Discovery of small molecule inhibitors of Leishmania braziliensis Hsp90 chaperone

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

doi:10.1080/14756366.2020.1726342

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.

Highlights

Therapeutic regimens for the treatment of neglected tropical diseases (NTDs) are limited, have high toxicity, restrictions on use by some patients, and are difficult to adhere because they generally require parenteral and long-term administration
Energy minimisation was performed in two consecutive steps: (i) the solvent alone was energy minimised for 1000 steps with the Steepest Descent algorithm (SD) and subsequent 200 steps with the Conjugate Gradient algorithm (CG); (ii) the whole solvated complex was energy minimised for 1500 steps SD and subsequent 6000 steps CG
The lack of structural details on LbHsp90N seriously limited the rational design of specific small molecule inhibitors

Summary

Introduction

Therapeutic regimens for the treatment of neglected tropical diseases (NTDs) are limited, have high toxicity, restrictions on use by some patients, and are difficult to adhere because they generally require parenteral and long-term administration. This scenario becomes even more complex given the low investment in research and development aimed at treating NTDs1. An increasing number of cases of acquired resistance to these drugs, coupled with toxicity, the lack of efficacy, and the need for parenteral administration (except Miltefosine) highlight the need of novel treatment options for leishmaniasis[2,4]

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Discussion

Conclusion