Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity

Bioorg Med Chem Lett. 2015 Aug 1;25(15):2923-6. doi: 10.1016/j.bmcl.2015.05.039. Epub 2015 May 23.

Abstract

A series of doubly flexible nucleoside analogues were designed based on the acyclic sugar scaffold of acyclovir and the flex-base moiety found in the fleximers. The target compounds were evaluated for their antiviral potential and found to inhibit several coronaviruses. Significantly, compound 2 displayed selective antiviral activity (CC50 >3× EC50) towards human coronavirus (HCoV)-NL63 and Middle East respiratory syndrome-coronavirus, but not severe acute respiratory syndrome-coronavirus. In the case of HCoV-NL63 the activity was highly promising with an EC50 <10 μM and a CC50 >100 μM. As such, these doubly flexible nucleoside analogues are viewed as a novel new class of drug candidates with potential for potent inhibition of coronaviruses.

Keywords: Acyclovir; Antiviral; Coronaviruses; Fleximers; MERS-CoV; Nucleosides; SARS.

Publication types

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

MeSH terms

  • Acyclovir / analogs & derivatives*
  • Acyclovir / pharmacology*
  • Animals
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Chlorocebus aethiops
  • Coronavirus / drug effects*
  • Coronavirus / physiology
  • Coronavirus Infections / drug therapy*
  • Coronavirus NL63, Human / drug effects
  • Coronavirus NL63, Human / physiology
  • Drug Design
  • Humans
  • Middle East Respiratory Syndrome Coronavirus / drug effects
  • Middle East Respiratory Syndrome Coronavirus / physiology
  • Nucleosides / chemistry
  • Nucleosides / pharmacology
  • Severe acute respiratory syndrome-related coronavirus / drug effects
  • Severe acute respiratory syndrome-related coronavirus / physiology
  • Vero Cells
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Nucleosides
  • Acyclovir