Discovery of small molecule inhibitors of Leishmania braziliensis Hsp90 chaperone

Fernanda A H Batista; Sérgio L Ramos Jr; Giusy Tassone; Andrei Leitão; Carlos A Montanari; Maurizio Botta; Mattia Mori; Júlio C Borges

doi:10.1080/14756366.2020.1726342

Discovery of small molecule inhibitors of Leishmania braziliensis Hsp90 chaperone

J Enzyme Inhib Med Chem. 2020 Dec;35(1):639-649. doi: 10.1080/14756366.2020.1726342.

Authors

Fernanda A H Batista¹, Sérgio L Ramos Jr¹, Giusy Tassone², Andrei Leitão³, Carlos A Montanari³, Maurizio Botta^{2

4

5}, Mattia Mori², Júlio C Borges¹

Affiliations

¹ São Carlos Institute of Chemistry (IQSC), University of São Paulo (USP), São Carlos, Brazil.
² Department of Biotechnology, Chemistry and Pharmacy - Department of Excellence 2018-2022, University of Siena, Siena, Italy.
³ Medicinal Chemistry Group (NEQUIMED), IQSC-USP, University of São Paulo, São Carlos, Brazil.
⁴ Lead Discovery Siena S.r., Siena, Italy.
⁵ Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA.

Abstract

Leishmaniasis is a neglected disease caused by the protozoa Leishmania ssp. Environmental differences found by the parasites in the vector and the host are translated into cellular stress, leading to the production of heat shock proteins (Hsp). These are molecular chaperones involved in the folding of nascent proteins as well as in the regulation of gene expression, signalling events and proteostasis. Since Leishmania spp. use Hsp90 to trigger important transitions between their different stages of the life cycle, this protein family becomes a profitable target in anti-parasite drug discovery. In this work, we implemented a multidisciplinary strategy coupling molecular modelling with in vitro assays to identify small molecules able to inhibit Hsp90 from L. braziliensis (LbHsp90). Overall, we identified some compounds able to kill the promastigote form of the L. braziliensis, and to inhibit LbHsp90 ATPase activity.

Keywords: Hsp90; fluorescence; inhibitors; leishmaniasis; molecular modelling.

MeSH terms

Adenosine Triphosphatases / antagonists & inhibitors
Adenosine Triphosphatases / metabolism
Antiprotozoal Agents / chemical synthesis
Antiprotozoal Agents / chemistry
Antiprotozoal Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / metabolism
Leishmania braziliensis / chemistry
Leishmania braziliensis / drug effects*
Models, Molecular
Molecular Chaperones / chemical synthesis
Molecular Chaperones / chemistry
Molecular Chaperones / pharmacology*
Molecular Structure
Parasitic Sensitivity Tests
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Antiprotozoal Agents
Enzyme Inhibitors
HSP90 Heat-Shock Proteins
Molecular Chaperones
Small Molecule Libraries
Adenosine Triphosphatases

Grants and funding

FAPESP [2011/23110–0; 2012/50161–8; 2013/10712–8, 2013/18009–4, 2014/07206–6, FAPESP: 2017/26131–5 and 2017/07335–9], CNPq [471415/2013–8 and 303129/2015–8] and CAPES.