7KE0
HIV-1 Integrase catalytic core domain complexed with allosteric inhibitor STP03-0404
Summary for 7KE0
| Entry DOI | 10.2210/pdb7ke0/pdb |
| Descriptor | Integrase, (2S)-tert-butoxy{4-(4-chlorophenyl)-2,3,6-trimethyl-1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}acetic acid (3 entities in total) |
| Functional Keywords | integrase, inhibitor, hiv, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Human immunodeficiency virus 1 (HIV-1) |
| Total number of polymer chains | 1 |
| Total formula weight | 18938.70 |
| Authors | Lindenberger, J.J.,Kvaratskhelia, M. (deposition date: 2020-10-09, release date: 2021-09-22, Last modification date: 2024-11-06) |
| Primary citation | Maehigashi, T.,Ahn, S.,Kim, U.I.,Lindenberger, J.,Oo, A.,Koneru, P.C.,Mahboubi, B.,Engelman, A.N.,Kvaratskhelia, M.,Kim, K.,Kim, B. A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site. Plos Pathog., 17:e1009671-e1009671, 2021 Cited by PubMed Abstract: Allosteric integrase inhibitors (ALLINIs) are a class of experimental anti-HIV agents that target the noncatalytic sites of the viral integrase (IN) and interfere with the IN-viral RNA interaction during viral maturation. Here, we report a highly potent and safe pyrrolopyridine-based ALLINI, STP0404, displaying picomolar IC50 in human PBMCs with a >24,000 therapeutic index against HIV-1. X-ray structural and biochemical analyses revealed that STP0404 binds to the host LEDGF/p75 protein binding pocket of the IN dimer, which induces aberrant IN oligomerization and blocks the IN-RNA interaction. Consequently, STP0404 inhibits proper localization of HIV-1 RNA genomes in viral particles during viral maturation. Y99H and A128T mutations at the LEDGF/p75 binding pocket render resistance to STP0404. Extensive in vivo pharmacological and toxicity investigations demonstrate that STP0404 harbors outstanding therapeutic and safety properties. Overall, STP0404 is a potent and first-in-class ALLINI that targets LEDGF/p75 binding site and has advanced to a human trial. PubMed: 34293041DOI: 10.1371/journal.ppat.1009671 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.19 Å) |
Structure validation
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