Leishmania and Trypanosoma are protozoan parasites causing vector-borne zoonosis that affect millions of people worldwide. These infections constitute a serious health issue in low-income countries but are endemic in developed countries as well, including the Mediterranean basin. Vaccines are lacking and current treatments are unsatisfactory due to toxicity, poor efficacy and resistance, thus new drugs are urgently needed.
This project aims at contributing to the development of an effective broad-spectrum trypanocidal drug through a rational structure-based approach focused on two promising protein targets, trypanothione reductase (TR) and ornithine decarboxylase (ODC), essential for proliferation and redox homeostasis of Trypanosomatidae. Structural and functional characterization of the targets will be carried out by state-of-the-art techniques, aiding the structure-based design of potent drug-like compounds and supporting the future work of research groups interested in trypanocidal drug development. In addition, we will explore a delivery strategy based on the encapsulation of eflornithine in the protein ferritin, with the double aim to validate ODC as a target and ferritin as a drug carrier for leishmaniasis.
The modular organization of the project, comprised of parallel work packages for the proposed targets, maximizes the probability of success, preventing the failure of one or more steps from compromising the entire research plan.
The project has the potential to boost the development of a broad-spectrum drug active on all trypanosomatid infections. This is clearly an ambitious goal because differences in biology and lifestyle of these parasites, although they are closely related genetically, could cause species-specific efficacy, as in the case of eflornithine (DFMO). Nonetheless, any result obtained on one specific parasite has the potential to be transferred to the other members of the family, making a huge impact on the field. Regardless of the achievement of the main objective, the study will deepen the structural characterization of the selected targets, supporting the future work of research groups interested in trypanocidal drug development.
The project will take advantage of fragment-based crystal screening, a cutting-edge technology in preclinical drug development never performed before on TR. The experiment will lead the identification of new molecular scaffolds and/or new binding pockets to be exploited for the design of more potent inhibitors targeting TR.
Besides targets characterization, the project will explore the feasibility of drug encapsulation and delivery for the treatment of leishmaniasis, exploiting the exceptional properties of ferritin as a carrier and of DFMO as a universal inhibitor of ODC. If successful, the study will have the double result of validating ODC as a target also for leishmaniasis and of providing a delivery system applicable in principle to any compound with trypanocidal activity, overcoming the limitations due to the intracellular lifestyle of Leishmania parasite.
The modular organization of the project, comprised of parallel work packages for the proposed targets, maximizes the probability of success, preventing the failure of one or more steps from compromising the entire research plan.