Design of novel metallodrugs and innovative administration routes for Leishmaniasis treatment

Abstract

Leishmania parasites cause leishmaniasis, an endemic neglected tropical disease with several clinical manifestations in humans, including visceral (VL) and cutaneous (CL) forms. In Brazil, it has been spreading, leading to an increase in cases in urbanized areas. As a drawback, drug options are limited. For almost a century, antimonials have remained the first line of treatment, even though they are toxic and require painful parenteral administration. Consequently, a central area in leishmaniasis research is the identification of less toxic therapies. Still, most reports focus on VL, and few efforts are found on CL topical treatments. In the last case, topical administration is considered more advantageous, though few ineffective options are available. Our research group has been investigating systematic series of Au(I) and Cu(I)-N-heterocyclic carbenes (NHC) for leishmaniasis treatment. As a result, we have found chemotypes with a significant selective index. Accordingly, the project goal is the development of a topical therapy for CL based on Au(I) or Cu(I)-NHC complexes. Three different approaches are proposed to reach the goal. Firstly, the development of NHCs to modulate the lipophilicity and pKa of the final metal complexes, tuning their distribution to the parasite. Secondly, conjugation of biochemical groups to the metal complexes, such as short peptides or nucleotides to create a targeted therapy. Thirdly, the evaluation of polymeric membranes for the topical-sustained release of the metallodrugs. The design of molecules will be supported by in silico and mechanistic studies, including cell uptake, membrane permeabilization, measurements of reactive oxygen species production, mitochondrial respiratory activity, and target inhibition using cell extracts, purified proteins, or models. The sustained release will be measured by diffusion methods, in vitro protocols, and in vivo models. (AU)