title: Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase-LEDGF/p75 interaction.
abstract: Though much progress has been made in the inhibition of HIV-1 integrase catalysis, clinical resistance mutations have limited the promise of long-term drug prescription. Consequently, allosteric inhibition of integrase activity has emerged as a promising approach to antiretroviral discovery and development. Specifically, inhibitors of the interaction between HIV-1 integrase and cellular cofactor LEDGF/p75 have been validated to diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Here, we have contributed to the development of novel allosteric integrase inhibitors with a high-throughput AlphaScreen-based random screening approach, with which we have identified novel 5-carbonyl-1H-imidazole-4-carboxamides capable of inhibiting the HIV-1 integrase-LEDGF/p75 interaction in vitro. Following a structure-activity relationship analysis of the initial 1H-imidazole-4,5-dicarbonyl core, we optimized the compound's structure through an industrial database search, and we went further to synthesize a selective and non-cytotoxic panel of inhibitors with enhanced potency.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Serrao
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Xu
authors.forename: Bikash
authors.initials: B
authors.lastname: Debnath
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Ya-Qiu
authors.initials: YQ
authors.lastname: Long
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D019428:HIV Integrase Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; C119380:lens epithelium-derived growth factor; C032566:imidazole-4-carboxamide; D000620:Aminoimidazole Carboxamide
keywords: 2B4J; 5-carbonyl-1H-Imidazole-4-carboxamide; 50% cytotoxic concentration; 50% effective concentration; 50% inhibitory concentration; Antiviral; CC(50); CCID(50); EC(50); HBA; HBD; HIV-1; HIV-1 integrase; IC(50); IN; Integrase; LEDGF/p75; Protein–protein interaction; cell culture infective dose; hydrogen bond acceptor; hydrogen bond donor; lens epithelium-derived growth factor/p75