NSC23766 and Ehop016 Suppress Herpes Simplex Virus-1 Replication by Inhibiting Rac1 Activity

Biol Pharm Bull. 2021 Sep 1;44(9):1263-1271. doi: 10.1248/bpb.b21-00054. Epub 2021 Jun 23.

Abstract

Herpes simplex virus-1 (HSV-1) infection of the eyes leads to herpes simplex virus keratitis (HSK), the main cause of infectious blindness in the world. As the current therapeutics for HSV-1 infection are rather limited and prolonged use of acyclovir (ACV)/ganciclovir (GCV) and in immunocompromised patients lead to the rise of drug resistant mutants, it underlines the urgent need for new antiviral agents with distinct mechanisms. Our study attempted to establish ras-related C3 botulinum toxin substrate 1 (Rac1) as a new therapeutic target for HSV-1 infection by using Rac1-specific inhibitors to evaluate the in vitro inhibition of virus growth. Our results showed that increased Rac1 activity facilitated HSV-1 replication and inhibition of Rac1 activity by NSC23766 and Ehop016 significantly reduced HSV-1 replication. Thus, we identified NSC23766 and Ehop016 as possessing potent anti-HSV-1 activities by suppressing the Rac1 activity, suggesting that Rac1 is a potential target for treating HSV-1-related diseases.

Keywords: Ehop016; NSC23766; herpes simplex virus-1 infection; ras-related C3 botulinum toxin substrate 1 activity.

MeSH terms

  • Aminoquinolines / pharmacology*
  • Aminoquinolines / therapeutic use
  • Animals
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Carbazoles / pharmacology*
  • Carbazoles / therapeutic use
  • Chlorocebus aethiops
  • Drug Evaluation, Preclinical
  • HeLa Cells
  • Herpes Simplex / drug therapy*
  • Herpes Simplex / virology
  • Herpesvirus 1, Human / drug effects
  • Herpesvirus 1, Human / physiology
  • Humans
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Vero Cells
  • Virus Replication / drug effects
  • rac1 GTP-Binding Protein / antagonists & inhibitors*
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Aminoquinolines
  • Antiviral Agents
  • Carbazoles
  • N4-(9-ethyl-9H-carbazol-3-yl)-N2-(3-morpholin-4-ylpropyl)-pyrimidine-2,4-diamine
  • NSC 23766
  • Pyrimidines
  • RAC1 protein, human
  • rac1 GTP-Binding Protein