RESUMO
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.
Assuntos
Antivirais/química , Hepacivirus/enzimologia , Lactamas/química , Compostos Organofosforados/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Animais , Antivirais/síntese química , Antivirais/metabolismo , Antivirais/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Genótipo , Meia-Vida , Haplorrinos , Hepacivirus/genética , Hepacivirus/fisiologia , Humanos , Lactamas/farmacologia , Camundongos , Simulação de Dinâmica Molecular , Compostos Organofosforados/farmacologia , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
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.
Assuntos
Antivirais/farmacologia , Genótipo , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Sítio Alostérico , Antivirais/química , Antivirais/metabolismo , Cristalografia por Raios X , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as a seven-membered ring sugar moiety, namely 9-(5-deoxy-beta-D-allo-septanosyl)-adenine, is reported. This compound was synthesized in 14 steps from the commercially available D-glycero-D-gulo-1,4-lactone. When evaluated in cell culture experiments against a broad range of viruses, it did not exhibit any significant antiviral effect or cytotoxicity.
Assuntos
Nucleosídeos/química , Nucleosídeos/síntese química , Oligossacarídeos/química , Oligossacarídeos/síntese química , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Flavivirus/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Modelos Químicos , Estrutura Molecular , Nucleosídeos/farmacologia , Pestivirus/efeitos dos fármacosRESUMO
The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as the sugar moiety was synthesized and evaluated as a potential inhibitor of several virus replication.