Metal Complex Bioconjugation as a Platform for Developing Targeted Therapies for Leishmaniasis

• Grant number: 24/18677-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2025
• End date: August 31, 2027
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Camilla Abbehausen
• Grantee: Rafaela Ribeiro Paixão
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 22/02618-0 - Design of novel metallodrugs and innovative administration routes for Leishmaniasis treatment, AP.PNGP.PI

Abstract

Leishmania protozoan parasites cause leishmaniasis, a disease with a range of clinical manifestations in humans, transmitted by sandfly bites. According to the World Health Organization, it is endemic in 88 countries and affects 12 million people worldwide, classified as one of the most neglected tropical diseases. Leishmaniasis control is puzzling, particularly in Brazil, where it has been spreading across the country, leading to an increase in the number of cases in urbanized areas. Drug options to treat patients are limited, with antimonials having remained as the first line of treatment for all forms of leishmaniasis for almost a century, even though they are toxic and require painful parenteral administration. Cysteine proteases (CP), trypanothione reductase (TR) and zinc finger (ZF) domains are essential proteins/enzymes for parasite survival and replication. Thus, they are significant molecular targets for drug design. One of the main challenges of medicinal inorganic chemistry is to create targeted therapies. In this context, we propose to bioconjugate peptides or nucleotides to the metallocompounds as a strategy for targeting. We envisage selecting one active chemotype (M-NHC) then modifying it by peptides or nucleotides conjugation, aiming to direct the compound to inhibit a specific target. The methodology consists in functionalizing the NHC with a carboxylate group for further coupling reaction amino-terminal groups. The small peptide/nucleotide sequences that specifically inhibit each one of the three proteins are described in the literature as discussed in the main project.