The impact of β-azido(or 1-piperidinyl)methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues
Maciej Maciejczyk
Department of Physics and Biophysics, Faculty of Food Science, University of Warmia and Mazury, Oczapowskiego 4, 10-719 Olsztyn, Poland
Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, ul. Ks. Trojdena 4, 02-109 Warsaw, Poland
contributed equally to this workSearch for more papers by this authorAnika Lasota
Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland
contributed equally to this workSearch for more papers by this authorOliwia Frączak
Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland
Search for more papers by this authorPiotr Kosson
Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 01-793 Warsaw, Poland
Search for more papers by this authorAleksandra Misicka
Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 01-793 Warsaw, Poland
Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
Search for more papers by this authorMichał Nowakowski
Centre of New Technologies, University of Warsaw, Banacha 2C, 02-097 Warsaw, Poland
Search for more papers by this authorAndrzej Ejchart
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5A, 02-106 Warsaw, Poland
Search for more papers by this authorCorresponding Author
Aleksandra Olma
Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland
Correspondence to: Aleksandra Olma, Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland. E-mail: [email protected]Search for more papers by this authorMaciej Maciejczyk
Department of Physics and Biophysics, Faculty of Food Science, University of Warmia and Mazury, Oczapowskiego 4, 10-719 Olsztyn, Poland
Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, ul. Ks. Trojdena 4, 02-109 Warsaw, Poland
contributed equally to this workSearch for more papers by this authorAnika Lasota
Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland
contributed equally to this workSearch for more papers by this authorOliwia Frączak
Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland
Search for more papers by this authorPiotr Kosson
Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 01-793 Warsaw, Poland
Search for more papers by this authorAleksandra Misicka
Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 01-793 Warsaw, Poland
Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
Search for more papers by this authorMichał Nowakowski
Centre of New Technologies, University of Warsaw, Banacha 2C, 02-097 Warsaw, Poland
Search for more papers by this authorAndrzej Ejchart
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5A, 02-106 Warsaw, Poland
Search for more papers by this authorCorresponding Author
Aleksandra Olma
Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland
Correspondence to: Aleksandra Olma, Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland. E-mail: [email protected]Search for more papers by this authorAbstract
The synthesis of new dermorphin analogues is described. The (R)-alanine or phenylalanine residues of natural dermorphin were substituted by the corresponding α-methyl-β-azidoalanine or α-benzyl-β-azido(1-piperidinyl)alanine residues. The potency and selectivity of the new analogues were evaluated by a competitive receptor binding assay in rat brain using [3H]DAMGO (a μ ligand) and [3H]DELT (a δ ligand). The most active analogue in this series, Tyr-(R)-Ala-(R)-α-benzyl-β-azidoAla-Gly-Tyr-Pro-Ser-NH2 and its epimer were analysed by 1H and 13C NMR spectroscopy and restrained molecular dynamics simulations. The dominant conformation of the investigated peptides depended on the absolute configuration around Cα in the α-benzyl-β-azidoAla residue in position 3. The (R) configuration led to the formation of a type I β-turn, whilst switching to the (S) configuration gave rise to an inverse β-turn of type I′, followed by the formation of a very short β-sheet. The selectivity of Tyr-(R)-Ala-(R) and (S)-α-benzyl-β-azidoAla-Gly-Tyr-Pro-Ser-NH2 was shown to be very similar; nevertheless, the two analogues exhibited different conformational preferences. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
Supporting Information
Table S6. 13C (part A) and 15N (part B) chemical shifts (in ppm) of Tyr-(R)-Ala-(S)-α-benzyl-β-azidoAla-Gly-Tyr-Pro-Ser-NH2 (III) and Tyr-(R)-Ala-(R)-α-benzyl-β-azidoAla-Gly-Tyr-Pro-Ser-NH2 (IV) (Aaa = α-benzyl-β-azidoAla). t and c correspond to trans and cis isomers, respectively.
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