Antimicrob Agents Chemother. 2014 Jan;58(1):386-96.

A small-molecule inhibitor of hepatitis C virus infectivity.

Bush CO, Pokrovskii MV, Saito R, Morganelli P, Canales E, Clarke MO, Lazerwith SE, Golde J, Reid BG, Babaoglu K, Pagratis N, Zhong W, Delaney WE 4th, Paulson MS, Beran RK.

Gilead Sciences, Inc., Foster City, California, USA.

 

ABSTRACT:

One of the most challenging goals of hepatitis C virus (HCV) research is to develop well-tolerated regimens with high cure rates across a variety of patient populations. Such a regimen will likely require a combination of at least two distinct direct-acting antivirals (DAAs). Combining two or more DAAs with different resistance profiles increases the number of mutations required for viral breakthrough. Currently, most DAAs inhibit HCV replication. We recently reported that the combination of two distinct classes of HCV inhibitors, entry inhibitors and replication inhibitors, prolonged reductions in extracellular HCV in persistently infected cells. We therefore sought to identify new inhibitors targeting aspects of the HCV replication cycle other than RNA replication. We report here the discovery of the first small-molecule HCV infectivity inhibitor, GS-563253, also called HCV infectivity inhibitor 1 (HCV II-1). HCV II-1 is a substituted tetrahydroquinoline that selectively inhibits genotype 1 and 2 HCVs with low-nanomolar 50% effective concentrations. It was identified through a high-throughput screen and subsequent chemical optimization. HCV II-1 only permits the production and release of noninfectious HCV particles from cells. Moreover, infectious HCV is rapidly inactivated in its presence. HCV II-1 resistance mutations map to HCV E2. In addition, HCV-II prevents HCV endosomal fusion, suggesting that it either locks the viral envelope in its prefusion state or promotes a viral envelope conformation change incapable of fusion. Importantly, the discovery of HCV II-1 opens up a new class of HCV inhibitors that prolong viral suppression by HCV replication inhibitors in persistently infected cell cultures.

PMID: 24165192

 

SUPPLEMENT:

Well-tolerated, simple regimens to cure chronic hepatitis C virus (HCV) infection are needed to address the 170 million infected patients worldwide. A well-tolerated curative regimen will likely require a combination of at least two distinct direct-acting antivirals. Combining two or more direct-acting antivirals with different resistance profiles increases the number of resistance mutations required for viral rebound. There are multiple HCV replication inhibitors already approved or in advanced clinical trials although many are only able to treat genotype 1 HCV. Thus, we sought new inhibitors targeting other aspects of the HCV lifecycle as potential complementary treatment agents.

Here we report the discovery of the first small-molecule HCV infectivity inhibitor, HCV Infectivity Inhibitor-1 (HCV II-1). HCV II-1 exhibits potent and selective inhibition of genotypes 1 and 2 HCV. It was found through a high-throughput screen and subsequent chemical optimization. HCV II-1 only permits the production and release of non-infectious HCV from cells. Moreover, infectious HCV is rapidly inactivated in its presence. Importantly, combination of HCV II-1 with HCV replication inhibitors prolonged suppression of virus production by persistently-infected cell cultures suggesting that this new class of HCV inhibitors could be a valuable addition to a replication inhibitor treatment regimen.

 

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