title: Metabolic stability of peptidomimetics: N-methyl and aza heptapeptide analogs of a PKB/Akt inhibitor.
abstract: Linear peptides suffer from poor pharmacokinetic and pharmacodynamic properties. Peptidomimetics are designed to overcome these pharmacological drawbacks while maintaining the biological effects of the parent peptides. Aza-peptides, in which an alpha carbon is replaced with nitrogen, are promising peptidomimetic analogs; however, little is known about the stability of these analogs toward enzymatic degradation. We performed systematic aza and N-methyl scans of a PKB/Akt inhibitor, PTR6154. We evaluated the stability of the aza-scan and N-methyl scan libraries toward enzymatic degradation by trypsin/chymotrypsin. Our results indicate that the modification site is important for metabolic stability and that aza-peptides have a more global effect than N-methylation, affecting cleavage sites distant from the modification site.
authors.affiliation: Institute of Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
authors.forename: Yftah
authors.initials: Y
authors.lastname: Tal-Gan
authors.forename: Noam S
authors.initials: NS
authors.lastname: Freeman
authors.forename: Shoshana
authors.initials: S
authors.lastname: Klein
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000595:Amino Acid Sequence; D001372:Aza Compounds / Q000737:chemistry*; D002918:Chymotrypsin / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D057786:Peptidomimetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
chemical_list: D001372:Aza Compounds; C550755:H-Arg-Pro-Arg-Nva-Tyr-Dap-Hol-NH2; D009842:Oligopeptides; D057786:Peptidomimetics; D047428:Protein Kinase Inhibitors; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D002918:Chymotrypsin; D014357:Trypsin