Macrocycles mimic the extended peptide conformation recognized by aspartic, serine, cysteine and metallo proteases.
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.
Tyndall
J D
JD
Centre for Drug Design and Development, University of Queensland, Brisbane, Queensland 4072, Australia.
Fairlie
D P
DP
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
D017320:HIV Protease Inhibitors; D010455:Peptides; D015842:Serine Proteinase Inhibitors; D010450:Endopeptidases; D012697:Serine Endopeptidases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases