TY - JOUR TI - Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors AU - Yang, Yang AU - Kang, Dongwei AU - Nguyen, Laura A AU - Smithline, Zachary B AU - Pannecouque, Christophe AU - Zhan, Peng AU - Liu, Xinyong AU - Steitz, Thomas A A2 - Brunger, Axel T A2 - Chakraborty, Arup K VL - 7 PY - 2018 DA - 2018/07/25 SP - e36340 C1 - eLife 2018;7:e36340 DO - 10.7554/eLife.36340 UR - https://doi.org/10.7554/eLife.36340 AB - 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. KW - HIV-1 KW - reverse transcriptase KW - non-nucleoside inhibitor KW - drug resistance KW - x-ray crystallography KW - piperidine-substituted thiophene[3,2-d]pyrimidine JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -