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Synthesis of Peptidyl Ene Diones: Selective Inactivators of the Cysteine Proteinases
Author(s) -
Darkins Paul,
Gilmore Brendan F.,
Hawthorne Susan J.,
Healy Adrienne,
Moncrieff Hazel,
McCarthy Noreen,
Anthony McKervey M.,
Brömme Dieter,
Pagano Maurice,
Walker Brian
Publication year - 2007
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2007.00490.x
Subject(s) - chemistry , proteases , stereochemistry , cysteine , serine , moiety , electrophile , cysteine protease , chymotrypsin , enzyme , organic chemistry , trypsin , catalysis
A series of synthetic peptides in which the C‐terminal carboxyl grouping (‐CO 2 H) of each has been chemically converted into a variety of ene dione derivatives (‐CO‐CH=CH‐CO‐X; X = ‐H, ‐Me, ‐OBut, ‐OEt, ‐OMe, ‐CO‐OMe), have been prepared and tested as inactivators against typical members of the serine and cysteine protease families. For example, the sequences Cbz‐Pro‐Phe‐CH=CH‐CO‐OEt (I) which fulfils the known primary and secondary specificity requirements of the serine protease chymotrypsin, and Cbz‐Phe‐Ala‐CH=CH‐CO‐OEt (II) which represents a general recognition sequence for cysteine proteases such as cathepsins B, L and S, have been tested as putative irreversible inactivators of their respective target proteases. It was found that, whereas II, for example, functioned as a time‐dependent, irreversible inactivator of each of the cysteine proteases, I behaved only as a modest competitive reversible inhibitor of chymotrypsin. Within the simple ester sequences Cbz‐Phe‐Ala‐CH=CH‐CO‐R, the rank order of inhibitor effectiveness decreases in the order R = ‐OMe > ‐OEt >> ‐OBut. It was also found that the presence of both an unsaturated double bond and an ester (or α ‐keto ester) moiety were indispensable for obtaining irreversible inactivators. Of the irreversible inactivators synthesized, Cbz‐Phe‐Ala‐CH=CH‐CO‐CO‐OEt (which contains a highly electrophilic α ‐keto ester grouping) was found to be the most effective exhibiting, for example, second‐order rate constants of approximately 1.7 × 10 6 m −1 min −1 and approximately 4.9 × 10 4 m −1 min −1 against recombinant human cathepsin S and human spleenic cathepsin B, respectively. This initial study thus holds out the promise that this class of inactivator may well be specific for the cysteine protease subclass.