title: Synthesis, antiviral activity, and conformational studies of a P3 aza-peptide analog of a potent macrocyclic tripeptide HCV protease inhibitor.
abstract: BILN 2061 is a macrocyclic tripeptide inhibitor of hepatitis C virus NS3-4A protease that has shown efficacy in the clinic for treating patients infected with HCV. We have synthesized a P3 aza-peptide analog of a potent macrocyclic tripeptide inhibitor closely related to BILN 2061. This aza-derivative was found to be >2 orders of magnitude less active than the parent macrocycle in both isolated enzyme (HCV NS3-4A) and HCV subgenomic replicon assays. NMR studies of P3 aza-peptides revealed these compounds adopt a beta-turn conformation stabilized by an intramolecular H-bonding interaction. Molecular models of these structures indicate a D-like configuration of the P3 aza-residue. Thus, the configurationally undefined nature at P3 in the aza-peptide allows the compound to adopt an H-bond stabilized conformation that is substantially different from that necessary for tight binding to the active site of HCV NS3 protease.
authors: Global Pharmaceutical Research and Development, Antiviral Research, 200 Abbott Park Road, Abbott Park, IL 60064, USA. john.randolph@abbott.com
authors: John T
authors: JT
authors: Randolph
authors: Xiaolin
authors: X
authors: Zhang
authors: Peggy P
authors: PP
authors: Huang
authors: Larry L
authors: LL
authors: Klein
authors: Kevin A
authors: KA
authors: Kurtz
authors: Alex K
authors: AK
authors: Konstantinidis
authors: Wenping
authors: W
authors: He
authors: Warren M
authors: WM
authors: Kati
authors: Dale J
authors: DJ
authors: Kempf
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry*; D002384:Catalysis; D036341:Intercellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D001372:Aza Compounds; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds; D010455:Peptides; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C485059:peptide P3