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Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 < em > in Vitro < /em >
This study could inform development and application of protease inhibitors for optimized antiviral treatments of COVID-19.PMID:34097489 | DOI:10.1128/AAC.02680-20 (Source: Antimicrobial Agents and Chemotherapy)
Source: Antimicrobial Agents and Chemotherapy - June 7, 2021 Category: Microbiology Authors: Karen A Gammeltoft Yuyong Zhou Carlos R Duarte Hernandez Andrea Galli Anna Offersgaard Rui Costa Long V Pham Ulrik Fahn øe Shan Feng Troels K H Scheel Santseharay Ramirez Jens Bukh Judith M Gottwein Source Type: research

Targeted design of drug binding sites in the main protease of SARS-CoV-2 reveals potential signatures of adaptation
Biochem Biophys Res Commun. 2021 Mar 26;555:147-153. doi: 10.1016/j.bbrc.2021.03.118. Online ahead of print.ABSTRACTSeveral existing drugs are currently being tested worldwide to treat COVID-19 patients. Recent data indicate that SARS-CoV-2 is rapidly evolving into more transmissible variants. It is therefore highly possible that SARS-CoV-2 can accumulate adaptive mutations modulating drug susceptibility and hampering viral antigenicity. Thus, it is vital to predict potential non-synonymous mutation sites and predict the evolution of protein structural modifications leading to drug tolerance. As two FDA-approved anti-hepat...
Source: Biochemical and Biophysical Research communications - April 4, 2021 Category: Biochemistry Authors: Aditya K Padhi Timir Tripathi Source Type: research

A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV2 main protease
by Jeremy D. Baker, Rikki L. Uhrich, Gerald C. Kraemer, Jason E. Love, Brian C. Kraemer Effective SARS-CoV-2 antiviral drugs are desperately needed. The SARS-CoV-2 main protease (Mpro) appears as an attractive target for drug development. We show that the existing pharmacopeia contains many drugs with potential for therapeutic repurposing as selective and potent inhibitors of SARS-Co V-2 Mpro. We screened a collection of ~6,070 drugs with a previous history of use in humans for compounds that inhibit the activity of Mproin vitro and found ~50 compounds with activity against Mpro. Subsequent dose validation studies demonst...
Source: PLoS One - February 1, 2021 Category: Biomedical Science Authors: Jeremy D. Baker Source Type: research

Computational drug discovery and repurposing for the treatment of COVID-19: A systematic review.
CONCLUSIONS: The present systematic review provides a list of existing drugs that have the potential to influence SARS-CoV2 through different mechanisms of action. For the majority of these drugs, direct clinical evidence on their efficacy for the treatment of COVID-19 is lacking. Future clinical studies examining these drugs might come to conclude, which can be more useful to inhibit COVID-19 progression. PMID: 33261845 [PubMed - as supplied by publisher] (Source: Bioorganic Chemistry)
Source: Bioorganic Chemistry - November 19, 2020 Category: Chemistry Authors: Mohamed K, Yazdanpanah N, Saghazadeh A, Rezaei N Tags: Bioorg Chem Source Type: research

Crowded environment affects the activity and inhibition of the NS3/4A protease.
Abstract Kinetic parameters characterizing the catalytic activities of enzymes are typically investigated in dilute solutions. However, in reality, these reactions occur in cells that, in addition to water and ions, are full of other macromolecules including proteins, nucleic acids, lipids, and metabolites. Such a crowded environment might affect enzyme-catalyzed reaction rates, so it is necessary to mimic the crowd in laboratory settings. We determined the effect of macromolecular crowders on the activity of the hepatitis C virus protease NS3/4A. As crowders we used polyethylene glycol (PEG), Ficoll, and ...
Source: Biochimie - July 23, 2020 Category: Biochemistry Authors: Popielec A, Ostrowska N, Wojciechowska M, Feig M, Trylska J Tags: Biochimie Source Type: research

A decade of hepatitis C at the University of Cape Town/Groote Schuur Hospital Liver Clinic, South Africa, in the pre-direct-acting antivirals era.
CONCLUSIONS: HCV patients in the Peg-IFN/RBV management era typified the epidemiology of HCV. GT distribution was pangenotypic, and treatment outcomes were encouraging despite treatment challenges. Patient selection, IL28B and sensible support of cytopenias probably accounted for these favourable outcomes. However, numbers treated were limited, and the DAA era of therapy allows for rapid expansion of therapy with now growing numbers of patients and a changing local epidemiology. PMID: 32657679 [PubMed - as supplied by publisher] (Source: South African Medical Journal)
Source: South African Medical Journal - July 14, 2020 Category: African Health Tags: S Afr Med J Source Type: research

