1 Semmelweis University, Department of Organic Chemistry, Budapest
Introduction: Peptidomimetic foldamers are stable to proteolysis or metabolism and have much better membrane permeability compared to natural α-peptide chains. β-Peptides are an important group of peptidomimetic compounds. Here the formation of ordered backbone conformation of new pentamer β-peptides was studied.
Aims: The investigated pentamers include trans-[R,R]-2-aminocyclohexanecarboxylic acid (trans-[R,R]-ACHC) building blocks interrupted by different elements in the middle of the chain in order to study the effect of new structural elements on conformation. trans-[R,R]-ACHC residues support H14 helix formation. The following β-amino acids were used as 3rd building blocks in the peptides: β-alanine, Z-dehydro-β-alanine and two different types of bicyclic elements, as diexo-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid (diexo-ABHEC) enantiomers or diexo-3-amino-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid (diexo-AOBHEC) enantiomers.
Methods: NMR (1H, ROESY, TOCSY, COSY NMR techniques) and ECD spectroscopy were used to study the β-peptides.
Results: In case of the flexible β-alanine building block, [1R,2R,3S,4S]-diexo-ABHEC and [1R,2S,3R,4S]-diexo-AOBHEC residues stable helices were discovered. Characteristic NOE-interactions for H14 helices were found and amide NH-ND exchange occurred over 10 hours. In ECD spectra intensive maximum and minimum bands were shown at 215 and 195 nm, which are also typical for H14 helices. Differences were found for the enantiomeric pairs, e.g. [1S,2S,3R,4R]-diexo-ABHEC, [1S,2R,3S,4R]-diexo-AOBHEC and for Z-β-dehydroalanine as 3rd unit, stable self-organization could not be observed.
Conclusion: Enantiodiscriminative helix formation was observed for β-peptides. In three peptides stable H14 helix was formed, in further three peptides less stable structures were identified. In case of bicyclic elements an effect was found on folding regarding the configuration. The O-atom in this residue has no effect on self-organization. A double bond in the middle unit (Z-dehydro-β-alanine) rules out the helix formation.
Doctoral School: Pharmaceutical Sciences
Program: Modern Trends in Pharmaceutical Scientific Research
Supervisor: Dr. István Mándity, Dr. Tamás Gáti
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