bHepatitis C virus (HCV), a member of the Flaviviridae family, affects approximately 3% of the world's population and is becoming the leading cause of liver disease in the world. Therefore, the development of novel or more effective treatment strategies to treat chronic HCV infection is urgently needed. In our previous study, we identified a potential HCV NS5A inhibitor, BP008. After further systemic optimization, we discovered a more potent HCV inhibitor, DBPR110. DBPR110 reduced the reporter expression of the HCV1b replicon with a 50% effective concentration (EC 50 ) and a selective index value of 3.9 ؎ 0.9 pM and >12,800,000, respectively. DBPR110 reduced HCV2a replicon activity with an EC 50 and a selective index value of 228.8 ؎ 98.4 pM and >173,130, respectively. Sequencing analyses of several individual clones derived from the DBPR110-resistant RNAs purified from cells harboring genotype 1b and 2a HCV replicons revealed that amino acid substitutions mainly within the N-terminal region (domain I) of NS5A were associated with decreased inhibitor susceptibility. P58L/T and Y93H/N in genotype 1b and T24A, P58L, and Y93H in the genotype 2a replicon were the key substitutions for resistance selection. In the 1b replicon, V153M, M202L, and M265V play a compensatory role in replication and drug resistance. Moreover, DBPR110 displayed synergistic effects with alpha interferon (IFN-␣), an NS3 protease inhibitor, and an NS5B polymerase inhibitor. In summary, our results present an effective small-molecule inhibitor, DBPR110, that potentially targets HCV NS5A. DBPR110 could be part of a more effective therapeutic strategy for HCV in the future. Hepatitis C virus (HCV) is a small enveloped RNA virus that affects nearly 170 million individuals worldwide, making it a leading cause of hepatitis C and liver disease (1). HCV infection is responsible for the development of severe chronic liver disease and cirrhosis and associated complications, including liver failure, portal hypertension, and hepatocellular carcinoma (2). The main goals of chronic HCV therapy are to eradicate the virus and prevent these potentially life-threatening complications. The mainstays of chronic HCV therapy are PEGylated alpha interferon (IFN-␣) and ribavirin, but these compounds are poorly tolerated and may eventually lead to a suboptimal response rate and a high incidence of adverse effects, including flu-like symptoms, depression, and anemia (3, 4). The chances of sustained viral clearance are only 40 to 50% for genotype 1 infection, which is the predominant genotype in worldwide populations. Therefore, the development of specific antiviral therapies for hepatitis C with improved efficacy and better tolerance is a major public health objective that is urgently important.HCV is a positive-strand RNA virus that has been classified as the sole member of the Hepacivirus genus within the Flaviviridae family. The HCV genome consists of a single strand of RNA that is approximately 9.6 kb long, with a large open reading frame encoding a polyprotein of ...

Hepatitis C virus (HCV) is a global health problem, affecting approximately 3% of the world's population. The standard treatment for HCV infection is often poorly tolerated and ineffective. Therefore, the development of novel or more effective treatment strategies to treat chronic HCV infection is urgently needed. In this report, BP008, a potent small-molecule inhibitor of HCV replication, was developed from a class of compounds with thiazol core structures by means of utilizing a cell-based HCV replicon system. The compound reduced the reporter expression of the HCV1b replicon with a 50% effective concentration (EC 50 ) and selective index value of 4.1 ؎ 0.7 nM and >12,195, respectively. Sequencing analyses of several individual clones derived from BP008-resistant RNAs purified from cells harboring HCV1b replicon revealed that amino acid substitutions mainly within the N-terminal region (domain I) of NS5A were associated with decreased inhibitor susceptibility. Q24L, P58S, and Y93H are the key substitutions for resistance selection; F149L and V153M play the compensatory role in the replication and drug resistance processes. Moreover, BP008 displayed synergistic effects with alpha interferon (IFN-␣), NS3 protease inhibitor, and NS5B polymerase inhibitor, as well as good oral bioavailability in SD rats and favorable exposure in rat liver. In summary, our results pointed to an effective small-molecule inhibitor, BP008, that potentially targets HCV NS5A. BP008 can be considered a part of a more effective therapeutic strategy for HCV in the future.

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