5MMB

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

Summary for 5MMB

• Entry DOI: 10.2210/pdb5mmb/pdb
• Descriptor: 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)
• Functional Keywords: hiv, pfv, prototype foamy virus, integrase, strand transfer, insti, tetramer, intasome, integration, inhibitor, drug, viral protein
• Biological source: Human spumaretrovirus (SFVcpz(hu)); More
• Total number of polymer chains: 4
• Total formula weight: 102378.03

Authors

Maskell, D.P.,Pye, V.E.,Cherepanov, P. (deposition date: 2016-12-09, release date: 2017-08-02, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.77 Å)