PT  - JOURNAL ARTICLE
AU  - Joseph Shaw
AU  - Rajendra Gosein
AU  - Monoj Mon Kalita
AU  - Jayakanth Kankanala
AU  - D. Ram Mahato
AU  - Toshana Foster
AU  - Claire Scott
AU  - Matthew Bentham
AU  - Laura Wetherill
AU  - Abigail Bloy
AU  - Adel Samson
AU  - Mark Harris
AU  - Andrew Macdonald
AU  - David Rowlands
AU  - Jamel Mankouri
AU  - Wolfgang Fischer
AU  - Richard Foster
AU  - Stephen Griffin
TI  - Targeting hepatitis C virus p7 channel activity reveals prospect for bimodal antiviral prophylaxis
AID  - 10.1101/374793
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 374793
4099  - http://biorxiv.org/content/early/2018/07/23/374793.short
4100  - http://biorxiv.org/content/early/2018/07/23/374793.full
AB  - Despite the success of channel blocking drugs, only a single class of agent targeting virus-encoded ion channels, or “viroporins”, has been licensed since the 1960s1–3. Although resistance to adamantane inhibitors of the influenza A virus (IAV) M2 proton channel arose, a growing number of clinically important and emerging viruses encode essential viroporins4–6, providing targets for new interventions. Here, we describe rational antiviral development targeting the p7 viroporin from hepatitis C virus (HCV) and reveal a second biological function for its channel activity. Lead-like oxindole inhibitors potently blocked p7 function during virion secretion, but were also active during virus entry, supporting the presence of channel complexes within infectious HCV particles. Hence, p7 inhibitors (p7i) represent dual-acting HCV antivirals targeting both the spread and establishment of infection, which may be relevant to future antiviral prophylaxis.