Abstract 1979 Designing Metal-Binding Peptides as Dimerization Disruptors of Ribose-5-Phosphate Isomerase B from Leishmania donovani

Leishmaniasis is a neglected tropical disease caused by protozoan parasites from over twenty Leishmania species. More research on developing treatments for this parasitic disease is warranted as many current therapies suffer from undesirable side effects or emerging drug resistance. An alternative approach to treating leishmaniasis involves causing parasitic death by targeting the dimerization of ribose-5-phosphate isomerase B (RpiB), an essential protein-protein interaction of the pentose-phosphate pathway in Leishmania parasites. In this work, RpiB-binding peptides (RBPs) with two amino acid side chains linked via a metal-binding hybrid coordination motif (HCM) are designed to bind the dimerization interface of RpiB monomers to block formation of the functional homodimer and destroy the parasite. Introduction of an HCM crosslink into short peptides is expected to induce an α-helical structure and confer properties favorable for a peptide therapeutic including enhanced cellular internalization, increased resistance to proteolytic cleavage, and improved binding to RpiB. While RBPs crosslinked with a metal-bound HCM have not exhibited greater α-helicity compared to their metal-free counterparts, they have shown greater proteolytic stability. The presented work will also compare the biophysical properties of metal-bound HCM bearing peptides to other commonly used peptide crosslinking strategies. Future work will focus on determining the binding affinity of HCM-crosslinked RBPs for their RpiB target and the extent to which they inhibit enzyme activity. I would like to acknowledge Cell Biology & Biochemistry Undergraduate Research at Bucknell University for funding.