Structural Basis for the Potent Calpain Inhibitory Activity of Peptidyl α-Ketoacids

Donkor, Isaac O.; Assefa, Haregewein; Liu, Jiuyu

doi:10.1021/jm800182c

Cited by 14 publications

(8 citation statements)

References 13 publications

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“…the dipeptide aldehydes calpeptin [209], MDL-28170 [210,211] and SJA-6017 [212] and the tripeptides ALLN and ALLM [213] (Fig. (8)), are effective inhibitors of both calpain 1 and calpain 2 [169,211,213,214].…”

Section: Peptide Aldehydesmentioning

confidence: 99%

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

Pietsch

Chua²,

Abell

2010

CTMC

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The physiological roles of calpains are discussed, as are the associated pathological disorders that result from their over-activation. We also present practical information for establishing functional inhibition assays and an overview of X-ray crystal structures of calpain-inhibitor complexes to aid inhibitor design. These structures reveal the expected extended beta-strand conformation for the inhibitor backbone, a geometry that has been engineered into inhibitors with the introduction of either an N-terminal heterocycle or a macrocycle that links the P(1) and P(3) residues. The structure and function of all the main classes of inhibitors are reviewed, with most examples being classified according to the nature of the C-terminal reactive warhead group that reacts with the active site cysteine of calpains. These inhibitor classes include epoxysuccinate derivatives, aldehydes, aldehyde prodrugs (hemiacetals) and alpha-keto carbonyl compounds. Inhibitors derived from the endogenous inhibitor calpastatin and examples lacking a warhead, are now known and these are also discussed.

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Section: Peptide Aldehydesmentioning

confidence: 99%

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

Pietsch

Chua²,

Abell

2010

CTMC

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“… a Reagents and conditions: (a) BnBr, NaH, DMF, 0 °C; (b) N -methylmorpholine, isobutyl chloroformate, CH 2 Cl 2 , −20 °C, then NaBH 4 , H 2 O, 0 °C (80% yield for two steps); (c) Dess−Martin periodinane, CH 2 Cl 2 , rt (96%); (d) Boc-Cha-OH, ethyl isocyanoacetate, CH 2 Cl 2 , rt (75%); (e) TFA, CH 2 Cl 2 , rt, then Et 3 N, rt (62%); (f) 4-morpholinecarbonyl chloride, Et 3 N, DMF, rt (82%); (g) R 1 COOH (789 different acids were used), HBTU, Et 3 N, DMF. The Dess-Martin oxidation of hydroxyl amide intermediates gave α-ketoamide inhibitors as a mixture of diastereomers at the α-center of the P1 site, , with diastereomeric ratios being 2:1 to 1:1 ( S , S : R , S ). …”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of α-Ketoamides as Cathepsin S Inhibitors with Potential Applications against Tumor Invasion and Angiogenesis

Chen¹,

Uang²,

Lyu³

et al. 2010

J. Med. Chem.

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A series of small molecules bearing an alpha-ketoamide warhead were synthesized and evaluated for their ability to inhibit cathepsin S, a key proteolytic enzyme upregulated in many cancers during tumor progression and metastasis. Most of the synthetic compounds were noncytotoxic, but several robustly inhibited cathepsin S (IC(50) < 10 nM) and potently suppressed cell migration, invasion, and capillary tube formation. These results highlight the potential of alpha-ketoamide therapy for preventing or delaying cancer spread.

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“…We report that thalassospiramide natural products are potent inhibitors of calpain and function differently from standard calpain inhibitors. Most inhibitors possess highly reactive aldehyde groups that bind covalently to the active site of calpain, causing disadvantages such as non-selectivity, instability, and excessive metabolism 34 35 36 37 . Although other examples of α,β-unsaturated amides have been reported as electrophilic inhibitors of cysteine proteases 38 39 40 , this is the first report that an α,β-unsaturated carbonyl moiety in a rigid ring system functions as an electrophilic warhead at nanomolar scale inhibitory activity against calpain.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Action of Thalassospiramides, A New Class of Calpain Inhibitors

Liang

Meehan

et al. 2015

Sci Rep

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Thalassospiramides comprise a large family of lipopeptide natural products produced by Thalassospira and Tistrella marine bacteria. Here we provide further evidence of their nanomolar inhibitory activity against the human calpain 1 protease. Analysis of structure-activity relationship data supported our hypothesis that the rigid 12-membered ring containing an α,β-unsaturated carbonyl moiety is the pharmacologically active functional group, in contrast to classic electrophilic “warheads” in known calpain inhibitors. Using a combination of chemical modifications, mass spectrometric techniques, site-directed mutagenesis, and molecular modeling, we show the covalent binding of thalassospiramide's α,β-unsaturated carbonyl moiety to the thiol group of calpain's catalytic Cys115 residue by a Michael 1,4-addition reaction. As nanomolar calpain inhibitors with promising selectivity and low toxicity from natural sources are rare, we consider thalassospiramides as promising drug leads.

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Structural Basis for the Potent Calpain Inhibitory Activity of Peptidyl α-Ketoacids

Cited by 14 publications

References 13 publications

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

Design and Synthesis of α-Ketoamides as Cathepsin S Inhibitors with Potential Applications against Tumor Invasion and Angiogenesis

Mechanism of Action of Thalassospiramides, A New Class of Calpain Inhibitors

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