Joel D.A. Tyndall and David P. Fairlie Pages 893 - 907 ( 15 )
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.
Macrocycles,Metallo Proteases,Protease enzymes,Activity,HIV-1 Protease Inhibitors,MACROCYCLIC,INHIBITORS,ASPARTIC PROTEASES,Renin
, Centre for Drug Design and Development, University of Queensland, Brisbane, Queensland 4072, Australia.