RNA-Dependent RNA Polymerase as a Target for COVID-19 Drug Discovery

SLAS Discov. 2020 Dec;25(10):1141-1151. doi: 10.1177/2472555220942123. Epub 2020 Jul 13.

Abstract

COVID-19 respiratory disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly become a global health issue since it emerged in December 2019. While great global efforts are underway to develop vaccines and to discover or repurpose therapeutic agents for this disease, as of this writing only the nucleoside drug remdesivir has been approved under Emergency Use Authorization to treat COVID-19. The RNA-dependent RNA polymerase (RdRP), a viral enzyme for viral RNA replication in host cells, is one of the most intriguing and promising drug targets for SARS-CoV-2 drug development. Because RdRP is a viral enzyme with no host cell homologs, selective SARS-CoV-2 RdRP inhibitors can be developed that have improved potency and fewer off-target effects against human host proteins and thus are safer and more effective therapeutics for treating COVID-19. This review focuses on biochemical enzyme and cell-based assays for RdRPs that could be used in high-throughput screening to discover new and repurposed drugs against SARS-CoV-2.

Keywords: COVID-19; RNA-dependent RNA polymerase; RdRP assays; RdRP inhibitors; SARS-CoV-2; coronavirus infection.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives
  • Adenosine Monophosphate / chemistry
  • Adenosine Monophosphate / pharmacology
  • Alanine / analogs & derivatives
  • Alanine / chemistry
  • Alanine / pharmacology
  • Amides / chemistry
  • Amides / pharmacology
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • COVID-19 / drug therapy*
  • Drug Discovery
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays / methods
  • Humans
  • Middle East Respiratory Syndrome Coronavirus / chemistry
  • Middle East Respiratory Syndrome Coronavirus / drug effects
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / chemistry
  • RNA-Dependent RNA Polymerase / metabolism
  • SARS-CoV-2 / chemistry
  • SARS-CoV-2 / drug effects
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / chemistry
  • Viral Proteins / metabolism
  • Virus Replication / drug effects

Substances

  • Amides
  • Antiviral Agents
  • Enzyme Inhibitors
  • Pyrazines
  • Viral Proteins
  • remdesivir
  • Adenosine Monophosphate
  • RNA-Dependent RNA Polymerase
  • favipiravir
  • Alanine

Supplementary concepts

  • COVID-19 drug treatment