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

Sci Adv. 2020 Aug 28;6(35):eaba7910. doi: 10.1126/sciadv.aba7910. eCollection 2020 Aug.

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 found 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 (IAVs), 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 and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Antiviral Agents / pharmacology*
  • Betacoronavirus / drug effects
  • Binding Sites / genetics
  • COVID-19
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Cinnamates / pharmacology*
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / pathology
  • Dogs
  • HEK293 Cells
  • HIV Infections / drug therapy*
  • HIV Infections / pathology
  • HIV-1 / drug effects
  • Host-Pathogen Interactions / drug effects
  • Humans
  • Influenza A virus / drug effects
  • Influenza, Human / drug therapy*
  • Influenza, Human / pathology
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle East Respiratory Syndrome Coronavirus / drug effects
  • Pandemics
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / pathology
  • Protein Binding / genetics
  • Protein Transport / drug effects
  • RNA, Viral / genetics
  • Receptor, Interferon alpha-beta / genetics
  • SARS-CoV-2
  • Transforming Growth Factor beta1 / metabolism
  • Vero Cells
  • Virus Replication / drug effects
  • Zika Virus / drug effects
  • Zika Virus Infection / pathology
  • ortho-Aminobenzoates / pharmacology*

Substances

  • AP2M1 protein, human
  • Adaptor Proteins, Vesicular Transport
  • Antiviral Agents
  • Cinnamates
  • RNA, Viral
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • ortho-Aminobenzoates
  • 4-amylcinnamoylanthranilic acid
  • Receptor, Interferon alpha-beta

Associated data

  • Dryad/10.5061/dryad.4qrfj6q79