Synthesis of peptidyl ene diones: Selective inactivators of the cysteine proteinases

P. Darkins, B.F. Gilmore, S.J. Hawthorne, A. Healy, H. Moncrieff, N. McCarthy, M. Anthony McKervey, D. Brömme, M. Pagano, B. Walker

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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
LanguageEnglish
Pages170-179
Number of pages10
JournalChemical Biology and Drug Design
Volume69
Issue number3
DOIs
Publication statusPublished - 2007

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Cysteine Proteases
Carbon Monoxide
Esters
Cathepsin B
cathepsin S
Chymotrypsin
Serine Proteases
Rate constants
Peptide Hydrolases
Derivatives
Peptides

Cite this

Darkins, P. ; Gilmore, B.F. ; Hawthorne, S.J. ; Healy, A. ; Moncrieff, H. ; McCarthy, N. ; Anthony McKervey, M. ; Brömme, D. ; Pagano, M. ; Walker, B. / Synthesis of peptidyl ene diones: Selective inactivators of the cysteine proteinases. In: Chemical Biology and Drug Design. 2007 ; Vol. 69, No. 3. pp. 170-179.
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abstract = "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",
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Darkins, P, Gilmore, BF, Hawthorne, SJ, Healy, A, Moncrieff, H, McCarthy, N, Anthony McKervey, M, Brömme, D, Pagano, M & Walker, B 2007, 'Synthesis of peptidyl ene diones: Selective inactivators of the cysteine proteinases', Chemical Biology and Drug Design, vol. 69, no. 3, pp. 170-179. https://doi.org/10.1111/j.1747-0285.2007.00490.x

Synthesis of peptidyl ene diones: Selective inactivators of the cysteine proteinases. / Darkins, P.; Gilmore, B.F.; Hawthorne, S.J.; Healy, A.; Moncrieff, H.; McCarthy, N.; Anthony McKervey, M.; Brömme, D.; Pagano, M.; Walker, B.

In: Chemical Biology and Drug Design, Vol. 69, No. 3, 2007, p. 170-179.

Research output: Contribution to journalArticle

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

VL - 69

SP - 170

EP - 179

JO - Chemical Biology and Drug Design

T2 - Chemical Biology and Drug Design

JF - Chemical Biology and Drug Design

SN - 1747-0277

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