P1 and P1; Optimization of [3,4]-Bicycloproline P2 Incorporated Tetrapeptidyl &amp;#945;-Ketoamide Based HCV Protease Inhibitors

Chen, Shuhui; Lamar, Jason; Yip, Yvonne Y.; Victor, Frantz; Johnson, Robert B.; Wang, Q. May; Glass, John I.; Heinz, Beverly A.; Colacino, Joseph M.; Guo, Deqi; Tebbe, Mark J.; Munroe, John E.

doi:10.2174/1570180053175115

Cited by 18 publications

(4 citation statements)

References 6 publications

(12 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Efforts were aided early on by the availability of a crystal structure of the enzyme's NS3/4A protease active site (1). Using the crystal structure in conjunction with computer-aided structure design, peptido-mimetic compounds were designed to occupy the enzyme active site, resulting in highly active, selective inhibitors of the HCV NS3/4A serine protease complex (7,9,27).…”

mentioning

confidence: 99%

Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032)

McPhee

Sheaffer

Friborg

et al. 2012

Antimicrob Agents Chemother

177

View full text Add to dashboard Cite

mentioning

confidence: 99%

Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032)

McPhee

Sheaffer

Friborg

et al. 2012

Antimicrob Agents Chemother

177

View full text Add to dashboard Cite

“…The crystal structure of HCV NS3/NS4A serine protease in complex with a noncovalent inhibitor, TMC-435 (PDB entry: 3KEE; genotype 1b) [ 17 ], was used for a docking study. It is the first noncovalent NS3/NS4A protease-inhibitor crystal complex determined at 2.4 Å resolution.…”

Section: Computational and Experimental Methodsmentioning

confidence: 99%

Identification of Novel Small Molecules as Inhibitors of Hepatitis C Virus by Structure-Based Virtual Screening

Liu

et al. 2013

IJMS

View full text Add to dashboard Cite

Hepatitis C virus (HCV) NS3/NS4A serine protease is essential for viral replication, which is regarded as a promising drug target for developing direct-acting anti-HCV agents. In this study, sixteen novel compounds with cell-based HCV replicon activity ranging from 3.0 to 28.2 μM (IC50) were successfully identified by means of structure-based virtual screening. Compound 5 and compound 11, with an IC50 of 3.0 μM and 5.1 μM, respectively, are the two most potent molecules with low cytotoxicity.

show abstract

“…No loss of chiral purity at P1 position was observed during chemical synthesis using the synthetic route outlined in Scheme 8. The structures (including purity of P1 chirality) of all tetrapeptidyl α-ketoamides were confirmed on the basis of their proton NMR and mass spectra analyses [78].…”

Section: Chemical Synthesismentioning

confidence: 96%

Discovery of Small-Molecule Inhibitors of HCV NS3-4A Protease as Potential Therapeutic Agents against HCV Infection

Chen¹,

Tan

2005

CMC

Self Cite

View full text Add to dashboard Cite

Chronic infection with hepatitis C virus (HCV) is associated with liver cirrhosis that often leads to hepatic failure and hepatocellular carcinoma (HCC). HCV infection has become a global health threat and the main cause of adult liver transplants in developed nations. Current approved anti-HCV therapies (interferon and pegylated interferon alone or in combination with ribavirin) are not effective in eliminating the viral infection in a significant population of patients (e.g., those infected with HCV genotype 1). Furthermore, these therapies are plagued with many undesirable side effects. Therefore, the HCV epidemic represents a huge unmet medical need that has triggered intensive research efforts towards the development of more effective drugs. Given its essential role in the process of HCV replication, the viral NS3/4A serine protease is arguably the most thoroughly characterized HCV enzyme and the most intensively pursued anti-HCV target for drug development. This is further fueled by the successful use of small-molecule inhibitors of the human immunodeficiency virus (HIV) viral protease, which have had an impressive effect on HIV-related morbidity and mortality, offering hope that analogous drugs might also have a similar impact against HCV. Here, we review the recent progress and development of small-molecule inhibitors of the HCV NS3/4A protease. In particular, we focus on the discovery of VX-950, the latest HCV NS3-4A protease inhibitor to be advanced to clinical studies. While the challenges of designing potent inhibitors of the viral protease have been solved, as highlighted by BILN 2061 and VX-950, it is still too early to determine whether these efforts will eventually yield promising drug candidates. For the emerging small-molecule HCV inhibitors, viral resistance will likely be a big problem. Thus, combination therapy of different drugs with different targets/mechanisms will be necessary to effectively inhibit HCV replication. It is also hoped that a detail characterization of how the resistance mutations that affect NS3 inhibitor binding may provide useful information for the design of inhibitors with the potential to treat resistant viruses that may arise during chronic HCV infection.

show abstract

P1 and P1; Optimization of [3,4]-Bicycloproline P2 Incorporated Tetrapeptidyl α-Ketoamide Based HCV Protease Inhibitors

Cited by 18 publications

References 6 publications

Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032)

Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032)

Identification of Novel Small Molecules as Inhibitors of Hepatitis C Virus by Structure-Based Virtual Screening

Discovery of Small-Molecule Inhibitors of HCV NS3-4A Protease as Potential Therapeutic Agents against HCV Infection

Contact Info

Product

Resources

About