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Design and synthesis of -turn peptidomimetics: Applications to angiotensin II
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This study addresses the issue of how to convert peptides into drug-like non-peptides while retaining the biological activity at peptide receptors. Angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Ang II) was used as a model peptide.

Small bioactive peptides are in most cases conformationally flexible molecules. Rigidified peptide analogues or peptidomimetic scaffolds can be introduced into the peptide, to enforce a particular backbone conformation, and thereby locate the side-chains at defined positions in space. The conformationally constrained analogues are of considerable value in determining biologically active conformation(s) of the studied peptide. The strategy applied in this thesis includes identification of non-pharmacophoric amino acid residues, rigidification, conformational analysis and incorporation of turn mimicking scaffolds in

Ang II. Several side-chain cyclized (disulfide and methylendithioether) Ang II analogues have been synthesized. The binding studies of the rigidified analogues demonstrated that the compounds designed for the AT1-receptor had affinity for both receptor subtypes, while the compounds designed for the AT2-receptor displayed high selectivity only for this receptor subtype. Conformational evaluation revealed that several of the cyclized Ang II analogues most probably adopt a γ-turn like conformation around Tyr-4 while interacting with the

Ang II receptor. Based on this hypothesis, three different γ-turn mimetics replacing amino acid residues 3-5 were designed, synthesized and incorporated into Ang II. One of the synthesized pseudopeptides, incorporating an azepine-containing γ-turn mimetic, exerted high binding affinity and agonistic activity. These results strongly support the theory that Ang II adopts a γ-turn like conformation when activating the AT1 receptor. The other Ang II analogues, incorporating bicyclic and aromatic γ-turn mimetics, did not display any binding to the AT1 receptor.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2001. , p. 68
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 243
Keywords [en]
Pharmaceutical chemistry, peptide synthesis, turn mimetics, molecular modelling, receptor binding affinity
Keywords [sv]
Farmaceutisk kemi
National Category
Medicinal Chemistry
Research subject
Organic Pharmaceutical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-553ISBN: 91-554-4882-8 (print)OAI: oai:DiVA.org:uu-553DiVA, id: diva2:166047
Public defence
2001-01-12, Sal B41, Uppsala Biomedicinska Centrum, Husargatan 3, Uppsala, Uppsala, 10:15
Available from: 2000-12-22 Created: 2000-12-22 Last updated: 2018-01-13Bibliographically approved

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