5MMB

Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and the INSTI XZ434 (compound 6p)

5MMB の概要

• エントリーDOI: 10.2210/pdb5mmb/pdb
• 分子名称: PFV INTEGRASE, DNA (5'-D(*AP*TP*TP*GP*TP*CP*AP*TP*GP*GP*AP*AP*TP*TP*TP*CP*GP*CP*A)-3'), DNA (5'-D(*TP*GP*CP*GP*AP*AP*AP*TP*TP*CP*CP*AP*TP*GP*AP*CP*A)-3'), ... (10 entities in total)
• 機能のキーワード: hiv, pfv, prototype foamy virus, integrase, strand transfer, insti, tetramer, intasome, integration, inhibitor, drug, viral protein
• 由来する生物種: Human spumaretrovirus (SFVcpz(hu)); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 102378.03

構造登録者

Maskell, D.P.,Pye, V.E.,Cherepanov, P. (登録日: 2016-12-09, 公開日: 2017-08-02, 最終更新日: 2024-01-17)

主引用文献

Zhao, X.Z.,Smith, S.J.,Maskell, D.P.,Metifiot, M.,Pye, V.E.,Fesen, K.,Marchand, C.,Pommier, Y.,Cherepanov, P.,Hughes, S.H.,Burke, T.R.
Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors.
J. Med. Chem., 60:7315-7332, 2017

PubMed Abstract: Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described.

PubMed: 28737946
DOI: 10.1021/acs.jmedchem.7b00596

実験手法

X-RAY DIFFRACTION (2.77 Å)