RESUMEN
A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound 28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC50 of 25 nM in the replicon cell-based assay.
Asunto(s)
Antivirales/síntesis química , Ácidos Borónicos/síntesis química , Proteínas Portadoras/antagonistas & inhibidores , Hepacivirus/efectos de los fármacos , Inhibidores de Proteasas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas Virales/antagonistas & inhibidores , Antivirales/química , Antivirales/farmacología , Ácidos Borónicos/química , Ácidos Borónicos/farmacología , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Genotipo , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Humanos , Péptidos y Proteínas de Señalización Intracelular , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/metabolismo , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
The synthesis and biochemical evaluation of novel cyanothiazolidine inhibitors of dipeptidyl peptidase 4 (DPP4) is described. Their main structural feature is a constrained bicyclic core that prevents the intramolecular formation of inactive cyclic species. The inhibitors show good to moderate biochemical potency against DPP4 and display distinct selectivity profiles towards DPP7, DPP8 and DPP9 depending on their substitution.
Asunto(s)
Compuestos de Azabiciclo/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores Enzimáticos/síntesis química , Nitrilos/síntesis química , Tiazolidinas/síntesis química , Compuestos de Azabiciclo/farmacología , Catálisis , Diabetes Mellitus/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Nitrilos/farmacología , Estructura Terciaria de Proteína , Pirrolidinas/química , Relación Estructura-Actividad , Tiazoles/química , Tiazolidinas/farmacología , Factores de TiempoRESUMEN
Dipeptide-based inhibitors with C-substituted (alkyl or aminoalkyl) alpha-amino acids in the P2 position and boro-norleucine (boro-Nle) in the P1 position were synthesized. Relative to boro-proline, boro-Nle as a P1 residue was shown able to significantly dial out DPP4, FAP, DPP8, and DPP9 activity. Dab-boro-Nle (4g) proved to be the most selective and potent DPP7 inhibitor with a DPP7 IC50 value of 480 pM.
Asunto(s)
Ácidos Borónicos , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/antagonistas & inhibidores , Norleucina/análogos & derivados , Dipéptidos/síntesis química , Dipéptidos/farmacología , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Norleucina/farmacología , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Characterization and functional annotation of the large number of proteins predicted from genome sequencing projects poses a major scientific challenge. Whereas several proteomics techniques have been developed to quantify the abundance of proteins, these methods provide little information regarding protein function. Here, we present a gel-free platform that permits ultrasensitive, quantitative, and high-resolution analyses of protein activities in proteomes, including highly problematic samples such as undiluted plasma. We demonstrate the value of this platform for the discovery of both disease-related enzyme activities and specific inhibitors that target these proteins.
