Trivalent Ultrashort Lipopeptides are Potent pH Dependent Antifungal Agents

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• 作者：Christopher J. Arnusch ; H. Bauke Albada ; Martin van Vaardegem ; Rob M. J. Liskamp ; Hans-Georg Sahl ; Yana Shadkchan ; Nir Osherov ; Yechiel Shai
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：February 9, 2012
• 年：2012
• 卷：55
• 期：3
• 页码：1296-1302
• 全文大小：255K
• 年卷期：v.55,no.3(February 9, 2012)
• ISSN：1520-4804

文摘

The activity of antimicrobial peptides (AMPs) that contain a large proportion of histidine residues (pK_a 6) depends on the physiological pH environment. Advantages of these AMPs include high activity in slightly acidic areas of the human body and relatively low toxicity in other areas. Also, many AMPs are highly active in a multivalent form, but this often increases toxicity. Here we designed pH dependent amphiphilic compounds consisting of multiple ultrashort histidine lipopeptides on a triazacyclophane scaffold, which showed high activity toward Aspergillus fumigatus and Cryptococcus neoformans at acidic pH, yet remained nontoxic. In vivo, treatment with a myristic acid conjugated trivalent histidine鈥揾istidine dipeptide resulted in 55% survival of mice (n = 9) in an otherwise lethal murine lung Aspergillus infection model. Fungal burden was assessed and showed completely sterile lungs in 80% of the mice (n = 5). At pH 5.5 and 7.5, differing peptide鈥搈embrane interactions and peptide nanostructures were observed. This study underscores the potential of unique AMPs to become the next generation of clinical antimicrobial therapy.