4IKF

PFV intasome with inhibitor MB-76

Summary for 4IKF

• Entry DOI: 10.2210/pdb4ikf/pdb
• Descriptor: Integrase, N-(4-fluorobenzyl)-2,3-dihydroxy-1-oxo-1,2-dihydroisoquinoline-4-carboxamide, 5'-D(*AP*TP*TP*GP*TP*CP*AP*TP*GP*GP*AP*AP*TP*TP*TP*CP*GP*CP*A)-3', ... (10 entities in total)
• Functional Keywords: integrase zinc binding, core and dna-binding domains, dna integration, inhibitor, nucleus, viral protein-dna-inhibitor complex, endonuclease, nucleotidyltransferase, recombination, hhcc motif, dde motif, viral protein/dna/inhibitor
• Biological source: Human spumaretrovirus (SFVcpz(hu))
• Total number of polymer chains: 4
• Total formula weight: 101082.61

Authors

Taltynov, O.,Demeulemeester, J.,Desimmie, B.A.,Suchaud, V.,Billamboz, M.,Lion, C.,Bailly, F.,Debyser, Z.,Cotelle, P.,Christ, F.,Strelkov, S.V. (deposition date: 2012-12-26, release date: 2013-04-03, Last modification date: 2024-02-28)

Primary citation

Desimmie, B.A.,Demeulemeester, J.,Suchaud, V.,Taltynov, O.,Billamboz, M.,Lion, C.,Bailly, F.,Strelkov, S.V.,Debyser, Z.,Cotelle, P.,Christ, F.
2-Hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs), novel inhibitors of HIV integrase with a high barrier to resistance.
Acs Chem.Biol., 8:1187-1194, 2013

PubMed Abstract: Clinical HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) potently inhibit viral replication with a dramatic drop in viral load. However, the emergence of resistance to these drugs underscores the need to develop next-generation IN catalytic site inhibitors with improved resistance profiles. Here, we present a novel candidate IN inhibitor, MB-76, a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) derivative. MB-76 potently blocks HIV integration and is active against a panel of wild-type as well as raltegravir-resistant HIV-1 variants. The lack of cross-resistance with other INSTIs and the absence of resistance selection in cell culture indicate the potential of HID derivatives compared to previous INSTIs. A crystal structure of MB-76 bound to the wild-type prototype foamy virus intasome reveals an overall binding mode similar to that of INSTIs. Its compact scaffold displays all three Mg(2+) chelating oxygen atoms from a single ring, ensuring that the only direct contacts with IN are the invariant P214 and Q215 residues of PFV IN (P145 and Q146 for HIV-1 IN, respectively), which may partially explain the difficulty of selecting replicating resistant variants. Moreover, the extended, dolutegravir-like linker connecting the MB-76 metal chelating core and p-fluorobenzyl group can provide additional flexibility in the perturbed active sites of raltegravir-resistant INs. The compound identified represents a potential candidate for further (pre)clinical development as next-generation HIV IN catalytic site inhibitor.

PubMed: 23517458
DOI: 10.1021/cb4000426

Experimental method

X-RAY DIFFRACTION (3.4 Å)