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Converting natural product leads into structure- and ligand-based drug discovery campaigns against Leishmaniasis and Chagas' Disease

Grant number: 18/14268-9
Support type:Research Projects - Thematic Grants
Duration: April 01, 2019 - March 31, 2022
Field of knowledge:Biological Sciences - Biophysics
Cooperation agreement: MRC, UKRI ; Newton Fund, with FAPESP as a partner institution in Brazil
Principal Investigator:Adriano Defini Andricopulo
Grantee:Adriano Defini Andricopulo
Principal investigator abroad: Kevin David Read
Institution abroad: University of Dundee, Scotland
Home Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Co-Principal Investigators:Mônica Tallarico Pupo
Assoc. researchers:Glaucius Oliva ; Ian Gilbert ; Paulo Cézar Vieira ; Susan Wyllie ; Vanderlan da Silva Bolzani

Abstract

The lack of robustly validated drug targets has proved a significant barrier to the discovery of new treatments for visceral leishmaniasis and Chagas' disease. Furthermore, target deconvolution studies with active leads emerging from current small molecule phenotypic screening have confirmed that the same relatively few molecular targets are being hit repeatedly. This project aims to address these issues through exploitation of more diverse chemistry hits available in the natural product (NP) arena to identify new drug targets and where possible new chemical start points.A number of pure, active NPs have been isolated from microbial symbionts of social insects that demonstrate potent activity against Leishmania donovani intracellular amastigotes. Additionally, the Nucleus of Bioassays, Biosynthesis, and Ecophysiology of Natural Products (NuBBE - UNESP) will offer an additional source of isolated NP compounds for investigation. Scale-up and purification of these NPS will be undertaken to deliver sufficient material for mode of action studies, using a number of orthogonal approaches including high-throughput genomics, cell biology/biochemistry and/or chemical proteomics to define the principal molecular targets(s) of the NPs, thus offering the opportunity to convert NP phenotypic hits into a collaborative structure-based drug discovery programme. Where possible, further scale-up will be undertaken to provide sufficient material to also assess developability, profiling in vitro and in vivo. A hit to lead chemistry campaign may be initiated if feasible. Furthermore, consideration of the presence of underlying 'natural product fragments' will be undertaken, these then tested in isolation to find simpler pharmacophore start points for medicinal chemistry.This project has potential to deliver novel target(s) for these key kinetoplastid diseases, enabling initiation of novel structure based small molecule drug discovery programmes. Additionally, the project has potential to deliver much needed early leads in novel chemical space. (AU)

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