title: 2-Hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs), novel inhibitors of HIV integrase with a high barrier to resistance.
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.
authors.affiliation: Molecular Virology and Gene Therapy and §Laboratory for Biocrystallography, KU Leuven , Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.
authors.forename: Belete A
authors.initials: BA
authors.lastname: Desimmie
authors.forename: Jonas
authors.initials: J
authors.lastname: Demeulemeester
authors.forename: Virginie
authors.initials: V
authors.lastname: Suchaud
authors.forename: Oliver
authors.initials: O
authors.lastname: Taltynov
authors.forename: Muriel
authors.initials: M
authors.lastname: Billamboz
authors.forename: Cedric
authors.initials: C
authors.lastname: Lion
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bailly
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Strelkov
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Philippe
authors.initials: P
authors.lastname: Cotelle
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
mesh_terms: D020134:Catalytic Domain / Q000187:drug effects; D002460:Cell Line; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology / Q000821:virology; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular
chemical_list: C558516:2-hydroxyisoquinoline-1,3(2H,4H)-dione; D019428:HIV Integrase Inhibitors; D007546:Isoquinolines; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1