7ADV

Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and the INSTI XZ447 (compound 6v)

7ADV の概要

• エントリーDOI: 10.2210/pdb7adv/pdb
• 分子名称: 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'), ... (9 entities in total)
• 機能のキーワード: integrase, intasome, protein dna complex, insti, drug, hiv, retrovirus, integration, 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: 102819.10

構造登録者

Pye, V.E.,Cherepanov, P. (登録日: 2020-09-16, 公開日: 2021-03-24, 最終更新日: 2024-01-31)

主引用文献

Smith, S.J.,Zhao, X.Z.,Passos, D.O.,Pye, V.E.,Cherepanov, P.,Lyumkis, D.,Burke Jr., T.R.,Hughes, S.H.
HIV-1 Integrase Inhibitors with Modifications That Affect Their Potencies against Drug Resistant Integrase Mutants.
Acs Infect Dis., 7:1469-1482, 2021

PubMed Abstract: Integrase strand transfer inhibitors (INSTIs) block the integration step of the retroviral lifecycle and are first-line drugs used for the treatment of HIV-1/AIDS. INSTIs have a polycyclic core with heteroatom triads, chelate the metal ions at the active site, and have a halobenzyl group that interacts with viral DNA attached to the core by a flexible linker. The most broadly effective INSTIs inhibit both wild-type (WT) integrase (IN) and a variety of well-known mutants. However, because there are mutations that reduce the potency of all of the available INSTIs, new and better compounds are needed. Models based on recent structures of HIV-1 and red-capped mangabey SIV INs suggest modifications in the INSTI structures that could enhance interactions with the 3'-terminal adenosine of the viral DNA, which could improve performance against INSTI resistant mutants. We designed and tested a series of INSTIs having modifications to their naphthyridine scaffold. One of the new compounds retained good potency against an expanded panel of HIV-1 IN mutants that we tested. Our results suggest the possibility of designing inhibitors that combine the best features of the existing compounds, which could provide additional efficacy against known HIV-1 IN mutants.

PubMed: 33686850
DOI: 10.1021/acsinfecdis.0c00819

実験手法

X-RAY DIFFRACTION (2.65 Å)