Identification of human immunodeficiency virus type-1 Gag-TSG101 interaction inhibitors by high-throughput screening

Biochem Biophys Res Commun. 2018 Sep 18;503(4):2970-2976. doi: 10.1016/j.bbrc.2018.08.079. Epub 2018 Aug 17.

Abstract

The interaction between viral protein Gag and cellular protein tumor susceptibility gene 101 (TSG101) is a crucial step in the HIV-1 replication cycle. This interaction initiates the viral assembly/budding via the cellular endosomal sorting complexes required for transport (ESCRT) pathway, making it a potential target for antiviral therapy. Here we developed a simple, robust, and reliable high-throughput screening (HTS) system based on enzyme-linked immunosorbent assay (ELISA) to identify compounds that inhibit HIV-1 replication by targeting Gag-TSG101 interaction. Through screening of the 9600-compound library using the established HTS system, several hit compounds, which inhibited Gag-TSG101 interaction, were identified. Subsequent assays revealed two hit compounds, HSM-9 and HSM-10, which have antiviral activity against CD4+ T cell-tropic NL4-3 and macrophage-tropic JR-CSF HIV-1 strains. These results suggest that our established HTS system is an indispensable tool for the identification of HIV-1 Gag-TSG101 interaction inhibitors.

Keywords: ELISA; Gag-TSG101 interaction inhibitors; HIV-1 Gag; HIV-1 inhibitor; High-throughput screening; TSG101.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / metabolism*
  • Drug Evaluation, Preclinical / methods
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • HIV-1*
  • Humans
  • Protein Binding / drug effects
  • Transcription Factors / metabolism*
  • Virus Replication / drug effects
  • gag Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • DNA-Binding Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Transcription Factors
  • Tsg101 protein
  • gag Gene Products, Human Immunodeficiency Virus