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
Original languageEnglish
Pages (from-to)170-179
Number of pages10
JournalChemical Biology and Drug Design
Volume69
Issue number3
DOIs
Publication statusPublished - 2007

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Cysteine Proteases
Carbon Monoxide
cathepsin S
Esters
Cathepsin B
Chymotrypsin
Serine Proteases
Cathepsin L
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

JF - Chemical Biology and Drug Design

SN - 1747-0277

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