA undetectable 24 weeks after end-of-treatment).Results: Five patients terminated treatment early due to adverse events (one at week 4, one at week 46), virological failures (one non-response and one breakthrough), and patient request (n = 1). Eight patients achieved HCV SVR (66.7% in full-analysis set and 72.7% in modified intention-to-treat population). The HCV SVR rate was 71.4% (5/7) in prior relapsers, 60.0% (3/5) in prior null responder; 75% in non-cirrhotic and 50% in cirrhotic patients. All four patients of prior non-cirrhotic relapsers received 36-week regimen and achieved HCV SVR. There was no HBV-related hepatic flare. All patients experienced at least one adverse event. Two had serious adverse events.Conclusion: Boceprevir plus peginterferon/ribavirin is effective in the treatment of HCV-1/HBV dually infected patients' refractory to prior peginterferon/ribavirin combination therapy. [ABSTRACT FROM AUTHOR]

The first generation protease inhibitors has been the mainstay of hepatitis C treatment for the last couple of years, showing marked improvement in sustained virological response, but also increased side effects. Infection has emerged as a common complication of telaprevir and boceprevir in combination with peginterferon and ribavirin, usually caused by common pathogens. We present the case of a 65 years old man who developed a Mycobacterium abscessus pulmonary infection during treatment with telaprevir, peginterferon and ribavirin. The patient was successfully treated with amikacin, imipenem and chlarithro-mycin. The present case is relevant for increasing awareness for recognition of opportunistic infections and particularly nontuberculous mycobacterial infections in patients receiving triple therapy for chronic hepatitis C, especially in cirrhotic subjects who develop significant lymphopenia.

Introduction. The triple therapy which consists of one of the protease inhibitor plus pegylated interferon and ribavirin (P/R) is the standard of care for the treatment of chronic hepatitis C virus (HCV) genotype 1(G1) infection both in treatment-naпve and experienced patients. Objective. The aim of this study was to analyze the efficacy and tolerability of this regime in hospital practice in Serbia. Methods. From July 2012 to October 2012, 20 previously treated patients with advanced fibrosis and HCV G1 infection were included in the triple antiviral regimen in six referral centers in Serbia. All patients were treated with response guide therapy (RGT) regime according to the boceprevir treatment protocol. During the 4-week lead-in period all patients received peginterferon plus ribavirin. After the lead-in period boceprevir was added in the dosage of 800 mg three times a day orally. The subsequent treatment varied according to virologic response and fibrosis. During the therapy HCV RNA level was measured at week 4, 8, 12, 24 of the treatment for the assessment of virologic response profile. All patients who completed therapy were assessed at the end of the treatment and at the end of an additional 24-week treatment-free period for a sustained virologic response (SVR). Results. The total of 20 patients with advanced fibrosis was treated. Among patients with an undetectable HCV RNA level at week 8 the rate of SVR was 100%. No patient with decrease in the HCV RNA level