Discovery of small molecule inhibitors of Leishmania braziliensis Hsp90 chaperone

Author(s)

Batista, Fernanda A. H. ^{[1, 2]} ; Ramos, Jr., Sergio L. ^[1] ; Tassone, Giusy ^[3] ; Leitao, Andrei ^[4] ; Montanari, Carlos A. ^[4] ; Botta, Maurizio ^{[3, 5, 6]} ; Mori, Mattia ^[3] ; Borges, Julio C. ^[1]

Affiliation

^[1] Univ Sao Paulo, Sao Carlos Inst Chem IQSC, Sao Carlos - Brazil

^[2] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Nacl Biosci Lab LNBio, Campinas, SP - Brazil

^[3] Univ Siena, Dept Biotechnol Chem & Pharm, Dept Excellence 2018 2022, Siena - Italy

^[4] Univ Sao Paulo, IQSC, Med Chem Grp NEQUIMED, Sao Carlos - Brazil

^[5] Lead Discovery Siena Sr, Siena - Italy

^[6] Temple Univ, Coll Sci & Technol, Ctr Biotechnol, Sbarro Inst Canc Res & Mol Med, Philadelphia, PA 19122 - USA

• Document type: Journal article
• Source: Journal of Enzyme Inhibition and Medicinal Chemistry; v. 35, n. 1, p. 639-649, JAN 1 2020.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 13/10712-8 - Identifying Molecules with Selective Inhibitory Action for leishmania, plasmodium and human Hsp90 ortologues: Thermodynamic and Comparative approach.
• Grantee: Fernanda Aparecida Heleno Batista
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/26131-5 - The chaperome: study of the relationship of the structure of its components and the maintenance of proteostasis
• Grantee: Carlos Henrique Inacio Ramos
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/07206-6 - Studies of the mitochondrial HSP70 of human and protozoa: structural and functional approaches
• Grantee: Julio Cesar Borges
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/23110-0 - Using isothermal titration calorimetry for the determination of thermodynamic properties of protein-ligand and protein-protein interactions
• Grantee: Julio Cesar Borges
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
• Grantee: Carlos Alberto Montanari
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/50161-8 - Study of the structure and function of the Hsp90 chaperone with emphasis on its role in cellular homeostasis
• Grantee: Carlos Henrique Inacio Ramos
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/07335-9 - Studies of human HSP70 isoforms residing in the cytoplasm and mitochondria and their high molecular weight oligomers: interaction with co-chaperones and client proteins
• Grantee: Julio Cesar Borges
• Support Opportunities: Regular Research Grants