Leishmaniasis Drug Development Using an Evolutionary Design Strategy

Linington, Roger

Abstract

Leishmaniasis is a debilitating disease prevalent across many of the inter-tropical regions of the world including India, Sudan and Brazil. Caused by over twenty species of intracellular parasite from the genus Leishmania, leishmaniasis can present itself in a number of different clinical manifestations. In the non-fatal mucosal form of the disease these include ulcerative skin lesions and the destruction of the mucous membranes of the nose, mouth and throat leading to permanent disfigurement; however it is the visceral form of the disease that represents the greatest threat to human health, with mortality rates as high as 80% for untreated infections. The recent discovery of the almiramide family of natural products as potent and effective anti-parasitic agents against the tropical parasite Leishmania donovani therefore provides a valuable opportunity for leishmaniasis drug development. Current treatments are limited to only a few viable alternatives, each of which suffers from drawbacks in terms of efficacy, toxicity or cost. Until recently the most widely used therapeutic in most regions of the world was the pentavalent antimony based drug Pentostam; however, given the growing levels of resistance to this drug and the high mortality rate caused by this treatment, new drugs are urgently needed. The high potency and low toxicity of the almiramides makes them excellent candidates in this regard. The Evolutionary Library Design strategy put forward in this proposal provides a novel strategy for the development of peptidic drug leads, such as the almiramides, by combining a unique conceptual approach to library design with modern methods in solid phase synthesis, high throughput automated purification, and biological evaluation. The resulting unified strategy for drug development is both highly targeted and efficient in execution, and is designed specifically to identify lead compounds with the best overall pharmacological and pharmacokinetic properties to move forward as pre-clinical drug candidates. In order to advance candidate structures to preclinical development it is imperative to show that these compounds display reasonable efficacy and toxicity profiles in vivo. This research program aims to resolve this issue by the large-scale production of the top candidate structures, and potency and DMPK evaluation in vivo. Because the synthetic route is short and can be completed entirely on the solid support, large-scale synthesis of multiple candidate structures can be accomplished rapidly and in high overall yield. Finally, target identification for this compound class is another valuable element of drug development, which has far reaching implications for both drug optimization and delivery strategies. A number of powerful chemical genetic techniques have recently emerged that provide the opportunity for rapid and accurate identification of molecular targets using chemical derivatization of lead structures. By employing the knowledge gained during the initial SAR phases of drug development, we aim to develop both fluorescent and photoaffinity probes for the direct identification of the mode of action of this compound class.

Public Health Relevance

Leishmaniasis is a debilitating disease common to South America, Africa, and India for which there are few available treatments. This project aims to develop a new class of marine natural products, the almiramides, as drug candidates against leishmaniasis. In the course of this study we aim to both develop new effective treatments for this disease and to determine the mechanism by which these drugs exert their effect against the target parasite.