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

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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.
Funding Information
  • Howard Hughes Medical Institute (Investigator Program)
  • National Institute of General Medical Sciences (GM022778)
  • National Natural Science Foundation of China (81273354)
  • Shandong Province (Key Research and Development Project: 2017CXGC1401)
  • Shandong Province (Major Project of Science and Technology: 2015ZDJS04001)
  • Shandong University (Young Scholars Program: 2016WLJH32)
  • National Natural Science Foundation of China (Key Project for International Cooperation: 81420108027)

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