Phosphinic Peptides: Synthetic Approaches and Biochemical Evaluation as Zn-Metalloprotease Inhibitors

Author(s): A. Yiotakis , D. Georgiadis , M. Matziari , A. Makaritis , V. Dive .

Journal Name: Current Organic Chemistry

Volume 8 , Issue 12 , 2004

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Abstract:

Over the course of the last decades, phosphinic peptides have emerged as an extremely important class of Zn-metalloprotease inhibitors. The intense interest in these compounds in the field of medicinal chemistry reflects a conjunction of synthetic advances and ideal physicochemical and biochemical properties. Among the latter, the optimal tetrahedral structure of phosphinic acid moiety, which perfectly fills the requirements of transition state theory, clearly defines the mechanistical frame of their function as metalloprotease inhibitors (transition state analogues, TSA). In particular, phosphinic peptides are peptidic isosters containing a chemically stable phosphinic acid moiety which mimics the transition state tetrahedral geometry of a scissile peptide bond during enzymatic hydrolysis. Moreover, the ionic interactions of phosphinic oxyanion with catalytic Zn2+ combined with the substrate-like primary interactions of pseudopeptidic backbone with enzymes active site, can aid the rationalization of the design and development of potent and selective Zn-protease inhibitors. In these review, we aim to resume the major achievements in this field over the last decades. In the first part, the fundamental principles of phosphinopeptidic chemistry, as these have been established by the pioneers of the field, as well as the synthesis of first-generation inhibitors are presented. In the second part, accounting as a turning point the introduction of SPPS and combinatorial practices in the field, a comprehensive description of all the recent synthetic novelties as well as the outstanding applications of phosphinopeptidic derivatives in enzymatic, biochemical and crystallographic studies is attempted.

Keywords: phosphinic peptides, zn-metalloprotease inhibitors, phosphinic acid moiety, metalloprotease inhibitors

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Article Details

VOLUME: 8
ISSUE: 12
Year: 2004
Page: [1135 - 1158]
Pages: 24
DOI: 10.2174/1385272043370177
Price: $58

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