ABSTRACT
Reversible tetrapeptide-based compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease. Inhibition of viral replicon RNA production in Huh-7 cells has also been demonstrated. We show herein that the inclusion of hydrogen bond donors on the P4 capping group of tetrapeptide-based inhibitors result in increased binding potency to the NS3.4A protease. The capping groups also impart significant effects on the pharmacokinetic profile of these inhibitors.
Subject(s)
Antiviral Agents/pharmacokinetics , Hepacivirus/drug effects , Protease Inhibitors/pharmacokinetics , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Animals , Antiviral Agents/chemical synthesis , Binding Sites , Cell Line , Crystallography, X-Ray , Drug Design , Hepacivirus/enzymology , Hydrogen Bonding , Mice , Microbial Sensitivity Tests , Oligopeptides/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Structure-Activity Relationship , Virus Replication/physiologyABSTRACT
Compounds of a combinatorial monocyclic beta-lactam library were found to be apparently uncompetitive inhibitors of HIV-1 protease, providing lead compounds for a new class of HIV protease inhibitors.
Subject(s)
Drug Design , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , HIV Protease/chemistry , beta-Lactams/chemistry , beta-Lactams/pharmacology , Animals , Binding, Competitive , Combinatorial Chemistry Techniques , Dimerization , HIV Protease/metabolism , Humans , Leukemia Virus, Murine/drug effects , Leukemia Virus, Murine/enzymology , Mice , Models, Molecular , Molecular Structure , Peptide Library , Structure-Activity RelationshipABSTRACT
We recently described the identification of an optimized alpha-ketoamide warhead for our series of HCV NS3.4A inhibitors. We report herein a series of HCV protease inhibitors incorporating 3-alkyl-substituted prolines in P(2). These compounds show exceptional enzymatic and cellular potency given their relatively small size. The marked enhancement of activity of these 3-substituted proline derivatives relative to previously reported 4-hydroxyproline derivatives constitutes additional evidence for the importance of the S(2) binding pocket as the defining pharmacophore for inhibition of the NS3.4A enzyme.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Oligopeptides/pharmacology , Proline/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Hepatitis C/enzymology , Intracellular Signaling Peptides and Proteins , Models, Molecular , Molecular Structure , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Proline/chemical synthesis , Proline/chemistry , Structure-Activity RelationshipABSTRACT
The alpha-ketoamide warhead (e.g., 15) was found to be a practical replacement for aliphatic aldehydes in a series of HCV NS3.4A protease inhibitors. Structure-activity relationships and prime side optimization are discussed.
Subject(s)
Hepacivirus/enzymology , Macrocyclic Compounds , Quinolines , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Carbamates/chemistry , Carbamates/metabolism , Hepacivirus/drug effects , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/metabolism , Viral Nonstructural Proteins/metabolismABSTRACT
Tetrapeptide-based peptidomimetic compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease without the need of a charged functionality. An aldehyde is used as a prototype reversible electrophilic warhead. The SAR of the P1 and P2 inhibitor positions is discussed.
