{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:29:45Z","timestamp":1790206185140,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,11,29]],"date-time":"2017-11-29T00:00:00Z","timestamp":1511913600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"National Institutes of Health training grant in Host-Pathogen Interactions","award":["T32AI089621B"],"award-info":[{"award-number":["T32AI089621B"]}]},{"name":"University of Maryland Cross-Campus Seed Grant"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p><jats:italic>Candida albicans<\/jats:italic> is an opportunistic fungal pathogen and a commensal organism that commonly colonizes mucosal surfaces, including those inside the human mouth. To help control <jats:italic>C.\u00a0albicans,<\/jats:italic> human saliva contains the antifungal peptide histatin 5 (Hst\u20105), which has strong antifungal activity against <jats:italic>C.\u00a0albicans<\/jats:italic>. However, the pathogen produces secreted aspartic proteases (Saps) that cleave Hst\u20105 at lysine residues and eliminate its antifungal properties. We designed variants of Hst\u20105 with its lysine residues substituted with arginine or leucine to evaluate the effect on proteolysis by Saps. We found site\u2010, residue\u2010, and Sap\u2010dependent 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\u20105. This decrease in proteolysis was accompanied by a reduction in cleavage on the C\u2010terminal side of K17, suggesting the Saps prefer lysine at K17 for cleavage. Incubation with <jats:italic>C.\u00a0albicans<\/jats:italic> cells and culture supernatant corroborated the results with purified Saps and highlighted their biological relevance. The modifications to Hst\u20105 do not diminish the antifungal activity of Hst\u20105, and, in fact, the K17R, K17L, and K11R peptides retained significantly more antifungal activity after treatment with Saps than Hst\u20105. 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.<\/jats:p>","DOI":"10.1111\/febs.14327","type":"journal-article","created":{"date-parts":[[2017,11,16]],"date-time":"2017-11-16T02:52:44Z","timestamp":1510800764000},"page":"146-159","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Engineering improved variants of the antifungal peptide histatin 5 with reduced susceptibility to <i>Candida albicans<\/i> secreted aspartic proteases and enhanced antimicrobial potency"],"prefix":"10.1111","volume":"285","author":[{"given":"Svetlana P.","family":"Ikonomova","sequence":"first","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering University of Maryland 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