Calpain inhibitors as potential treatment for stroke and other neurodegenerative diseases: recent trends and developments

Wells, Gregory J.; Bihovsky, Ron

doi:10.1517/13543776.8.12.1707

Cited by 38 publications

(21 citation statements)

References 84 publications

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“…Many of the reversible inhibitors of the calpains are peptidyl aldehydes. Two recent reviews summarize the properties and structures of 59 calpain inhibitors (477) and the properties and therapeutic values of some of these inhibitors (472); these reviews should be consulted for a more complete list and information on the properties of these inhibitors.…”

Section: Physiological Functions Of the Calpain Systemmentioning

confidence: 99%

The Calpain System

Goll

Thompson

et al. 2003

Physiological Reviews

2,569

2,801

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Goll, Darrel E., Valery F. Thompson, Hongqi Li, Wei Wei, and Jinyang Cong. The Calpain System. Physiol Rev 83: 731–801, 2003; 10.1152/physrev.00029.2002.—The calpain system originally comprised three molecules: two Ca2+-dependent proteases, μ-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both μ- and m-calpain are heterodimers containing an identical 28-kDa subunit and an 80-kDa subunit that shares 55–65% sequence homology between the two proteases. The crystallographic structure of m-calpain reveals six “domains” in the 80-kDa subunit: 1) a 19-amino acid NH2-terminal sequence; 2) and 3) two domains that constitute the active site, IIa and IIb; 4) domain III; 5) an 18-amino acid extended sequence linking domain III to domain IV; and 6) domain IV, which resembles the penta EF-hand family of polypeptides. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. Since 1989, cDNA cloning has identified 12 additional mRNAs in mammals that encode polypeptides homologous to domains IIa and IIb of the 80-kDa subunit of μ- and m-calpain, and calpain-like mRNAs have been identified in other organisms. The molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma.

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Section: Physiological Functions Of the Calpain Systemmentioning

confidence: 99%

The Calpain System

Goll

Thompson

et al. 2003

Physiological Reviews

2,569

2,801

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“…These inhibitors inactivate calpain in a transient manner by forming a reversible covalent bond (hemithioacetal or hemithioketal) with the cysteine thiol [17]. However, most of these inhibitors displayed limited selectivity [9] and to enhance the potency and selectivity, peptidomimetic inhibitors were developed such as urea based [18], alpha-ketoamides [19,20], alphaketohydroxamates [21] and others [22,23]. a-ketoamides and a-ketohydroxamate derivatives were found to be promising inhibitors against calpain I and hence quantitative structural activity relationship studies have been carried out in order to investigate the role of various physico-chemical parameters and their quantitative contribution towards activity of compounds.…”

Section: Introductionmentioning

confidence: 99%

QSAR studies on peptide α-ketoamides and α-ketohydroxamate derivatives as calpain I inhibitors

Dondapati

Gódi

Babu

2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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Quantitative Structure Activity Relationship (QSAR) studies were conducted on 34 peptide a-ketoamide and a-ketohydroxamate derivatives of Calpain I using multiple linear regression (MLR) procedure. The activity contributions of these compounds were determined from regression equation and the validation procedures that analyze the predictive ability of QSAR models were described. Among forty six descriptors that were considered in generating the QSAR model, three descriptors such as LogP, Heat of formation and HOMO resulted in a statistically significant model with 0.877 r 2 and 0.937 q 2 respectively. The inter-correlation between descriptors was 0.42. The proposed QSAR model indicates an increase in logP value increases hydrophobicity in order to achieve cellular permeability and an increase in heat of formation as well as decrease in HOMO energy favors better binding and activity towards development of potent calpain I inhibitors.

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“…Of particular interest in this context is the bound conformation of the 27-mer peptide, CP1B-w1-27x (compound 1; see Figure 1A), derived from subdomain 1B of human calpastatin, because this peptide inhibits calpain almost as efficiently as the parent whole inhibitory domain 1 of the protein (Maki et al, 1989). Amongst the synthetic calpain inhibitors that have been developed so far (for reviews see Wells and Bihovsky, 1998;Donkor, 2000), CP1B-w1-27x (1) stands out due to its unequaled affinity/selectivity profile. Consequently, these unique properties have been utilized in cell biological studies.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human μ-calpain by conformationally constrained calpastatin peptides

Pfizer

Assfalg-Machleidt

Machleidt

et al. 2007

BCHM

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The 27-mer peptide CP1B-w1-27x derived from exon 1B of calpastatin stands out among the known inhibitors for m-and m-calpain due to its high potency and selectivity.By systematical truncation, a 20-mer peptide, CP1B-w4-23x, was identified as the core sequence required to maintain the affinity/selectivity profile of CP1B-w1-27x. Starting with this peptide, the turn-like region Glu 10 (i)-Leu 11 (iq1)-Gly 12 (iq2)-Lys 13 (iq3) was investigated. Sequence alignment of subdomains 1B, 2B, 3B and 4B from different mammalians revealed that the amino acid residues in position iq1 and iq2 are almost invariably flanked by oppositely charged residues, pointing towards a turn-like conformation stabilized by salt bridge/H-bond interaction. Accordingly, using different combinations of acidic and basic residues in position i and iq3, a series of conformationally constrained variants of CP1B-w4-23x were synthesized by macrolactamization utilizing the side chain functionalities of these residues. With the combination of Glu(i)/Dab(iq3), the maximum of conformational rigidity without substantial loss in affinity/selectivity was reached. These results clearly demonstrate that the linear peptide chain corresponding to subdomain 1B reverses its direction in the region Glu 10 -Lys 13 upon binding to m-calpain, and thereby adopts a loop-like rather than a tight turn conformation at this site.

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Calpain inhibitors as potential treatment for stroke and other neurodegenerative diseases: recent trends and developments

Cited by 38 publications

References 84 publications

The Calpain System

The Calpain System

QSAR studies on peptide α-ketoamides and α-ketohydroxamate derivatives as calpain I inhibitors

Inhibition of human μ-calpain by conformationally constrained calpastatin peptides

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