ABSTRACT
BACKGROUND: HIV-1 integrase is a clinically validated therapeutic target for the treatment of HIV-1 infection, with one approved therapeutic currently on the market. This enzyme represents an attractive target for the development of new inhibitors to HIV-1 that are effective against the current resistance mutations. METHODS: A fragment-based screening method employing surface plasmon resonance and NMR was initially used to detect interactions between integrase and fragments. The binding sites of the fragments were elucidated by crystallography and the structural information used to design and synthesize improved ligands. RESULTS: The location of binding of fragments to the catalytic core of integrase was found to be in a previously undescribed binding site, adjacent to the mobile loop. Enzyme assays confirmed that formation of enzyme-fragment complexes inhibits the catalytic activity of integrase and the structural data was utilized to further develop these fragments into more potent novel enzyme inhibitors. CONCLUSIONS: We have defined a new site in integrase as a valid region for the structure-based design of allosteric integrase inhibitors. Using a structure-based design process we have improved the activity of the initial fragments 45-fold.
Subject(s)
Catalytic Domain , Crystallography/methods , HIV Integrase Inhibitors/chemical synthesis , Indoles/chemistry , Isatin/analogs & derivatives , Alkylation , Dioxoles/chemistry , Drug Design , HIV Infections/drug therapy , HIV Integrase Inhibitors/chemistry , HIV-1/drug effects , HIV-1/enzymology , Ligands , Magnetic Resonance Spectroscopy/methods , Protein Binding , Structure-Activity Relationship , Surface Plasmon Resonance/methodsABSTRACT
HIV integrase inhibitors based on a novel bicyclic pyrimidinone core is presented. Nine variations of the core scaffold are evaluated leading to optimization of the 6:6 core giving compound 48 with an EC(50) of 3 nM against wild type HIV infected T-cells.
Subject(s)
Bridged Bicyclo Compounds/chemistry , HIV Integrase Inhibitors/chemistry , HIV Integrase/chemistry , Pyridines/chemistry , Pyrimidines/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacology , Drug Design , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , Humans , Pyridines/chemical synthesis , Pyridines/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity Relationship , T-Lymphocytes/virologyABSTRACT
Synthesis of a diverse set of azoles and their utilizations as an amide isostere in the design of HIV integrase inhibitors is described. The Letter identified thiazole, oxazole, and imidazole as the most promising heterocycles. Initial SAR studies indicated that these novel series of integrase inhibitors are amenable to lead optimization. Several compounds with low nanomolar inhibitory potency are reported.
