Publications & Reports

Oxazole-benzenesulfonamide derivatives inhibit HIV-1 reverse transcriptase interaction with cellular eEF1A and reduce viral replication.

Rawle DJ, Li D, Wu Z, Wang L, Choong M, Lor M, Reid RC, Fairlie DP, Harris J, Tachedjian G, Poulsen SA, Harrich D
Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Herston, Qld, 4029, Australia.

Abstract

HIV-1 replication requires direct interaction between HIV-1 reverse transcriptase (RT) and cellular eukaryotic translation elongation factor 1A (eEF1A). Our previous work showed that disrupting this interaction inhibited HIV-1 uncoating, reverse transcription and replication, indicating its potential as an anti-HIV-1 target. Here we develop a sensitive, live-cell split luciferase complementation assay (NanoBiT) to quantitatively measure inhibition of HIV-1 RT interacting with eEF1A. We used this to screen a small molecule library and discovered small molecule oxazole-benzenesulfonamides (C7, C8, C9), which dose-dependently and specifically inhibited the HIV-1 RT interaction with eEF1A. These compounds directly bound to HIV-1 RT in a dose-dependent manner, as assessed by a biolayer-interferometry (BLI) assay, but did not bind to eEF1A. These oxazole-benzenesulfonamides did not inhibit enzymatic activity of recombinant HIV-1 RT in a homopolymer assay, but did inhibit reverse transcription and infection of both wild type (WT) and NNRTI-resistant HIV-1 in a dose-dependent manner in HEK293T cells. Infection of HeLa cells was significantly inhibited by the oxazole-benzenesulfonamides and the antiviral activity was most potent against replication stages before 8 h post-infection. In human primary activated CD4(+) T cells, C7 inhibited HIV-1 infectivity and replication up to 6 days post-infection. The data suggest a novel mechanism of HIV-1 inhibition and further elucidate how the RT-eEF1A interaction is important for HIV-1 replication. These compounds provide potential to develop a new class of anti-HIV-1 drugs to treat WT and NNRTI-resistant strains in people infected with HIV.IMPORTANCE Antiretroviral drugs protect many HIV-positive people, but their success can be compromised by drug resistant strains. To combat these strains, the development of new classes of HIV-1 inhibitors is essential and a priority in the field. In this study we identified small molecules that bind directly to HIV-1 reverse transcriptase (RT) and inhibit its interaction with cellular eEF1A, an interaction which we have previously identified as crucial for HIV-1 replication. These compounds inhibit intracellular HIV-1 reverse transcription and replication of WT HIV-1, as well as HIV-1 mutants that are resistant to current RT inhibitors. A novel mechanism of action involving inhibition of the HIV-1 RT-eEF1A interaction is an important finding and a potential new way to combat drug-resistant HIV-1 strains in infected people.

Link to publisher’s web site

Publication

  • Journal: Journal of Virology
  • Published: 29/05/2019
  • Volume: 93
  • Issue: 12
  • Pagination: e00239-19

Author