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

Duke University, Durham NC

Investigators

Abstract

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.