[beta]-Amino acids as secondary structure inducers in peptides

Malesevic M (2002)
Bielefeld (Germany): Bielefeld University.

Bielefelder E-Dissertation | Englisch
Malesevic, Miroslav
Sewald, Norbert (Prof. Dr.)
Abstract / Bemerkung
Different spectroscopic methods (FTIR, CD, NMR) have been used to study the conformational properties of cyclic hexa-, penta-, and tetrapeptides, with or without [beta]-homoproline, and to examine the influence of this [beta]-amino acid on the peptide conformation in different solvents. Combination of these three analytical techniques revealed that [beta]-homoproline is an excellent inducer of secondary structure when inserted into a cyclic peptide. This residue stabilizes a pseudo-[gamma]-turn, or less frequently a pseudo-[beta]-turn. Twenty new cyclic peptides that mimic the VCAM-1 binding epitope (R36TQID40SPLN44) have been synthesized using Fmoc chemistry and cyclization in solution. D-amino acids, [beta]-amino acids and proline are used as secondary structure inducers for the spatial screening of the pharmacophoric groups. These peptides, designed as [alpha]4[beta]1 integrin antagonists, could have numerous medical applications and might be very useful in future studies of cell-cell and cell-extracellular matrix interactions. A new method for cyclization in solution using two injection pumps for separate addition of peptide and coupling reagent solutions to the reaction mixture and a purification by precipitation extraction method was developed. Combination of these two methods allows any solvent to be used for peptide cyclization. HOAt as additive, a rational design of the linear peptide precursor and slow addition rate of the peptide solution to the reaction mixture suppresses dimerization and epimerization, the main side reactions of the cyclization. A [beta]-homoamino acid in a central position of the linear precursor enhances the cyclization rate, and suppresses dimerization by bringing the peptide in a proper conformation. Two cyclic constrained peptide mimics of the invasin binding epitope in which D-amino acids were designed to lock the peptide conformation in such a way that the critical Asp residue occurs in i+1 position of the [beta]-turn were synthesized. The adhesion test shows that these peptides bind to [alpha]3[beta]1 integrin with low affinity (mM range) and inhibit binding of laminin-5 to the integrin. The third peptide is a combination of a cyclic hexapeptide with the SDMS sequence with an arginine residue connected via a linker to mimic the synergistic activity of Arg883 located 30 Å apart from the binding epitope. This peptide completely suppresses the binding of laminin-5 to the [alpha]3[beta]1 integrin and the IC50 value is in the µM range. Five new RGD peptides were synthesized and tested as inhibitors of the interaction between OV-MZ-6 carcinoma cells with three different extracellular matrix proteins (vitronectin, fibronectin and collagen typ I). Two of them show very strong inhibitor activity toward interaction of [alpha]v[beta]3 with vitronectin. Linear peptides with a C-terminal thioester are key intermediates for enzymatic macrocyclization using peptide synthetases. These precursors were synthesized on Kenner's sulfonamide "safety-catch" linker. N-acetylcysteamine is used for nucleophilic displacement and cleavage of the peptides from the activated linker. Cyclizations of linear precursors of the antibiotic tyrocidine A and its analogs proceed smoothly and with negligible rate of hydrolysis using isolated and purified TycC TE domain.
Cyclopeptide , Konformation , Lösungsmittel , Zirkulardichroismus , NMR-Spektroskopie , FT-IR-Spektroskopie , Aminosäuren (beta-) , Cyclisation , Peptidsynthese , [beta]-Amino acids , Integrin , VCAM-1 (Vascular cell adhesion molecule-1) , Invasin
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Malesevic M. [beta]-Amino acids as secondary structure inducers in peptides. Bielefeld (Germany): Bielefeld University; 2002.
Malesevic, M. (2002). [beta]-Amino acids as secondary structure inducers in peptides. Bielefeld (Germany): Bielefeld University.
Malesevic, M. (2002). [beta]-Amino acids as secondary structure inducers in peptides. Bielefeld (Germany): Bielefeld University.
Malesevic, M., 2002. [beta]-Amino acids as secondary structure inducers in peptides, Bielefeld (Germany): Bielefeld University.
M. Malesevic, [beta]-Amino acids as secondary structure inducers in peptides, Bielefeld (Germany): Bielefeld University, 2002.
Malesevic, M.: [beta]-Amino acids as secondary structure inducers in peptides. Bielefeld University, Bielefeld (Germany) (2002).
Malesevic, Miroslav. [beta]-Amino acids as secondary structure inducers in peptides. Bielefeld (Germany): Bielefeld University, 2002.
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