title: Macrocycles mimic the extended peptide conformation recognized by aspartic, serine, cysteine and metallo proteases.
abstract: It has been previously demonstrated that aspartic, serine, metallo and cysteine proteases bind to their inhibitors and substrate analogues in a single conformation, the saw-tooth or extended beta-strand. Consequently a generic approach to the development of protease inhibitors is the use of constraints that conformationally restrict putative inhibitor molecules to an extended form. In this way the inhibitor is pre-organized for binding to a protease and does not need to rearrange its structure. One constraining device that has proven to be effective for such pre-organization is macrocyclization. This article illustrates the general principle that macrocycles, especially those composed of 3-4 amino acids and usually 13-17 ring atoms, can effectively mimic the extended conformation of short peptide sequences. Such structure-stabilising macrocycles are stable to degradation by proteases, valuable components of potent protease inhibitors, and in many cases they are also bioavailable.
authors.affiliation: Centre for Drug Design and Development, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: J D
authors.initials: JD
authors.lastname: Tyndall
authors.forename: D P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000187:drug effects; D010450:Endopeptidases / Q000737:chemistry* / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008666:Metalloendopeptidases / Q000737:chemistry / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D017320:HIV Protease Inhibitors; D010455:Peptides; D015842:Serine Proteinase Inhibitors; D010450:Endopeptidases; D012697:Serine Endopeptidases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases