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

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

Journal Name: Current Medicinal Chemistry

Volume 8 , Issue 8 , 2001

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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.

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

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Article Details

VOLUME: 8
ISSUE: 8
Year: 2001
Page: [893 - 907]
Pages: 15
DOI: 10.2174/0929867013372715
Price: $58

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