Specifically targeted antiviral therapy for hepatitis C virus

Abstract

Hepatitis C virus (HCV) infection affects 180 million people worldwide with the predominant prevalence being infection with genotype 1, followed by genotypes 2 and 3. Standard anti-HCV therapy currently aims to enhance natural immune responses to the virus, whereas new therapeutic concepts directly target HCV RNA and viral enzymes or influence host-virus interactions. Novel treatment options now in development are focused on inhibitors of HCVspecific enzymes, NS3 protease and NS5B polymerase. These agents acting in concert represent the concept of specifically targeted antiviral therapy for HCV (STAT-C). STAT-C is an attractive strategy in which the main goal is to increase the effectiveness of antiviral responses across all genotypes, with shorter treatment duration and better tolerability. However, the emergence of resistant mutations that limit the use of these compounds in monotherapy complicates the regimens. Thus, a predictable scenario for HCV treatment in the future will be combinations of drugs with distinct mechanisms of action. For now, it seems that interferon will remain a fundamental component of any new anti-HCV therapeutic regimens in the near future; therefore, there is pressure to develop forms of interferon that are more effective, less toxic, and more convenient than pegylated interferon.

Natural products as promising drug candidates for the treatment of hepatitis B and C

“…The combination of IFN-α and ribavirin is only effective in approximately 50% of patients. Individuals infected with genotypes 2 and 3 achieve sustained viral response (SVR) after treatment in approximately 90% of cases, but those infected with genotype 1 (mostly in Europe and the USA) achieve SVR in only 33%-42% of cases [10] . Nearly all treated patients suffer from side-effects.…”

Direct acting anti-hepatitis C virus drugs: Clinical pharmacology and future direction

“…It affects approximately 180 million people worldwide; about 3% of the world population. [1] Three to four million persons are newly infected each year, with the predominant prevalence being infection with genotype 1, followed by genotypes 2 and 3. The other genotypes, 4, 5, and 6, have specific geographical distribution.…”

Resistance Analysis of the Hepatitis C Virus NS5A Inhibitor BMS-790052 in an In Vitro Replicon System

“…For genotypes 1a and 1b, accounting for ϳ60% of global infections, long-term efficacy or a sustained virological response is achieved in only ϳ50% of chronically infected individuals (3, 24). An increasing number of small-molecule inhibitors targeting specific viral proteins are entering into clinical evaluation (1,25,27,30,38). Collectively, these inhibitors are often referred to as direct-acting antiviral agents (DAA).…”

“…Collectively, these inhibitors are often referred to as direct-acting antiviral agents (DAA). The most advanced of these inhibitors target enzymatic activities of the HCV nonstructural proteins NS3 (serine protease) and NS5B (RNA-dependent RNA polymerase) (1,27). We recently described a potent inhibitor of HCV RNA replication, BMS-790052, that targets HCV NS5A (6).…”