ABSTRACT
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.
Subject(s)
Antiviral Agents/chemical synthesis , Boronic Acids/chemical synthesis , Carrier Proteins/antagonists & inhibitors , Hepacivirus/drug effects , Protease Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Boronic Acids/chemistry , Boronic Acids/pharmacology , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line, Tumor , Genotype , Hepacivirus/genetics , Hepatitis C/drug therapy , Humans , Intracellular Signaling Peptides and Proteins , Mutant Proteins/antagonists & inhibitors , Mutant Proteins/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Viral Proteins/genetics , Viral Proteins/metabolismABSTRACT
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.
Subject(s)
Azabicyclo Compounds/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Nitriles/chemical synthesis , Thiazolidines/chemical synthesis , Azabicyclo Compounds/pharmacology , Catalysis , Diabetes Mellitus/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Nitriles/pharmacology , Protein Structure, Tertiary , Pyrrolidines/chemistry , Structure-Activity Relationship , Thiazoles/chemistry , Thiazolidines/pharmacology , Time FactorsABSTRACT
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.
Subject(s)
Boronic Acids , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors , Norleucine/analogs & derivatives , Dipeptides/chemical synthesis , Dipeptides/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Norleucine/pharmacology , Structure-Activity Relationship , Substrate SpecificityABSTRACT
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.
