Synthesis and Biological Evaluation of Heat-Shock Protein 90 Inhibitors: Geldanamycin Derivatives With Broad Antiviral Activities

Antivir Chem Chemother. 2010 Aug 11;20(6):259-68. doi: 10.3851/IMP1631.

Abstract

Background: Previous studies have suggested that geldanamycin (GA) inhibits the replication of several viruses in vitro. Here, we aimed to synthesize and evaluate the antiviral activity of 17-amino-17-demethoxygeldanamycin derivatives.

Methods: A series of 17-substituted and 17-,19-disubstituted GA derivatives were screened for antiviral activities against eight different viral strains, including herpesvirus, hepatitis virus, retrovirus and picornavirus.

Results: Most of the tested compounds showed inhibitory activity against the viruses and showed reduced cytotoxicity in vitro as compared with the parent compound GA. In vivo efficacy evaluation results showed that compound 6 noticeably inhibited duckling hepatitis B virus DNA replication in duckling serum after oral administration. Viral rebound did not occur after termination of the treatment. The modified GA derivatives also showed median lethal dose values that were higher than that of the parent GA in mice intraperitoneally treated with the study compounds.

Conclusions: Targeting heat-shock protein 90 could be a new antiviral approach that is not prone to the development of drug resistance. The 17-amino-17-demethoxygeldanamycin derivatives could be novel agents with potential antiviral activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / toxicity
  • Benzoquinones / chemistry
  • Benzoquinones / pharmacology*
  • Benzoquinones / toxicity
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Ducks
  • Enterovirus B, Human / drug effects*
  • HIV-1 / drug effects*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Hepadnaviridae Infections / drug therapy
  • Hepadnaviridae Infections / virology
  • Hepatitis B Virus, Duck / drug effects
  • Hepatitis B Virus, Duck / physiology
  • Hepatitis Viruses / drug effects*
  • Herpesviridae / drug effects*
  • Humans
  • Lactams, Macrocyclic / chemistry
  • Lactams, Macrocyclic / pharmacology*
  • Lactams, Macrocyclic / toxicity
  • Mice
  • Microbial Sensitivity Tests
  • Vero Cells
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • geldanamycin