Premium
Conformation‐based design of two cyclic physalaemin analogues
Author(s) -
Hölzemann Günter,
Jonczyk Alfred,
Eiermann Volker,
Pachler Klaus C. R.,
Barnickel Gerhard,
Regoli Domenico
Publication year - 1991
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.360310614
Subject(s) - chemistry , tachykinin receptor , salt bridge , eledoisin , stereochemistry , hydrogen bond , intramolecular force , amide , side chain , proton nmr , receptor , substance p , molecule , organic chemistry , biochemistry , neuropeptide , mutant , gene , polymer
Two new cyclic analogues of physalaemin were designed on the basis of the conformation found in DMSO solution. Glp‐Ala‐cyclo(‐Asp‐Pro‐Asn‐Lys‐)‐Phe‐Tyr‐Gly‐Leu‐Met‐NH 2 ( 1 ) was synthesized by cyclization of physalaemin. In 2 the Asp residue was replaced by Glu. The linear analogue of 2 was synthesized by the solid phase method and subsequently cyclized. Two‐dimensional nmr methods were employed to assign the proton and carbon resonances. Proton–proton distances were extracted from rotating frame nuclear Overhauser effect spectra and used as restraints in the molecular dynamics calculations. Analogue 1 was found to have a similar conformation as physalaemin, whereas 2 did not form intramolecular hydrogen bonds. The pharmacological evaluation revealed that both peptides have similar potencies as physalaemin in the dog carotid artery (NK‐1 receptor). Therefore, the charged side chains of physalaemin appear not essential for NK‐1 activation. However, the other tachykinin receptors show good sensitivity to the cyclic peptides. It is concluded that the replacement of a salt bridge by an amide bond connecting the side chains of natural residues might provide useful information about the biological significance of some charged side chains of neurokinins.