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1.
Bioorg Med Chem Lett ; 27(11): 2634-2640, 2017 06 01.
Article in English | MEDLINE | ID: mdl-28416131

ABSTRACT

Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence is an attractive target for selective inhibition. This paper describes the discovery of a novel family of HCV NS5B non-nucleoside inhibitors inspired by the bioisosterism between sulfonamide and phosphonamide. Systematic structural optimization in this new series led to the identification of IDX375, a potent non-nucleoside inhibitor that is selective for genotypes 1a and 1b. The structure and binding domain of IDX375 were confirmed by X-ray co-crystalisation study.


Subject(s)
Antiviral Agents/chemistry , Hepacivirus/enzymology , Lactams/chemistry , Organophosphorus Compounds/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Allosteric Regulation , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Binding Sites , Crystallography, X-Ray , Genotype , Half-Life , Haplorhini , Hepacivirus/genetics , Hepacivirus/physiology , Humans , Lactams/pharmacology , Mice , Molecular Dynamics Simulation , Organophosphorus Compounds/pharmacology , Protein Structure, Tertiary , Rats , Structure-Activity Relationship , Sulfonamides/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
2.
Bioorg Med Chem Lett ; 26(18): 4536-4541, 2016 09 15.
Article in English | MEDLINE | ID: mdl-27520942

ABSTRACT

The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.


Subject(s)
Antiviral Agents/pharmacology , Genotype , Hepacivirus/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Allosteric Site , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Crystallography, X-Ray , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism
3.
Biochem Pharmacol ; 67(9): 1751-61, 2004 May 01.
Article in English | MEDLINE | ID: mdl-15081874

ABSTRACT

Human Immunodeficiency Virus type 1 (HIV-1) integrase (IN) is an attractive target for the development of new antiviral therapies. Recently, several HIV-1 recombinant IN (rIN) in vitro inhibitors have been described. However, the great majority of them failed to block the virus replication in cell-based assays, suggesting the inadequacy of the in vitro assay systems used for inhibitor screening. To improve these systems, we designed a 40(mer) duplex DNA reaction substrate consisting of recognition sequences from both U3 and U5 HIV-1 long terminal repeat (LTR) termini. The HIV-1 rIN was able to catalyze its enzyme activities recognizing both ends of the 40(mer) dsDNA. Using this substrate we assayed the effects on rIN catalysis of different classes of compounds which inhibit the HIV-1 rIN in vitro when the reaction substrate is the standard 21(mer) U5 dsDNA, and that are either active or inactive on the HIV-1 replication. We also compared the efficacy of these compounds when added to the reaction before or after the formation of the rIN-dsDNA complex. In this system, the enzyme preincubation with the two-ended 40(mer) dsDNA before the addition of the compounds allowed a strong correlation between the effects of hydroxylated aromatics derivatives on rIN activity in cell-free assays and their effects on viral replication in cell-culture assays. This increase in drug selectivity of the rIN in vitro assay was explored by investigating whether it was due to the length of the 40(mer), longer than the standard 21(mer), or to presence of both viral ends, versus only one viral end. To this purpose we designed four 40(mer) oligonucleotides containing either only one viral end or two-repetitive ends, finding that the architecture of the rIN-dsDNA complex and its compound susceptibility is significantly influenced by the sequence of the dsDNA substrate.


Subject(s)
HIV Integrase Inhibitors/pharmacology , HIV Integrase/analysis , HIV-1/enzymology , Oligonucleotides/pharmacology , Anti-HIV Agents/pharmacology , DNA, Viral/metabolism , HIV Integrase/genetics , HIV Integrase/metabolism , HIV Long Terminal Repeat/drug effects , HIV-1/genetics , Humans , Kinetics , Recombinant Proteins/metabolism , Substrate Specificity
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