New chemotypes to fight HCV infection: discovery of selective inhibitors of HCV replication with pyrazolobenzothiazine scaffold

Hepatitis C virus (HCV) is the major causative agent of acute and chronic liver diseases. Nearly 200 million people worldwide, including 1,5-2 million in Italy,1 are chronically infected with HCV. In the developed world, HCV accounts for two-thirds of all cases of liver cancer and transplants. With the approval in 2011 of the NS3/4A protease inhibitors boceprevir (VictrelisTM) and telaprevir (IncivekTM), direct-acting antivirals (DAAs) have begun to revolutionize HCV treatment.2 Although the addition of telaprevir or bocepevir to pegylated interferon α and ribavirin (pIFNα/RBV) may improve cure rates and shorten the treatment duration of the ‘‘old’’ standard of care, this triple therapy will not be suitable for patients intolerant to pIFNα or RBV. The efficacy of this triple therapy will also certainly be attenuated in pIFNα/RBV nonresponders. Thus, there is an important need for the identification of new potent anti-HCV agents. One of the main targets for the development of DAAs is the viral protein NS5B, a key enzyme in the virus replication cycle having RNA-dependent RNA polymerase activity, a functionality that is not present in human cells. The NS5B polymerase offers a wide range of possibilities for the discovery of new molecular entities, containing one active site and at least five allosteric druggable sites.3