Structure-activity relationship studies of gomesin: Importance of the disulfide bridges for conformation, bioactivities, and serum stability

Structure-activity relationship studies of gomesin: Importance of the disulfide bridges for conformation, bioactivities, and serum stability

Author Fazio, M. A. Google Scholar
Oliveira, V. X. Google Scholar
Bulet, P. Google Scholar
Miranda, MTM Google Scholar
Daffre, S. Google Scholar
Miranda, A. Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Bernex
Universidade de São Paulo (USP)
Abstract Gomesin is an antimicrobial peptide isolated from hemocytes of the Brazilian spider Acanthoscurria gomesiana that contains two disulfide bridges Cys(2-15)/Cys(6-11) and presents a beta-hairpin structure. To investigate the role of the disulfide bridges on gomesin conformation, bioactivities, and serum stability, structure-activity relationship (SAR) studies were conducted. Initially, gomesin and variants lacking one or both disulfide bridges were synthesized. CD studies showed that the gomesin structure is very rigid independently of the solvent enviromnent. On the other hand, the linearized analogues adopted secondary structures according to the environment, while the monocyclic disulfide-bridged peptides had a tendency to adopt a turn structure. the absence of one or both bridges resulted in a decrease in the antimicrobial and hemolytic activities. in addition, serum stability studies revealed that, contrasting to gomesin that was stable even after 48 h of incubation, the linearized analogues were rapidly degraded. the replacement of the disulfide bounds by lactam bridges led to monocyclic and bicyclic compounds. SAR studies indicated that the monocyclic lactam-bridged analogues tend to assume a alpha-helical structure being less potent, hemolytic, and serum stable than the wild-type gomesin. On the other hand, the bicyclic lactam/disulfide-bridged analogues displayed a similar conformation and degradation kinetics identical to gomesin. However, the antimicrobial activity appeared to be dependent on the lactam bridge position and size. These findings indicated that (i) the secondary structure plays a pivotal role for the full activity of gomesin; (ii) the antimicrobial and hemolytic activities of gomesin are correlated events; (iii) while at least one of the disulfide bridges is needed for the maintenance of a significant antimicrobial activity of gomesin, both bridges are required for high serum stability and optimal conformation; and finally (iv) the best analogue obtained was the bicyclo (2-15,6-11)[Glu(2), Cys(6.11), Lys(15) J-Gm since it is as stable and potent as gomesin. (c) 2005 Wiley Periodicals, Inc.
Keywords gomesin
antimicrobial peptide
disulfide bridge
lactam bridge
circular dichroism
serum stability
innate immunity
spider
Language English
Date 2006-01-01
Published in Biopolymers. Hoboken: John Wiley & Sons Inc, v. 84, n. 2, p. 205-218, 2006.
ISSN 0006-3525 (Sherpa/Romeo, impact factor)
Publisher Wiley-Blackwell
Extent 205-218
Origin http://dx.doi.org/10.1002/bip.20396
Access rights Closed access
Type Article
Web of Science ID WOS:000236389000007
URI http://repositorio.unifesp.br/handle/11600/28623

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