Scaffolds and Biological Targets Avenue to Fight Against Drug Resistance in Leishmaniasis

Leishmaniasis is causing a major health problem worldwide and only five to six drugs are available for its control. Among them, antimonials, amphotericin, and miltefosine have been introduced starting in the 1940s and have proved to be effective for many years. However, the appearance of resistance threatens the success of anti-Leishmania treatment and spontaneous resistance to classical first- and second-line anti-Leishmania therapy reveals the major need to develop novel and less toxic drugs. A deep understanding of the mechanisms of drug resistance may help in the design of novel anti-Leishmania agents to be exploited in combination or as second-line therapy. Moreover, the discovery and validation of novel and druggable targets represent a useful tool to tackle drug resistance in leishmaniasis. Some biological processes such as redox metabolism, folate biosynthesis, protein synthesis, and turnover are potentially suitable to develop novel effective agents since they involve proteins showing a unique biological profile with respect to the human metabolism. Phenotypic screening and target-based drug discovery are promising tools to be exploited in drug discovery and development for leishmaniasis. Herein, we outline the most recent efforts in the identification of novel chemical scaffolds using both drug discovery strategies. We finally discuss the breakthroughs in the identification and validation of new biological targets, including Leishmania infantum initiation factor 4A, Leishmania casein kinase 1.2 (LmCK1.2), and methionyl-tRNA synthetase in Leishmania parasites. Different medicinal chemistry teams are currently exploring these targets aiming to pick out compounds displaying an improved profile to reinforce the drug pipeline.