Cyclic disulfide analogues of the complement component C3a Synthesis and conformational investigations

Content Provider	Scilit
Author	Pohls, Martina Ambrosius, Dorothee Grötzinger, Joachim Kretzschmar, Titus Saunders, Derek Wollmer, Axel Brandenburg, Dietrich Bitter-Suermann, Dieter Höcker, Hartwig
Copyright Year	2009
Description	Journal: International journal of peptide and protein research The flexible C-terminal region of the anaphylatoxic peptide C3a was reported to contain the receptor binding site. To elucidate the receptor binding conformation of the C-terminus, as well as to examine a synthetic approach to potential C3a-antagonists, 26 cyclic disulfide bridged C3a analogues were synthesized. Solid phase peptide synthesis was performed on different polymeric supports by individual peptide synthesis, with Fmoc strategy, and simultaneous multiple peptide synthesis, using Boc and Fmoc strategies. Both strategies gave open-chain peptides in comparable yields. Syntheses using the Boc strategy employed the HF-labile 4(methoxy)benzyl group (Mob) for beta-thiol protection of cysteine; in contrast, the TFA-stable protecting groups, acetamidomethyl (Acm) and trityl (Trt), were chosen for syntheses employing Fmoc strategy. Ring closure reactions by iodine oxidation were carried out starting from protected (Acm/Acm, Trt/Acm) or unprotected dithiols. The resulting cyclic C3a analogues were characterized by HPLC, amino acid analysis, and FAB-MS. Conformational investigations using CD spectroscopy and theoretical structural investigations by means of molecular dynamics calculations revealed that slight variations in sequence result in pronounced conformational consequences. The potential of cyclic C3a analogues to activate or to desensitize guinea pig platelets, a standard test system for biological activities of anaphylatoxic peptides like C3a, revealed relatively low activities for cyclic peptides (< 0.1% C3a activity). N-terminal acylation with cationic, arginine-rich sequences like YRRGR- led to amplified biological effects. Three of the synthesized peptides, namely CAALCLAR (P1), YRRGRCGGLCLAR (P5) and YRRGRAhxCGGLCLAR (P8), point in the direction of C3a antagonists.
Related Links	http://onlinelibrary.wiley.com/doi/10.1111/j.1399-3011.1993.tb00452.x/pdf
Ending Page	375
Page Count	14
Starting Page	362
ISSN	03678377
DOI	10.1111/j.1399-3011.1993.tb00452.x
Journal	International journal of peptide and protein research
Issue Number	4
Volume Number	41
Language	English
Publisher	Wiley-Blackwell
Publisher Date	2009-01-12
Access Restriction	Open
Subject Keyword	Journal: International journal of peptide and protein research Medicinal Chemistry Boc Strategy Circular Dichroism Cyclic C3a Analogues Disulfide Bridges Fmoc Strategy Molecular Dynamics Simulation Multiple Peptide Synthesis
Content Type	Text
Resource Type	Article
Subject	Biochemistry