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The peptide is natively secreted by human salivary glands and shows promise as an alternative therapeutic against infections caused by <jats:italic>C. albicans<\/jats:italic>. However, Hst\u20105 can be cleaved and inactivated by a family of secreted aspartic proteases (Saps) produced by <jats:italic>C. albicans<\/jats:italic>. Single\u2010residue substitutions can significantly affect the proteolytic resistance of Hst\u20105 to Saps and its antifungal activity; the K17R substitution increases resistance to proteolysis, while the K11R substitution enhances antifungal activity. In this work, we showed that the positive effects of these two single\u2010residue modifications can be combined in a single peptide, K11R\u2013K17R, with improved proteolytic resistance and antifungal activity. We also investigated the effect of additional single\u2010residue substitutions, with a focus on the effect of addition or removal of negatively charged residues, and found Sap\u2010dependent effects on degradation. Both single\u2010 and double\u2010substitutions affected the kinetics of proteolytic degradation of the intact peptide and of the fragments formed during degradation. Our results demonstrate the importance of considering proteolytic stability and not just antimicrobial activity when designing peptides for potential therapeutic applications.<\/jats:p>","DOI":"10.1002\/pro.3767","type":"journal-article","created":{"date-parts":[[2019,11,1]],"date-time":"2019-11-01T15:13:06Z","timestamp":1572621186000},"page":"480-493","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Effects of histatin 5 modifications on antifungal activity and kinetics of proteolysis"],"prefix":"10.1002","volume":"29","author":[{"given":"Svetlana P.","family":"Ikonomova","sequence":"first","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering University of Maryland  College Park Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parisa","family":"Moghaddam\u2010Taaheri","sequence":"additional","affiliation":[{"name":"Fischell Department of Bioengineering University of 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