According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion–toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 (TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain.

Accelerating Drug Discovery Efforts for Trypanosomatidic Infections Using an Integrated Transnational Academic Drug Discovery Platform

Elisa Uliassi;Maria Laura Bolognesi;
2019

Abstract

According to the World Health Organization, more than 1 billion people are at risk of or are affected by neglected tropical diseases. Examples of such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all of which are prevalent in Africa, South America, and India. Our aim within the New Medicines for Trypanosomatidic Infections project was to use (1) synthetic and natural product libraries, (2) screening, and (3) a preclinical absorption, distribution, metabolism, and excretion–toxicity (ADME-Tox) profiling platform to identify compounds that can enter the trypanosomatidic drug discovery value chain. The synthetic compound libraries originated from multiple scaffolds with known antiparasitic activity and natural products from the Hypha Discovery MycoDiverse natural products library. Our focus was first to employ target-based screening to identify inhibitors of the protozoan Trypanosoma brucei pteridine reductase 1 (TbPTR1) and second to use a Trypanosoma brucei phenotypic assay that made use of the T. brucei brucei parasite to identify compounds that inhibited cell growth and caused death. Some of the compounds underwent structure-activity relationship expansion and, when appropriate, were evaluated in a preclinical ADME-Tox assay panel. This preclinical platform has led to the identification of lead-like compounds as well as validated hits in the trypanosomatidic drug discovery value chain.
Carolina B. Moraes, Gesa Witt, Maria Kuzikov, Bernhard Ellinger, Theodora Calogeropoulou, Kyriakos C. Prousis, Stefano Mangani, Flavio Di Pisa, Giacomo Landi, Lucia Dello Iacono, Cecilia Pozzi, Lucio H. Freitas-Junior, Bruno dos Santos Pascoalino, Claudia P. Bertolacini, Birte Behrens, Oliver Keminer, Jennifer Leu, Markus Wolf, Jeanette Reinshagen, Anabela Cordeiro-da-Silva, Nuno Santarem, Alberto Venturelli, Stephen Wrigley, Deepa Karunakaran, Bethlehem Kebede, Ina Pöhner, Wolfgang Müller, Joanna Panecka-Hofman, Rebecca C. Wade, Martina Fenske, Joachim Clos, José María Alunda, María Jesús Corral, Elisa Uliassi, Maria Laura Bolognesi, Pasquale Linciano, Antonio Quotadamo, Stefania Ferrari, Matteo Santucci, Chiara Borsari, Maria Paola Costi, Sheraz Gul
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/700003
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