Phosphinic peptides as zinc metalloproteinase inhibitors

Abstract

Solid-phase synthesis of phosphinic peptides was introduced 10 years ago. A major application of this chemistry has been the development of potent synthetic inhibitors of zinc metalloproteases. Specific properties of the inhibitors produced in recent years are reviewed, supporting the notion that phosphinic pseudo-peptides are useful tools for studying the structural and functional biology of zinc proteases.

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

“…However, since they rely in zinc chelating for activity, a poor selectivity towards MMPs have been observed [93] and disappointing results have been obtained for most compounds except phosphinic acids (reviewed by [11]). …”

“…Phosphinic peptides are a family of pseudo-peptides where the peptide bond is replaced by a phosphinic acid moiety (reviewed by Dive et al [93]). Zinc chelating properties of phosphinic group are of weaker potency than hydroxamate group but its chemical structure provides the opportunity to develop more selective inhibitors.…”

The influence of α-aminophosphonic acids on the activity of aminopeptidase from barley seeds—an approach to determine the enzyme specificity

“…In these reactions, at least one intermediate, in which the carbon atom participating in the reaction adopts the sp 3 configuration, is formed. Since phosphonic moiety also has tetrahedral structure and is mimicking this state, phosphonates exhibit inhibitory action towards proteolytic enzymes (Giannousis and Bartlett 1987;Dive et al 2004;Lejczak et al 1989;Mucha et al 2008Mucha et al , 2010Drąg et al 2005). Thus, they might be used as tools for differentiating aminopeptidases from various sources and to determine the structural requirements for their N-terminal fragment binding.…”

Stereoselective Synthesis of α-Amino-C-phosphinic Acids and Derivatives

“…This is the basis for synthetic applications of these compounds as chiral precursors in several stereospecific transformations [15]. Although, different structures of phosphonic and phosphinic groups compared with the carboxylic function could a priori disrupt enzyme-ligand interactions, they frequently are recognized by enzymes or receptors as inhibitors or false substrates [16,17]. Phosphinopeptides containing C-terminal α-aminophosphinic acids have been prepared by similar methods to those used with their phosphonic analogues, for example the coupling of N-protected amino acids or their active esters with α-aminophosphinates [18], or with free α-aminophosphinic acids in organic or aqueous-organic media has been reported [19].…”

“…Moreover, they can act as simple analogues of amino acids replacing the carboxylic group by the phosphinic moiety, as nonhydrolysable phosphate analogues or as chelating agents of metal ions present in the active site of the enzymes [22]. A number of excellent reviews on various aspects of their activity in natural systems have been published [16,17].…”