1030622-03-7Relevant academic research and scientific papers
Synthesis, antiviral activity, and conformational studies of a P3 aza-peptide analog of a potent macrocyclic tripeptide HCV protease inhibitor
Randolph, John T.,Zhang, Xiaolin,Huang, Peggy P.,Klein, Larry L.,Kurtz, Kevin A.,Konstantinidis, Alex K.,He, Wenping,Kati, Warren M.,Kempf, Dale J.
, p. 2745 - 2750 (2008/12/21)
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 β-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.
