SRX3177, a CDK4/6-PI3K-BET inhibitor, in combination with an RdRp inhibitor, Molnupiravir, or an entry inhibitor MU-UNMC-2, has potent antiviral activity against the Omicron variant of SARS-CoV-2

Antiviral Res. 2024 Jul:227:105904. doi: 10.1016/j.antiviral.2024.105904. Epub 2024 May 8.

Abstract

Despite considerable progress in developing vaccines and antivirals to combat COVID-19, the rapid mutations of the SARS-CoV-2 genome have limited the durability and efficacy of the current vaccines and therapeutic interventions. Hence, it necessitates the development of novel therapeutic approaches or repurposing existing drugs that target either viral life cycle, host factors, or both. Here, we report that SRX3177, a potent triple-activity CDK4/6-PI3K-BET inhibitor, blocks replication of the SARS-CoV-2 Omicron variant with IC50 values at sub-micromolar concentrations without any impact on the cell proliferation of Calu-3 cells at and below its IC50 concentration. When SRX3177 is combined with EIDD-1931 (active moiety of a small-molecule prodrug Molnupiravir) or MU-UNMC-2 (a SARS-CoV-2 entry inhibitor) at a fixed doses matrix, a synergistic effect was observed, leading to the significant reduction in the dose of the individual compounds to achieve similar inhibition of SARS-CoV-2 replication. Herein, we report that the combination of SRX3177/MPV or SRX3177/UM-UNMC-2 has the potential for further development as a combinational therapy against SARS-CoV-2 and in any future outbreak of beta coronavirus.

Keywords: Combinatorial; Entry inhibitor; MU-UNMC-2; Omicron; RdRp inhibitor; SARS-CoV-2; SRX3177; Triple inhibitor.

Publication types

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

MeSH terms

  • Animals
  • Antiviral Agents* / pharmacology
  • COVID-19 / virology
  • COVID-19 Drug Treatment*
  • Cell Line
  • Chlorocebus aethiops
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cytidine / analogs & derivatives
  • Cytidine / pharmacology
  • Drug Synergism
  • Humans
  • Hydroxylamines / pharmacology
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • SARS-CoV-2* / drug effects
  • Vero Cells
  • Virus Internalization / drug effects
  • Virus Replication* / drug effects

Substances

  • Antiviral Agents
  • molnupiravir
  • Cytidine
  • Hydroxylamines
  • Phosphoinositide-3 Kinase Inhibitors
  • Leucine
  • Cyclin-Dependent Kinase 4

Supplementary concepts

  • SARS-CoV-2 variants