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dc.contributor.authorIkonomova, S.P.
dc.contributor.authorMoghaddam-Taaheri, P.
dc.contributor.authorJabra-Rizk, M.A.
dc.date.accessioned2019-05-17T12:53:06Z
dc.date.available2019-05-17T12:53:06Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85036546240&doi=10.1111%2ffebs.14327&partnerID=40&md5=217b25bc940f7eda8a1400e6c5c538c1
dc.identifier.urihttp://hdl.handle.net/10713/9110
dc.description.abstractCandida albicans is an opportunistic fungal pathogen and a commensal organism that commonly colonizes mucosal surfaces, including those inside the human mouth. To help control C. albicans, human saliva contains the antifungal peptide histatin 5 (Hst-5), which has strong antifungal activity against C. albicans. However, the pathogen produces secreted aspartic proteases (Saps) that cleave Hst-5 at lysine residues and eliminate its antifungal properties. We designed variants of Hst-5 with its lysine residues substituted with arginine or leucine to evaluate the effect on proteolysis by Saps. We found site-, residue-, and Sap-dependent effects from single amino acid substitutions. The K17R and K17L modifications led to dramatic results, with over 77% and 100% intact peptide remaining after incubation with Sap9 and Sap2, respectively, compared to 47% and 61% of Hst-5. This decrease in proteolysis was accompanied by a reduction in cleavage on the C-terminal side of K17, suggesting the Saps prefer lysine at K17 for cleavage. Incubation with C. albicans cells and culture supernatant corroborated the results with purified Saps and highlighted their biological relevance. The modifications to Hst-5 do not diminish the antifungal activity of Hst-5, and, in fact, the K17R, K17L, and K11R peptides retained significantly more antifungal activity after treatment with Saps than Hst-5. Our results indicate that single amino acid modifications drastically impact both proteolysis at the modification sites and the overall level of proteolysis of the peptide, demonstrating the potential of designing peptides for resistance to proteolysis as a means for improving therapeutic efficacy. Copyright 2017 Federation of European Biochemical Societiesen_US
dc.description.sponsorshipWe thank Bernhard Hube for providing the purified Saps. This work was supported by a National Institutes of Health training grant in Host-Pathogen Interactions (T32AI089621B) and a University of Maryland Cross-Campus Seed Grant.en_US
dc.description.urihttps://dx.doi.org/10.1111/febs.14327en_US
dc.language.isoen_USen_US
dc.publisherBlackwell Publishing Ltden_US
dc.relation.ispartofFEBS Journal
dc.subjectantimicrobial peptidesen_US
dc.subjectCandida albicansen_US
dc.subjecthistatin-5en_US
dc.subjectproteolysisen_US
dc.subjectsecreted aspartic proteasesen_US
dc.titleEngineering improved variants of the antifungal peptide histatin 5 with reduced susceptibility to Candida albicans secreted aspartic proteases and enhanced antimicrobial potencyen_US
dc.typeArticleen_US
dc.identifier.doi10.1111/febs.14327
dc.identifier.pmid29143452


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