7KE0

HIV-1 Integrase catalytic core domain complexed with allosteric inhibitor STP03-0404

7KE0 の概要

• エントリーDOI: 10.2210/pdb7ke0/pdb
• 分子名称: 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)
• 機能のキーワード: integrase, inhibitor, hiv, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Human immunodeficiency virus 1 (HIV-1)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18938.70

構造登録者

Lindenberger, J.J.,Kvaratskhelia, M. (登録日: 2020-10-09, 公開日: 2021-09-22, 最終更新日: 2024-11-06)

主引用文献

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

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: 34293041
DOI: 10.1371/journal.ppat.1009671

実験手法

X-RAY DIFFRACTION (2.19 Å)