Viruses harness YxxØ motif to interact with host AP2M1 for replication: A vulnerable broad-spectrum antiviral target

Abstract

Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here we discovered a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-Amylcinnamoyl)anthranilic acid (ACA) was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAV), zika virus (ZIKV), human immunodeficiency virus and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein as well as diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral-target.

Development of Three-Dimensional Human Intestinal Organoids as a Physiologically Relevant Model for Characterizing the Viral Replication Kinetics and Antiviral Susceptibility of Enteroviruses

“…Viral load reduction assay was performed to evaluate the antiviral activity of ITZ against EV-A71 infection as previously described with modifications [ 19 , 20 , 21 , 22 ]. Briefly, EV-A71-infected RD cells (MOI = 0.01), Caco-2 cells (MOI = 0.05), and organoids (MOI = 0.05) were treated with different concentrations of ITZ or 0.5% DMSO.…”

In silico structure-based discovery of a SARS-CoV-2 main protease inhibitor

“…One TCID 50 was interpreted as the amount of virus that causes cytopathic effects in 50% of inoculated wells. All experiments with live SARS-CoV-2 was conducted in the Biosafety Level 3 facility of The University of Hong Kong [31][32][33].…”

“…Mounting was performed with the Diamond Prolong Antifade mountant from Thermo Fisher Scientific. Imaging was taken and processed as we previously described [46].…”

Coronaviruses exploit a host cysteine-aspartic protease for efficient replication

“…SARS-CoV-2 HKU-001a was isolated from a nasopharyngeal aspirate specimen taken from a laboratory-confirmed COVID-19 patient in Hong Kong 35 . SARS-CoV-1 GZ50, HCoV-229E, HCoV-OC43, enterovirus A71, and influenza A virus strain A/Hong Kong/415742/2009(H1N1)pdm09 were archived clinical isolates at Department of Microbiology, HKU 39,40 . All infectious experiments involving MERS-CoV, SARS-CoV-2 and SARS-CoV-1 followed the approved standard operating procedures of the Biosafety Level 3 facility at the Department of Microbiology, HKU.…”