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Title: Biological and structural characterization of new linear gomesin analogues with improved therapeutic indices
Authors: Fazio, Marcos A.
Jouvensal, Laurence
Vovelle, Francoise
Bulet, Philippe
Miranda, M. Teresa M.
Daffre, Sirlei
Miranda, Antonio
Universidade Federal de São Paulo (UNIFESP)
Univ Orleans
Atheris Labs
Universidade de São Paulo (USP)
Keywords: antimicrobial peptide
circular dichroism
serum stability
nuclear magnetic resonance
Issue Date: 1-Jan-2007
Publisher: Wiley-Blackwell
Citation: Biopolymers. Hoboken: John Wiley & Sons Inc, v. 88, n. 3, p. 386-400, 2007.
Abstract: Gomesin (Gm) is a potent antimicrobial peptide isolated from the spider Acanthoscurria gomesiana. the two disulfide bridges Cys(2,15) and Cys(6,11) facilitate the folding of the molecule in a P-hairpin structure, conferring on the peptide a high stability in human plasma. We report herein biological and structural features of new linear Gm analogues, obtained by combining the removal of both disulfide bridges and the incorporation of a D- or L-proline. Regarding their biological properties, two analogues, namely, [D-Thr(2,6,11,15), Pro(9)]-D-Gm and [Thr(2,6,11,15), D-Pro(9)]-Gm, are as potent as Gm against Candida albicans and only fourfold less against Staphylococcus aureus and Escherichia coli. in addition, at 100 mu M they are approximately threefold less hemolytic than Gm. the best therapeutic indices were found for [D-Thr(2,6,11,15), Pro(9)]-D-Gm and for [(Des-pGlu(1), -Thr(2), -Arg(3))], Thr(6,11,15), with a 32-fold increase of their activity against bacteria, and from 128- to 512-fold against yeast when compared with Gm. Regarding the stability, [D-Thr(2,6,11,15), Pro(9)]-D-Gm appeared to be the most resistant in human serum, along with [D-Thr2,6,11,15, Pro(8)]-D-Gm and [Thr-(2,6,11,15), D-Arg(4,16), D-Pro(9)]-Gm. When evaluating their conformation by CD spectroscopy in sodium dodecyl sulfate (SDS), most linear analogues display beta-conformation characteristics. Moreover, considering its high therapeutic index and stability in serum, [D-Thr(2,6,11,15), Pro(9)]-D-Gm was ftirther analyzed by NMR spectroscopy. H-1 NMR expertiments in SDS micelles demonstrated that [D-Thr(2,6,11,15), Pro(9)]-D-Gm presents a conformation very similar to that of Gm. in our search for Gm analogues with enhanced potential for drug development, we demonstrated that designing cysteine-free analogues can improve the therapeutic index of Gm derivatives. (c) 2006 Wiley Periodicals, Inc.
ISSN: 0006-3525
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