Inhibition of human mu-calpain by conformationally constrained calpastatin peptides

Pfizer J, Assfalg-Machleidt I, Machleidt W, Schaschke N (2008)
BIOLOGICAL CHEMISTRY 389(1): 83-90.

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Abstract
The 27-mer peptide CP1 B-[1-27] derived from exon 1B of calpastatin stands out among the known inhibitors for mu- and m-calpain due to its high potency and selectivity. By systematical truncation, a 20-mer peptide, CP1B-[4-23], was identified as the core sequence required to maintain the affinity/selectivity profile of CP1B-[1-27]. Starting with this peptide, the turn-like region Glu(10)(i)-Leu(11)(i+1)-Gly(12)(i+2)-Lys(13)(i +3) was investigated. Sequence alignment of subdomains 1B, 2B, 3B and 4B from different mammalians revealed that the amino acid residues in position i+1 and i+2 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 i+3, a series of conformationally constrained variants of CP1 B-[4-23] were synthesized by macrolactamization utilizing the side chain functionalities of these residues. With the combination of Glu(i)/Dab(i+3), 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 mu-calpain, and thereby adopts a loop-like rather than a tight turn conformation at this site.
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Pfizer J, Assfalg-Machleidt I, Machleidt W, Schaschke N. Inhibition of human mu-calpain by conformationally constrained calpastatin peptides. BIOLOGICAL CHEMISTRY. 2008;389(1):83-90.
Pfizer, J., Assfalg-Machleidt, I., Machleidt, W., & Schaschke, N. (2008). Inhibition of human mu-calpain by conformationally constrained calpastatin peptides. BIOLOGICAL CHEMISTRY, 389(1), 83-90.
Pfizer, J., Assfalg-Machleidt, I., Machleidt, W., and Schaschke, N. (2008). Inhibition of human mu-calpain by conformationally constrained calpastatin peptides. BIOLOGICAL CHEMISTRY 389, 83-90.
Pfizer, J., et al., 2008. Inhibition of human mu-calpain by conformationally constrained calpastatin peptides. BIOLOGICAL CHEMISTRY, 389(1), p 83-90.
J. Pfizer, et al., “Inhibition of human mu-calpain by conformationally constrained calpastatin peptides”, BIOLOGICAL CHEMISTRY, vol. 389, 2008, pp. 83-90.
Pfizer, J., Assfalg-Machleidt, I., Machleidt, W., Schaschke, N.: Inhibition of human mu-calpain by conformationally constrained calpastatin peptides. BIOLOGICAL CHEMISTRY. 389, 83-90 (2008).
Pfizer, Jose, Assfalg-Machleidt, Irmgard, Machleidt, Werner, and Schaschke, Norbert. “Inhibition of human mu-calpain by conformationally constrained calpastatin peptides”. BIOLOGICAL CHEMISTRY 389.1 (2008): 83-90.
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