Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy

Abstract

29 Brenner Building, St James' University Hospital, Leeds LS9 7TF. Telephone: (+44)113 30 3438637 31 Dr Richard Foster (R.Foster@leeds.ac.uk), School of Chemistry, Faculty of Maths 32 and Physical Sciences and Astbury Centre for Structural Molecular Biology, University of 33 Leeds, Leeds, LS2 9JT. Telephone: (+44)113 3435759 34 35 † Current AddressAbstract 46 Since the 1960s, a single class of agent has been licensed targeting virus-encoded ion 47 channels, or "viroporins", contrasting the success of channel blocking drugs in other 48 areas of medicine. Although resistance arose to these prototypic adamantane inhibitors 49 of the influenza A virus (IAV) M2 proton channel, a growing number of clinically and 50 economically important viruses are now recognised to encode essential viroporins 51 providing potential targets for modern drug discovery. 52 We describe the first rationally designed viroporin inhibitor with a comprehensive 53 structure-activity relationship (SAR). This step-change in understanding not only 54 revealed a second biological function for the p7 viroporin from hepatitis C virus 55 (HCV) during virus entry, but also enabled the synthesis of a labelled tool compound 56 that retained biological activity. Hence, p7 inhibitors (p7i) represent a unique class of 57 HCV antiviral targeting both the spread and establishment of infection, as well as a 58 precedent for future viroporin-targeted drug discovery. 59 60 149 words 61 62 63 MAIN TEXT 64 65 66 Hepatitis C virus (HCV) represents a global clinical challenge as a major cause of chronic 67 liver disease, with severe complications including cirrhosis, liver failure and primary liver 68 cancers (hepatocellular-and intrahepatic cholangio-carcinomas (HCC, iCCA)). Acute 69 infection is predominantly asymptomatic which, combined with limited awareness and 70 population screening, means that liver disease is often advanced upon diagnosis. WHO 71 estimates put the total number of deaths due to HCV infection in 2015 at more than 400 72 000, with ~1.75 million new infections annually. 73 HCV antiviral therapy, originally comprising recombinant type 1 interferon (IFN) 74 combined with the guanosine analogue ribavirin, has been revolutionised by new direct-75 acting antivirals (DAA). DAA are an unprecedented drug development success, capable of 76 achieving high rates of cure with favourable toxicity profiles enabling their use in patients 77 with advanced disease(1). Current DAA target three proteins within the viral replicase 78 (NS3/4A protease, NS5A and the NS5B RNA-dependent RNA Polymerase (RdRP)), with 79 drug combinations available for treating each of the eight viral genotypes. 80 However, the absence of an HCV vaccine, or other means of prophylaxis, makes DAA-81 based eradication strategies proposed for ~71 million chronically infected individuals 82 immensely challenging. DAA availability remains limited by cost, coincident with poor 83diagnostic rates and rapidly increasing burden in low/middle income countries (LMIC). 84 Resistant viral ...