Discovery of small molecule inhibitors of Leishmania braziliensis Hsp90 chaperone

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
• inhibitors
• fluorescence
• leishmaniasis
• molecular modelling

Acknowledgements

The authors wish to thank the OpenEye Free Academic Licencing Programme for providing a free academic licence for molecular modelling and chemoinformatics software.

We acknowledge Prof. Dr. Reinaldo Alves de Brito and Dr. Felipe Rafael Torres (Department of Genetics and Evolution, Federal University of São Carlos) by the access to the equipment and technical support during DSF experiments.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

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.