Pressurized DNA state inside herpes capsids-A novel antiviral target

PLoS Pathog. 2020 Jul 23;16(7):e1008604. doi: 10.1371/journal.ppat.1008604. eCollection 2020 Jul.

Abstract

Drug resistance in viruses represents one of the major challenges of healthcare. As part of an effort to provide a treatment that avoids the possibility of drug resistance, we discovered a novel mechanism of action (MOA) and specific compounds to treat all nine human herpesviruses and animal herpesviruses. The novel MOA targets the pressurized genome state in a viral capsid, "turns off" capsid pressure, and blocks viral genome ejection into a cell nucleus, preventing viral replication. This work serves as a proof-of-concept to demonstrate the feasibility of a new antiviral target-suppressing pressure-driven viral genome ejection-that is likely impervious to developing drug resistance. This pivotal finding presents a platform for discovery of a new class of broad-spectrum treatments for herpesviruses and other viral infections with genome-pressure-dependent replication. A biophysical approach to antiviral treatment such as this is also a vital strategy to prevent the spread of emerging viruses where vaccine development is challenged by high mutation rates or other evasion mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Capsid / drug effects*
  • Capsid / physiology
  • Chlorocebus aethiops
  • DNA, Viral / drug effects*
  • DNA, Viral / physiology
  • Herpesviridae / drug effects*
  • Herpesviridae / physiology
  • Herpesviridae Infections*
  • Humans
  • Mice
  • Proof of Concept Study
  • Rats
  • Vero Cells
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • DNA, Viral

Grant support

This work was supported by the National Science Foundation CHE-1744061 (AE), the Swedish Research Council grants (VR) 621-2014-5537 and 349- 2014-3962 (AE), and Mats Paulsson Foundation to AE. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.