New Chemotherapy Against Trypanosomiasis and Leishmaniasis

Pp. 454-530 (77)

Jair L. de Siqueira-Neto

Abstract

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi affecting mostly the American continent eventually leading to chronic cardiomyopathy or digestive syndromes. Human African Trypanosomiasis is caused by the related parasite T. brucei, endemic in the African continent and being characterized by invasion and damage in the central nervous system. Leishmaniasis is caused by a number of species from the genera Leishmania and can manifest with different clinical outcomes including skin ulcers and visceral organ damage, being endemic in 88 countries in tropical areas of the globe. Despite having different geographical distribution and unique clinical symptoms, these diseases are all caused by related protozoan parasites from the order Kinetoplastida. Another aspect shared by these diseases is related to the treatment options currently available, unfortunately, all inadequate. Serious problems are toxicity and inefficacy due parasite acquired resistance or lack of natural susceptibility. The population affected by these three diseases does not represent an attractive economic market, reflecting on little pharmaceutical industry interest in developing better chemotherapies. However, in the last decade, the situation has dramatically improved, with the active engagement of philanthropic financial support, national government organizations, research centers, the pharmaceutical industry and the Drugs for Neglected Diseases Initiative (DNDi). After the development of screening assays, millions of molecules have been tested, and some have reached Clinical Trials stage. A milestone has been set for the year 2020, by the London Declaration: control of Chagas disease and leishmaniasis, and elimination of Human African Trypanosomiasis. Advances and progress to achieve these goals are presented in this chapter.

Keywords:

African Trypanosomiasis, Chagas Disease, Chemotherapy, Drug development, High-throughput hit selection, Lead optimization, Leishmaniasis, Medicinal chemistry, Neglected Diseases, Pharmacokinetics.

Affiliation:

Skaggs School of Pharmacy and Pharmaceutical Sciences / Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego, La Jolla, CA 92093, USA.