Discovery of Novel Urea-Based Hepatitis C Protease Inhibitors with High Potency against Protease-Inhibitor-Resistant Mutants

2012 ◽  
Vol 55 (7) ◽  
pp. 3021-3026 ◽  
Author(s):  
Wieslaw M. Kazmierski ◽  
Robert Hamatake ◽  
Maosheng Duan ◽  
Lois L. Wright ◽  
Gary K. Smith ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
High Potency ◽  
Resistant Mutants

scholarly journals Computer-aided identification of a series of novel ligands showing high potency as hepatitis C virus NS3/4A protease inhibitors

2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Stephen Ejeh ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Stephen E. Abechi
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Binding Energy ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Antiviral Agents ◽  
High Potency ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

Abstract Background Hepatitis C virus (HCV) is a global medical condition that causes several life-threatening chronic diseases in the liver. The conventional interferon-free treatment regimens are currently in use by a blend of direct-acting antiviral agents (DAAs) aiming at the viral NS3 protease. However, major concerns may be the issue of DAA-resistant HCV strains and the limited availability to the DAAs due to their high price. Due to this crisis, the developments of a new molecule with high potency as an NS3/4A protease inhibitor of the hepatitis-C virus remain a high priority for medical research. This study aimed to use in-silico methods to identify high potent molecule as an NS3/4A protease inhibitor and investigating the binding energy of the identified molecule in comparison with approved direct-acting antiviral agents (Telaprevir, Simeprevir, and Voxilaprevir) through molecular docking. Results The model obtained by in-silico method have the following statistical records, coefficient of determination (r2) of 0.7704, cross-validation (q2LOO = 0.6914); external test set (r2(pred) = 0.7049) and Y-randomization assessment (cR2p = 0.7025). The results from the model were used to identify 12 new potential human HCV NS3/4A protease inhibitors, and it was observed that the identified molecule is well-fixed when docked with the receptor and was found to have the lowest binding energy of − 10.7, compared to approved direct-acting antiviral agents (Telaprevir, Simeprevir, and Voxilaprevir) with − 9.5, − 10.0, − 10.5 binding energy, respectively. Conclusion The binding affinity (− 10.7) of the newly identified molecule docked with 3D structures of HCV NS3/4a protease/helicase (PDB ID: 4A92) was found to be better than that of Telaprevir, Simeprevir, and Voxilaprevir (approved direct-acting antiviral agents) which are − 9.5, − 10.0, and − 10.5, respectively. Hence, a novel molecule was identified showing high potency as HCV NS3/4a protease inhibitors.

scholarly journals In VitroResistance Profile of the Hepatitis C Virus NS3 Protease Inhibitor BI 201335

2011 ◽  
Vol 56 (1) ◽  
pp. 569-572 ◽  
Author(s):  
Lisette Lagacé ◽  
Peter W. White ◽  
Christiane Bousquet ◽  
Nathalie Dansereau ◽  
Florence Dô ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Alpha Interferon ◽  
Phenotypic Characterization ◽  
Genotype 1A ◽  
Ns3 Protease

ABSTRACTThein vitroresistance profile of BI 201335 was evaluated through selection and characterization of variants in genotype 1a (GT 1a) and genotype 1b (GT 1b) replicons. NS3 R155K and D168V were the most frequently observed resistant variants. Phenotypic characterization of the mutants revealed shifts in sensitivity specific to BI 201335 that did not alter susceptibility to alpha interferon. In contrast to macrocyclic and covalent protease inhibitors, changes at V36, T54, F43, and Q80 did not confer resistance to BI 201335.

scholarly journals The Hepatitis C Virus Replicon Presents a Higher Barrier to Resistance to Nucleoside Analogs than to Nonnucleoside Polymerase or Protease Inhibitors

2008 ◽  
Vol 52 (5) ◽  
pp. 1604-1612 ◽  
Author(s):  
Matthew F. McCown ◽  
Sonal Rajyaguru ◽  
Sophie Le Pogam ◽  
Samir Ali ◽  
Wen-Rong Jiang ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Nucleoside Analogs ◽  
Genetic Barrier ◽  
Nonnucleoside Inhibitors ◽  
Nucleoside Inhibitors ◽  
Selection Of ◽  
Selection Of Resistance

ABSTRACT Specific inhibitors of hepatitis C virus (HCV) replication that target the NS3/4A protease (e.g., VX-950) or the NS5B polymerase (e.g., R1479/R1626, PSI-6130/R7128, NM107/NM283, and HCV-796) have advanced into clinical development. Treatment of patients with VX-950 or HCV-796 rapidly selected for drug-resistant variants after a 14-day monotherapy treatment period. However, no viral resistance was identified after monotherapy with R1626 (prodrug of R1479) or NM283 (prodrug of NM107) after 14 days of monotherapy. Based upon the rapid selection of resistance to the protease and nonnucleoside inhibitors during clinical trials and the lack of selection of resistance to the nucleoside inhibitors, we used the replicon system to determine whether nucleoside inhibitors demonstrate a higher genetic barrier to resistance than protease and nonnucleoside inhibitors. Treatment of replicon cells with nucleoside inhibitors at 10 and 15 times the 50% effective concentration resulted in clearance of the replicon, while treatment with a nonnucleoside or protease inhibitor selected resistant colonies. In combination, the presence of a nucleoside inhibitor reduced the frequency of colonies resistant to the other classes of inhibitors. These results indicate that the HCV replicon presents a higher barrier to the selection of resistance to nucleoside inhibitors than to nonnucleoside or protease inhibitors. Furthermore, the combination of a nonnucleoside or protease inhibitor with a nucleoside polymerase inhibitor could have a clear clinical benefit through the delay of resistance emergence.

scholarly journals Pharmacokinetic Interactions Between the Hepatitis C Virus Protease Inhibitor Boceprevir and Ritonavir-Boosted HIV-1 Protease Inhibitors Atazanavir, Darunavir, and Lopinavir

2012 ◽  
Vol 56 (5) ◽  
pp. 718-726 ◽  
Author(s):  
Ellen G. J. Hulskotte ◽  
Hwa-Ping Feng ◽  
Fengjuan Xuan ◽  
Marga G. J. A. van Zutven ◽  
Michelle A. Treitel ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Pharmacokinetic Interactions ◽  
Hiv 1

Cyclic Urea Amides:  HIV-1 Protease Inhibitors with Low Nanomolar Potency against both Wild Type and Protease Inhibitor Resistant Mutants of HIV

1997 ◽  
Vol 40 (2) ◽  
pp. 181-191 ◽  
Author(s):  
Prabhakar K. Jadhav ◽  
Paul Ala ◽  
Francis J. Woerner ◽  
Chong-Hwan Chang ◽  
Sena S. Garber ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Wild Type ◽  
Resistant Mutants ◽  
Hiv 1

Macrocyclic Hepatitis C Virus NS3/4A Protease Inhibitors: An Overview of Medicinal Chemistry

2016 ◽  
Vol 23 (29) ◽  
pp. 3404-3447 ◽  
Author(s):  
Thanigaimalai Pillaiyar ◽  
Vigneshwaran Namasivayam ◽  
Manoj Manickam
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Medicinal Chemistry
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