Cost-effectiveness analysis is a mandatory strategy for health systems: evidence from a study involving therapies for hepatitis C.
Abstract Cost-effectiveness analysis is essential in health decision making. Several countries use it as synthesis of evidence to incorporate health technologies. The protease inhibitors (PI) boceprevir (BOC) and telaprevir (TVR) are indicated for chronic hepatitis C treatment and were incorporated in guidelines worldwide. Pre-marketing clinical trials showed higher sustained virological response rates in relation to previous therapies, but the incorporation of PIs generated a significant financial impact. The aim of this study was to discuss the relevance of cost-effectiveness analysis through a study tha...
Source: Cadernos de Saude Publica - February 6, 2020 Category: International Medicine & Public Health Authors: Rodrigues JPV, Cazarim MS, Chachá SGF, Martinelli ALC, Pereira LRL Tags: Cad Saude Publica Source Type: research

Simplified monitoring for hepatitis C virus treatment with glecaprevir plus pibrentasvir, a randomised non-inferiority trial
Globally, an estimated 71 million people have chronic hepatitis C virus (HCV) infection.[1] HCV treatment was interferon-based for more than two decades, with the addition of ribavirin,[2] pegylated-interferon,[3] and first-generation protease inhibitor direct acting antiviral (DAA) therapies (telaprevir, boceprevir),[4,5] providing stepwise improvements in efficacy as defined by sustained virological response (SVR). Despite these improvements, treatment uptake remained low in most countries, with (Source: Journal of Hepatology)
Source: Journal of Hepatology - October 22, 2019 Category: Gastroenterology Authors: Gregory J. Dore, Jordan J Feld, Alex Thompson, Marianne Martinello, Andrew J. Muir, Kosh Agarwal, Beat M üllhaupt, Heiner Wedemeyer, Karine Lacombe, Gail V. Matthews, Michael Schultz, Marina Klein, Christophe Hezode, Gerard Estivill Mercade, Danny Kho, K Source Type: research

The Investigation of Drug Resistance Substitutions in NS3 Protease Sequence of Hepatitis C Virus from Non-Responder Patients.
Conclusion: A low frequency of PIs resistance mutations in our HCV infected population is a hopeful point of starting these drugs in HCV infected patients. PMID: 31450900 [PubMed - in process] (Source: Asian Pacific Journal of Cancer Prevention)
Source: Asian Pacific Journal of Cancer Prevention - August 28, 2019 Category: Cancer & Oncology Tags: Asian Pac J Cancer Prev Source Type: research

Solid dispersions of telaprevir with improved solubility prepared by co-milling: formulation, physicochemical characterization, and cytotoxicity evaluation
Publication date: December 2019Source: Materials Science and Engineering: C, Volume 105Author(s): Xinnuo Xiong, Man Zhang, Quan Hou, Peixiao Tang, Zili Suo, Yujie Zhu, Hui LiAbstractTelaprevir (TVR) is typically a poorly soluble drug with an extremely low bioavailability of 1.7%. Polymorph modifications cannot improve the solubility of TVR because it only has a single unsolvated crystalline form. Co-crystals also provide limited bioavailability enhancement for TVR. Thus, in this study, we increased the solubility and dissolution rate of TVR through formulations of TVR–polymer solid dispersions. Three solid dispersions of...
Source: Materials Science and Engineering: C - August 15, 2019 Category: Materials Science Source Type: research

Conformational study on telaprevir by HPLC -DAD-MS and theoretical calculation.
Abstract Telaprevir is a potent, selective, peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3-4A serine protease, it is used for the treatment of HCV infection in combination with peginterferon alfa and ribavirin. In the present work, the E-Z isomerization process of telaprevir in solution was revealed by online HPLC-DAD (diode array detector)-MS, variable-temperature and variable-gradient experiments. The molecular geometry information of the two isomers was established by molecular mechanics calculations, and good correlation between the two isomers' Uv-vis spectra and their molecular geometry ...
Source: Biomedical Chromatography : BMC - July 4, 2019 Category: Biomedical Science Authors: Sun X, Jiang Y, Ju X Tags: Biomed Chromatogr Source Type: research

A rare and severe cutaneous adverse effect of telaprevir: drug rash with eosinophilia and systemic symptoms.
We report a case of DRESS due to telaprevir. A 64-year-old Caucasian man with chronic hepatitis C developed a progressive diffuse, painful maculopapular exanthema with fever, facial edema, lymphadenopathy at week 11 of chronic hepatitis C therapy with telaprevir, Peg-Interferon alfa-2a, and ribavirin. He had no exposures to any other medications. He presented an eosinophilia (up to 6.29 X 109 cells/L), skin biopsy was consistent with a drug reaction. The HCV treatment was stopped and methylprednisolone 0.75 mg/kg/day was started. Cutaneous and systemic symptoms had a rapid resolution in few days. Telaprevir can activate se...
Source: Giornale Italiano di Dermatologia e Venereologia - June 30, 2019 Category: Dermatology Tags: G Ital Dermatol Venereol Source Type: research