Protease, Polymerase, and Assembly Inhibitors for the Treatment of Hepatitis C Virus Infection
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
The first DAAs approved for clinical use in HCV genotype 1 infection were the first-generation NS3/4A protease inhibitors, telaprevir and boceprevir. In an HCV subtype 1b replicon assay, the telaprevir 50% effective concentration (EC50) against wild-type (WT) HCV was 354 nM in a 2-day cell culture assay; in a subtype 1a infectious virus assay, the EC50 value was 280 nM in a 5-day cell culture assay (Vertex Pharmaceuticals, 2013). In a study of clinical isolates, the WT G1b replicon had a mean telaprevir EC50 (± s.d.) of 482 nM (122) and 269 nM (96) in 48-hour and 96-hour assays, respectively, whereas the WT G1a replicon had a mean telaprevir EC50 (± s.d.) of 961 nM (132) in the 96-hour assay (Jiang et al., 2013). Similarly, the EC50 value for boceprevir against an HCV replicon constructed from a single genotype 1b isolate was approximately 200 nM in a 72-hour cell culture assay, and anti-HCV activity was approximately twofold lower for an HCV replicon derived from a single genotype 1a isolate relative to the replicon derived from the 1b isolate (Merck, 2015).
Managing hepatitis C therapy failures and chronic kidney disease
Published in Expert Review of Clinical Pharmacology, 2018
Fabrizio Fabrizi, Piergiorgio Messa
The understanding of the life cycle of HCV has helped the development of novel therapies toward HCV. In 2011, boceprevir and telaprevir were the first drugs provided with direct antiviral activity and approved for the treatment of chronic HCV. Boceprevir and telaprevir were NS3/4a non-structural protease inhibitors and were combined with peg-IFN interferon and ribavirin (RBV) to prevent the occurrence of resistances, a major concern commonly observed when these agents were used in mono-therapy. The SVR rates obtained with triple antiviral regimens (pegIFN, RBV, and telaprevir of boceprevir) increased to approximately 75% in some patient subgroups with the potential to shorten treatment duration. However, adverse events continued to be common due to the need to use both IFNs and RBV in combination. The data in the medical literature regarding these antiviral regimens in the CKD population are extremely limited [10].
Supervised Molecular Dynamics (SuMD) Insights into the mechanism of action of SARS-CoV-2 main protease inhibitor PF-07321332
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Matteo Pavan, Giovanni Bolcato, Davide Bassani, Mattia Sturlese, Stefano Moro
Boceprevir is a protease inhibitor originally developed for the Hepatitis C Virus (HCV) NS3 protease30. It shares many common structural features with PF-07321332, such as the cyclopropyl proline residue at P2 and the alanine at the P3 position but has a different reactive group (α-ketoamide), a cyclobutyl alanine at P1, and a tert-butyl carbamate capping moiety at P4. From a binding mode point of view, the most prominent difference between the newly developed inhibitor and Boceprevir regards the hydrogen bond with His163 (absent in Boceprevir complex with the protease) which, as previously mentioned, is a crucial interaction also for natural peptidic substrates.
Natural products for the management of the hepatitis C virus: a biochemical review
Published in Archives of Physiology and Biochemistry, 2020
Walid Hamdy El-Tantawy, Abeer Temraz
Due to lack of a preventive vaccine, infected individuals have relied on a standard treatment, consisting of PEGylated (PEG)-interferon (IFN)-α in combination with ribavirin (RBV) for over a decade. This regimen is expensive and often associated with a poor antiviral response and unwanted side effects (Negro 2010). Although novel protease inhibitors such as boceprevir and telaprevir have been approved as treatments for hepatitis C, these medications lack pan-genotype activity and are accompanied by drug toxicity and the development of resistant mutants (Thomas 2012, Wartelle-Bladou et al.2012).
Related Knowledge Centers
- Anemia
- Dysgeusia
- Protease Inhibitor
- Ribavirin
- Hepatitis C Virus NONstructural Protein 3
- Ledipasvir/Sofosbuvir
- Peginterferon Alfa-2B
- Nirmatrelvir/Ritonavir
- Covid-19
- Telaprevir