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Novel strategy for the synthesis of template‐assembled analogues of rat relaxin 1 1
Author(s) -
Mathieu Marc N.,
Wade John D.,
Tan YeanYeow,
Summers Roger J.,
Tregear Geoffrey W.
Publication year - 2000
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/(sici)1099-1387(200005)6:5<235::aid-psc247>3.0.co;2-j
Subject(s) - thioether , thiazolidine , chemistry , moiety , chemical ligation , peptide , stereochemistry , combinatorial chemistry , residue (chemistry) , steric effects , tripeptide , cysteine , molecule , small molecule , cysteamine , native chemical ligation , chemical synthesis , biochemistry , organic chemistry , enzyme , in vitro
Abstract The ‘template‐assembled synthetic protein’ (TASP) concept provides a simple and elegant approach for the preparation of analogues that retain key structural elements. We have synthesized TASP molecules containing the putative active site of relaxin, a peptide that has similar structural features to insulin but a markedly different biological role. Two types of chemoselective thiol ligation strategies (thioether and thiazolidine) were used and compared. The synthetic pendant peptides contain an essential region for bioactivity that is located in the α‐helical region of the relaxin B‐chain. Depending on whether the thioether or the thiazolidine chemistry was used to attach the peptides to the template, the reacting amino acid was placed either at the C ‐terminus or N ‐terminus, respectively, thus allowing the choice of orientation relative to the carrier molecule. The template molecule consists of a decapeptide with two proline–glycine turns and four evenly spaced lysine residues that were functionalized with the appropriate chemical moiety. This allowed reaction with the appropriately derivatized peptides in solution. To improve the template ligation step using the thioether approach, a pendant peptide C ‐terminal cysteamine residue was used to reduce potential steric hindrance during conjugation. The design of the peptides as well as the synthetic strategy resulted in the acquisition of mimetics showing weak non‐competitive and weak competitive antagonist properties. Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd.