Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2- d]pyrimidine non-nucleoside inhibitors

Elife. 2018 Jul 25:7:e36340. doi: 10.7554/eLife.36340.

Abstract

Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 Å resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor-binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.

Keywords: HIV-1; drug resistance; infectious disease; microbiology; molecular biophysics; non-nucleoside inhibitor; piperidine-substituted thiophene[3,2-d]pyrimidine; reverse transcriptase; structural biology; virus; x-ray crystallography.

Publication types

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

MeSH terms

  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Binding Sites
  • Cells, Cultured
  • Crystallography, X-Ray
  • Drug Design
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Humans
  • Models, Molecular
  • Mutation
  • Protein Conformation
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology

Substances

  • Anti-HIV Agents
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • Thiophenes
  • HIV Reverse Transcriptase