7ADU

Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and the INSTI XZ440 (compound 5j)

Summary for 7ADU

• Entry DOI: 10.2210/pdb7adu/pdb
• Descriptor: 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)
• Functional Keywords: integrase, intasome, protein dna complex, insti, drug, hiv, retrovirus, integration, viral protein
• Biological source: Human spumaretrovirus (SFVcpz(hu)); More
• Total number of polymer chains: 4
• Total formula weight: 102239.39

Authors

Pye, V.E.,Cherepanov, P. (deposition date: 2020-09-16, release date: 2021-03-24, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.62 Å)