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

Abstract

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.

Dissociation of a MAVS/IPS-1/VISA/Cardif-IKKε Molecular Complex from the Mitochondrial Outer Membrane by Hepatitis C Virus NS3-4A Proteolytic Cleavage

“…The essential localization of this CARD domain-containing adapter to the mitochondria furthermore suggests an important function in the coordination of the innate immune and apoptotic responses. The implications for the study of HCV pathogenesis are particularly profound, given that experimental compounds, such as BILN2061 and VX-950, that block NS3-4A protease activity may accomplish two goals: inhibition of virus multiplication and processing and restoration of the early innate immune response that is critical to the development of a robust adaptive response in patients (9,22).…”

Development of novel agents for the treatment of chronic hepatitis C infection: Summary of the FDA Antiviral Products Advisory Committee recommendations

“…Such resistance is well established in other viral diseases including HIV and HBV, and early data on HCV-active agents suggests that monotherapy has the potential to select early for key resistance mutations. 7 Regarding induction therapy, the committee agreed that monotherapy may be a feasible option if used as the first element of a sequential therapy plan. The rationale for this approach is that an induction phase to quickly lower the viral load prior to addition or substitution of an IFNbased regimen may enhance response rates and decrease the emergence of drug-resistant variants.…”

“…Both forms of mutation are highly relevant to new drug development, because binding site targeting may be genotype specific and emergence of site polymorphisms may lead to viral escape. 7 Chronic HCV infection leads to development of liver fibrosis in many but not all patients. Variable rates of fibrotic progression are described, and may be influenced by gender, age, and comorbidities including HIV coinfection, alcohol use, and presence of fatty liver (steatosis).…”

Highly sensitive determination of HCV protease inhibitors boceprevir (SCH 503034) and telaprevir (VX 950) in human plasma by LC–MS/MS

“…Specifically Targeted Antiviral Therapy against hepatitis C virus (STAT-C) stands for a new era in the treatment of patients with chronic hepatitis C. Various STAT-C compounds including boceprevir (SCH 503034) and telaprevir (VX 950) have already entered clinical trial phases. These compounds are blocking the NS3/4A protease of the hepatitis C virus which is located in the N-terminal domain of the HCV NS3 protein [3]. The NS3 protease is a serine protease essential for HCV polyprotein processing and therefore viral replication.…”