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

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

Author information

1
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States.
2
Howard Hughes Medical Institute, Yale University, New Haven, United States.
3
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, China.
4
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
5
Department of Chemistry, Yale University, New Haven, United States.
#
Contributed equally

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

PMID:
30044217
PMCID:
PMC6080946
DOI:
10.7554/eLife.36340
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

YY, DK, LN, ZS, CP, PZ, XL, TS No competing interests declared

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