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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.

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


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.


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

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Conflict of interest statement

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

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