Elucidating the Reactive Species Responsible for the Antifungal Activity of a Metallopeptide

阐明负责金属肽抗真菌活性的反应物种

• 批准号: 1808710
• 负责人: Katherine Franz
• 金额: $ 47.1万
• 依托单位: Duke University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1808710&HistoricalAwards=false
• 关键词: Elucidating; Reactive; Species; Responsible; Antifungal

This award from the Chemistry of Life Processes Program in the Chemistry Division will support work by Professor Katherine J. Franz at Duke University to elucidate the basis for the antifungal activity of histatins, a family of naturally occurring peptides found in saliva. As part of the immune system, histatins are known to provide a layer of protection against infection, although the chemical details of how they do this is not well understood. The experimental work of this award will test the hypothesis that histatin peptides generate reactive complexes with copper that are capable of damaging fungal targets. Graduate and undergraduate students will acquire training in methods of bioinorganic chemistry in an interdisciplinary and supportive research environment that promotes diversity and inclusion as a vehicle for creativity and excellence. The outcomes will provide detailed understanding of metal-dependent processes responsible for fungal cell killing, thereby filling a knowledge gap that currently limits a comprehensive understanding of the diverse mechanisms used by the innate immune system to ward off infection.Histatins are peptides of the innate immune system that range in length from 7 to 38 residues, including multiple metal-ligating amino acid side chains arranged in motifs characteristic of metalloproteins and metallopeptides. While it has long been speculated that histatins' capacity to bind metal ions is important for its biological activity, the molecular details linking metallopeptide formation and antifungal activity have been lacking. This work will test the hypothesis that histatin peptides generate reactive copper-oxygen species that are capable of damaging specific fungal targets as part of their antifungal mechanism. This hypothesis derives from recently published work from the Franz Lab that established a dependence for copper on histatins' fungicidal activity and identified previously unrecognized Cu(I) binding sites that are required for cell killing. The experiments supported by this award will identify spectroscopic features and reactivity profiles of the molecular species formed by reaction of Cu(I) and Cu(II) peptide complexes with oxygen species and identify likely substrates that such intermediates may alter. Outcomes of these studies will provide new insights into the activity of peptides that represent primitive elements of the innate immune system.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该奖项来自化学部生命过程计划的化学，将支持杜克大学的凯瑟琳J.弗朗茨教授的工作，以阐明组蛋白抗真菌活性的基础，组蛋白是唾液中发现的天然肽家族。作为免疫系统的一部分，已知组胺素可以提供一层抗感染的保护，尽管它们如何做到这一点的化学细节尚不清楚。该奖项的实验工作将测试组胺素肽与铜产生反应性复合物的假设，这些复合物能够破坏真菌靶标。研究生和本科生将在跨学科和支持性的研究环境中获得生物无机化学方法的培训，该环境促进多样性和包容性，作为创造力和卓越的载体。这些结果将提供对负责真菌细胞杀伤的金属依赖性过程的详细了解，从而填补目前限制对先天免疫系统抵御感染的多种机制的全面理解的知识空白。组胺素是先天免疫系统的肽，长度范围从7到38个残基，包括以金属蛋白和金属肽的特征性基序排列的多个金属连接氨基酸侧链。虽然长期以来一直推测组蛋白结合金属离子的能力对其生物活性很重要，但缺乏将金属肽形成与抗真菌活性联系起来的分子细节。这项工作将测试的假设，组胺肽产生活性铜氧物种，能够破坏特定的真菌目标作为其抗真菌机制的一部分。这一假设来自Franz实验室最近发表的工作，该工作建立了铜对组胺素的杀真菌活性的依赖性，并确定了细胞杀伤所需的先前未被识别的Cu（I）结合位点。该奖项支持的实验将确定Cu（I）和Cu（II）肽复合物与氧物种反应形成的分子物种的光谱特征和反应性特征，并确定此类中间体可能改变的可能底物。这些研究的结果将为代表先天免疫系统原始元素的肽的活性提供新的见解。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

项目成果

Intestinal mucin is a chaperone of multivalent copper

肠粘蛋白是多价铜的伴侣

• DOI: 10.1016/j.cell.2022.09.021
• 发表时间: 2022
• 期刊: Cell
• 影响因子: 64.5
• 作者: Reznik, Nava;Gallo, Annastassia D.;Rush, Katherine W.;Javitt, Gabriel;Fridmann-Sirkis, Yael;Ilani, Tal;Nairner, Noa A.;Fishilevich, Simon;Gokhman, David;Chacón, Kelly N.
• 通讯作者: Chacón, Kelly N.