Macrocycles Mimic The Extended Peptide Conformation Recognized By Aspartic, Serine, Cysteine and Metallo Proteases

Title: Macrocycles Mimic The Extended Peptide Conformation Recognized By Aspartic, Serine, Cysteine and Metallo Proteases

Volume: 8 Issue: 8

Author(s): Joel D.A. Tyndall and David P. Fairlie

Affiliation:

Keywords: Macrocycles, Metallo Proteases, Protease enzymes, Activity, HIV-1 Protease Inhibitors, MACROCYCLIC, INHIBITORS, ASPARTIC PROTEASES, Renin

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.

Cite this article as:

Tyndall D.A. Joel and Fairlie P. David, Macrocycles Mimic The Extended Peptide Conformation Recognized By Aspartic, Serine, Cysteine and Metallo Proteases, Current Medicinal Chemistry 2001; 8 (8) . https://dx.doi.org/10.2174/0929867013372715