Discovery of dihydroxyindole-2-carboxylic acid derivatives as dual allosteric HIV-1 Integrase and Reverse Transcriptase associated Ribonuclease H inhibitors

Antiviral Res. 2020 Feb;174:104671. doi: 10.1016/j.antiviral.2019.104671. Epub 2019 Dec 5.


The management of Human Immunodeficiency Virus type 1 (HIV-1) infection requires life-long treatment that is associated with chronic toxicity and possible selection of drug-resistant strains. A new opportunity for drug intervention is offered by antivirals that act as allosteric inhibitors targeting two viral functions (dual inhibitors). In this work, we investigated the effects of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derivatives on both HIV-1 Integrase (IN) and Reverse Transcriptase associated Ribonuclease H (RNase H) activities. Among the tested compounds, the dihydroxyindole-carboxamide 5 was able to inhibit in the low micromolar range (1-18 μM) multiple functions of IN, including functional IN-IN interactions, IN-LEDGF/p75 binding and IN catalytic activity. Docking and site-directed mutagenesis studies have suggested that compound 5 binds to a previously described HIV-1 IN allosteric pocket. These observations indicate that 5 is structurally and mechanistically distinct from the published allosteric HIV-1 IN inhibitors. Moreover, compound 5 also inhibited HIV-1 RNase H function, classifying this molecule as a dual HIV-1 IN and RNase H inhibitor able to impair the HIV-1 virus replication in cell culture. Overall, we identified a new scaffold as a suitable platform for the development of novel dual HIV-1 inhibitors.

Keywords: Dihydroxyindole-2-carboxylic acids; HIV dual inhibitors; IN; IN-LEDGF binding inhibitors; RNase H; Sucrose binding site.

Publication types

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

MeSH terms

  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Cell Line
  • Drug Discovery
  • HIV Infections / virology
  • HIV Integrase / metabolism
  • HIV Integrase Inhibitors / chemistry
  • HIV Integrase Inhibitors / pharmacology*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Ribonuclease H, Human Immunodeficiency Virus / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Carboxylic Acids
  • HIV Integrase Inhibitors
  • HIV Integrase
  • HIV Reverse Transcriptase
  • Ribonuclease H, Human Immunodeficiency Virus
  • p31 integrase protein, Human immunodeficiency virus 1