Drug repositioning for the development of innovative therapies for cutaneous leishmaniasis: exploring trypanothione reductase as a molecular target

• Grant number: 24/05272-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: December 01, 2024
• End date: April 30, 2028
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Luiz Felipe Domingues Passero
• Grantee: Sarah Santos de Lima Melchert
• Host Institution: Instituto de Biociências (IB-CLP). Universidade Estadual Paulista (UNESP). Campus Experimental do Litoral Paulista. São Vicente , SP, Brazil

Abstract

Leishmaniasis is a neglected tropical disease that affects approximately 1 million people annually worldwide. Although leishmaniasis is a disease with a high number of species infecting humans and causing a wide range of clinical manifestations, few drugs are used in treatment. The administration of these drugs results in numerous disadvantages during therapy, including limited effectiveness, parasite resistance, severe side effects, and high costs. Thus, the search for new therapies directed for leishmaniasis is urgent and necessary. Drug repositioning is a technique that allows the selection of drugs already approved for use in new diseases. The use of computational modelling proves to be an effective approach for identifying the affinity between a molecule (drug) and a selected target protein, enabling the development of therapies more quickly, safely, and at a lower cost, proving to be a strong ally in drug repositioning strategy. However, the selection of a target protein is of utmost relevance during therapy development, as it can influence the drug's selectivity toward the pathogen.Trypanothione reductase is an enzyme exclusive to the Trypanosomatidae family, which plays a role in the redox control of these protozoa and has been shown to be a strong candidate as a target in antiLeishmania drugs. Thus, this study aims to reposition drugs in leishmaniasis that have the ability to inhibit the trypanothione reductase enzyme of L. (L.) amazonensis. Specific objectives include: 1) assess the interaction of drugs with the trypanothione reductase enzyme of L. (L.) infantum using computational methods and selecting drugs with the highest potential for enzyme inhibition; 2) produce a recombinant TR protein and evaluate the ability of selected drugs to inhibit TR enzyme activity; 3) evaluate the activity of selected drugs in promastigote and intracellular amastigote forms of L. (L.) amazonensis, evaluating possible action mechanisms; 4) produce and characterize a nanoformulation with the most active drug; 5) assess the therapeutic efficacy of the nanoformulated drug in experimental skin leishmaniasis; and 6) evaluate histopathological and immunological changes in in vivo studies.