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

该奖项来自化学学部生命过程化学项目，将支持杜克大学Katherine J. Franz教授阐明组他汀类药物抗真菌活性基础的研究。组他汀类药物是唾液中发现的一类天然多肽。作为免疫系统的一部分，组他汀类药物可以提供一层防止感染的保护，尽管它们如何做到这一点的化学细节还不是很清楚。该奖项的实验工作将验证组蛋白肽与铜产生反应性复合物的假设，该复合物能够破坏真菌目标。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，以促进多样性和包容性，作为创造力和卓越的载体。这些结果将提供对真菌细胞杀伤的金属依赖过程的详细了解，从而填补了目前限制对先天免疫系统用于抵御感染的多种机制的全面理解的知识空白。组抑素是先天免疫系统的肽，长度从7到38个残基不等，包括金属蛋白和金属肽特征基序中排列的多个金属连接氨基酸侧链。虽然长期以来人们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，但金属肽形成和抗真菌活性之间的分子细节一直缺乏。这项工作将验证组蛋白肽产生活性铜氧物质的假设，这些活性铜氧物质能够破坏特定的真菌目标，作为其抗真菌机制的一部分。这一假设来源于Franz实验室最近发表的研究成果，该研究证实了组他汀类药物的杀真菌活性依赖于铜，并发现了以前未被识别的杀死细胞所需的铜(I)结合位点。该奖项支持的实验将确定由Cu(I)和Cu（II）肽复合物与氧反应形成的分子种类的光谱特征和反应性，并确定这些中间体可能改变的底物。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。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.