8VU9
Crystal structure of wild-type HIV-1 reverse transcriptase in complex with non-nucleoside inhibitor 5i3
Summary for 8VU9
| Entry DOI | 10.2210/pdb8vu9/pdb |
| Descriptor | Reverse transcriptase/ribonuclease H, p51 RT, (2E)-3-[4-({2-[(1-{[4-(methanesulfonyl)phenyl]methyl}piperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-4-yl}oxy)-3,5-dimethylphenyl]prop-2-enenitrile, ... (7 entities in total) |
| Functional Keywords | non-nucleoside reverse transcriptase inhibitor, transferase, transferase-transferase inhibitor complex, viral protein, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Human immunodeficiency virus type 1 BH10 More |
| Total number of polymer chains | 2 |
| Total formula weight | 115451.38 |
| Authors | Rumrill, S.,Ruiz, F.X.,Arnold, E. (deposition date: 2024-01-29, release date: 2025-05-07, Last modification date: 2025-06-11) |
| Primary citation | Wang, Z.,Rumrill, S.,Kang, D.,Guma, S.D.,Feng, D.,De Clercq, E.,Pannecouque, C.,Chen, C.H.,Arnold, E.,Ruiz, F.X.,Liu, X.,Zhan, P. Development of enhanced HIV-1 non-nucleoside reverse transcriptase inhibitors with improved resistance and pharmacokinetic profiles. Sci Adv, 11:eadt8916-eadt8916, 2025 Cited by PubMed Abstract: HIV-1 infection is a manageable chronic condition, with non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) remaining a cornerstone of antiretroviral therapy. Nevertheless, drug resistance to existing therapeutics is a serious and immediate concern. Using structure-based and scaffold-hopping approaches, we designed evolved diarylpyrimidine analogs targeting reverse transcriptase (RT), exploiting chemical space surrounding the NNRTI-binding pocket. We identified compounds and , with robust antiviral efficacy against wild-type HIV-1 and rilpivirine-resistant strains. Encouragingly, in vitro selection of mutant strains with took 39 passages to select resistance, with no phenotypic cross-resistance observed with known RT drugs. Co-crystal structures of wild-type and mutant RT with and revealed their resilience toward resistance mutations due to enhanced conformational flexibility and positional adaptability. exhibited good pharmacokinetic properties and favorable safety profiles, without substantial cytochrome P450 inhibition, and excellent oral bioavailability. These derivatives represent a promising scaffold for the development of anti-HIV drugs. PubMed: 40446037DOI: 10.1126/sciadv.adt8916 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.99 Å) |
Structure validation
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