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

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dc.contributor.authorFazio, M. A.
dc.contributor.authorOliveira, V. X.
dc.contributor.authorBulet, P.
dc.contributor.authorMiranda, MTM
dc.contributor.authorDaffre, S.
dc.contributor.authorMiranda, A.
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionBernex
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.date.accessioned2016-01-24T12:38:15Z
dc.date.available2016-01-24T12:38:15Z
dc.date.issued2006-01-01
dc.description.abstractGomesin 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.en
dc.description.affiliationUniversidade Federal de São Paulo, Dept Biophys, São Paulo, Brazil
dc.description.affiliationBernex, Atheris Labs, Geneva, Switzerland
dc.description.affiliationUniv São Paulo, Dept Biochem, IQ, São Paulo, Brazil
dc.description.affiliationUniv São Paulo, ICB, Dept Parasitol, São Paulo, Brazil
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Biophys, São Paulo, Brazil
dc.description.sourceWeb of Science
dc.format.extent205-218
dc.identifierhttp://dx.doi.org/10.1002/bip.20396
dc.identifier.citationBiopolymers. Hoboken: John Wiley & Sons Inc, v. 84, n. 2, p. 205-218, 2006.
dc.identifier.doi10.1002/bip.20396
dc.identifier.issn0006-3525
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/28623
dc.identifier.wosWOS:000236389000007
dc.language.isoeng
dc.publisherWiley-Blackwell
dc.relation.ispartofBiopolymers
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.rights.licensehttp://olabout.wiley.com/WileyCDA/Section/id-406071.html
dc.subjectgomesinen
dc.subjectantimicrobial peptideen
dc.subjectdisulfide bridgeen
dc.subjectlactam bridgeen
dc.subjectcircular dichroismen
dc.subjectserum stabilityen
dc.subjectinnate immunityen
dc.subjectspideren
dc.titleStructure-activity relationship studies of gomesin: Importance of the disulfide bridges for conformation, bioactivities, and serum stabilityen
dc.typeinfo:eu-repo/semantics/article
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