5KRT

HIV-1 Integrase Catalytic Core Domain (CCD) in Complex with a Fragment-Derived Allosteric Inhibitor

5KRT の概要

• エントリーDOI: 10.2210/pdb5krt/pdb
• 関連するPDBエントリー: 5KRS
• 分子名称: Integrase, 3-[2,5-bis(chloranyl)pyrrol-1-yl]thiophene-2-carboxylic acid (3 entities in total)
• 機能のキーワード: hiv-1 integrase; catalytic core domain (ccd); p75/ledgf inhibitor, hydrolase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17506.26

構造登録者

Patel, D.,Bauman, J.D.,Arnold, E. (登録日: 2016-07-07, 公開日: 2016-09-28, 最終更新日: 2024-10-30)

主引用文献

Patel, D.,Antwi, J.,Koneru, P.C.,Serrao, E.,Forli, S.,Kessl, J.J.,Feng, L.,Deng, N.,Levy, R.M.,Fuchs, J.R.,Olson, A.J.,Engelman, A.N.,Bauman, J.D.,Kvaratskhelia, M.,Arnold, E.
A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain.
J.Biol.Chem., 291:23569-23577, 2016

PubMed Abstract: HIV-1 integrase (IN) is essential for virus replication and represents an important multifunctional therapeutic target. Recently discovered quinoline-based allosteric IN inhibitors (ALLINIs) potently impair HIV-1 replication and are currently in clinical trials. ALLINIs exhibit a multimodal mechanism of action by inducing aberrant IN multimerization during virion morphogenesis and by competing with IN for binding to its cognate cellular cofactor LEDGF/p75 during early steps of HIV-1 infection. However, quinoline-based ALLINIs impose a low genetic barrier for the evolution of resistant phenotypes, which highlights a need for discovery of second-generation inhibitors. Using crystallographic screening of a library of 971 fragments against the HIV-1 IN catalytic core domain (CCD) followed by a fragment expansion approach, we have identified thiophenecarboxylic acid derivatives that bind at the CCD-CCD dimer interface at the principal lens epithelium-derived growth factor (LEDGF)/p75 binding pocket. The most active derivative (5) inhibited LEDGF/p75-dependent HIV-1 IN activity in vitro with an IC of 72 μm and impaired HIV-1 infection of T cells at an EC of 36 μm The identified lead compound, with a relatively small molecular weight (221 Da), provides an optimal building block for developing a new class of inhibitors. Furthermore, although structurally distinct thiophenecarboxylic acid derivatives target a similar pocket at the IN dimer interface as the quinoline-based ALLINIs, the lead compound, 5, inhibited IN mutants that confer resistance to quinoline-based compounds. Collectively, our findings provide a plausible path for structure-based development of second-generation ALLINIs.

PubMed: 27645997
DOI: 10.1074/jbc.M116.753384

実験手法

X-RAY DIFFRACTION (1.651 Å)