Development of Antiparasitic Agents from Natural Peptides and Peptidomimetics

Abstract

Neglected Tropical Diseases (NTDs) affect hundreds of millions of people worldwide, resulting in significant mortality rates and devastating social and economic consequences. Current treatments for parasitic NTDs are far from ideal. Natural products have been, and continue to be, invaluable sources of inspiration in drug design and development, and they offer considerable potential in the field of NTDs.
A family of cyclic peptides, Chaiyaphumines, were isolated from Xenorhabdus bacteria, and they were found to show promising activity against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Plasmodium falciparum, as well as low toxicity for mammalian L6 cells. In this work a versatile and efficient total synthesis of two natural Chaiyaphumines, and a series of amide analogues was developed. The improved synthetic process was also used to carry out an alanine scan on one of the most promising amide analogues.
Antimicrobial peptides (AMPs) have been studied previously as potential scaffolds for the development of new anti-leishmanials. Herein, the solid phase synthesis of two small libraries of AMPs (derived from the Temporin and Histatin families) has been carried out. The AMPs prepared were tested against L. major and L. amazonensis promastigotes, L. mexicana, promastigotes and axenic amastigotes. This was the first time a Histatin library of AMPs has been tested against three different types of leishmania parasites. Although the peptides prepared were found to have low biological activity, the information gathered adds to our understanding of the potential that AMPs could have in the development of new treatments for NTDs.
Finally, this thesis investigated the potential application of simple lipo-peptoids as a new source of NTD agents. Peptoids are a class of peptide-mimetics that given their easy of synthesis and enhanced proteolytic stability perhaps offer a better opportunity for the development of new anti-leishmanial therapeutics compared to peptides. A library of linear peptoids and lipo-peptoids was synthesised using a Ugi-4CR in a one-pot reaction. The peptoid library prepared was then screened against both the promastigote and amastigote stages of the Leishmania mexicana parasite. From this library, seven peptoids showed antileishmanial activity against the axenic form of the parasite, with EC50’s of less than 25 nM.