TY - JOUR
T1 - Synthesis of peptidyl ene diones: Selective inactivators of the cysteine proteinases
AU - Darkins, P.
AU - Gilmore, B.F.
AU - Hawthorne, S.J.
AU - Healy, A.
AU - Moncrieff, H.
AU - McCarthy, N.
AU - Anthony McKervey, M.
AU - Brömme, D.
AU - Pagano, M.
AU - Walker, B.
N1 - cited By 4
PY - 2007
Y1 - 2007
N2 - A series of synthetic peptides in which the C-terminal carboxyl grouping (-CO2H) 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 × 106m-1min-1 and approximately 4.9 × 104m-1min-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
AB - A series of synthetic peptides in which the C-terminal carboxyl grouping (-CO2H) 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 × 106m-1min-1 and approximately 4.9 × 104m-1min-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
U2 - 10.1111/j.1747-0285.2007.00490.x
DO - 10.1111/j.1747-0285.2007.00490.x
M3 - Article
SN - 1747-0285
VL - 69
SP - 170
EP - 179
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
IS - 3
ER -