My laboratory uses methods in molecular and structural biology (X-ray crystallography and Nuclear Magnetic Resonance) to characterize the protein synthesis machinery of parasites, such as the ones causing Leishmaniasis and Malaria, that significantly burden public health. Our long-term goal is to harness this information to develop safe and effective antiparasitic drugs.
Modulation of translation initiation in Leishmania major.
Leishmania parasites, which cause human leishmaniasis, are transmitted to humans through the bite of infected sandflies. Parasites can cause disfiguration through chronic skin lesion and in some cases can disseminate to visceral organs and be lethal. Most of the expression of Leishmania gene products are regulated at the level of translation, and parasites contain at least six cap-binding orthologs of the human cap-binding protein eIF4E. Of these isoforms, LeishIF4E-1 is the only isoform that is expressed in amastigotes (human stage of the parasite). As part of a longstanding collaboration with the laboratory of Dr. Michal Shapira (Ben-Gurion University of the Negev, Israel), we identified a novel interacting partner for LeishIF4E-1 (Leish4E-IP1) and determined the X-ray crystal structure of LeishIF4E-1 bound to an extended fragment of Leish4E-IP1. We used the structure, along with NMR experiments and in vitro cap-binding assays, to show that Leish4E-IP1 allosterically destabilizes the binding of LeishIF4E-1 to the 5′ mRNA cap. This work has begun to reveal peculiarities of translation in this group of human parasites and indicate that translation factors are attractive targets for the identification of small molecules inhibiting protein-protein interactions specifically in parasites.
Modulation of translation initiation in Malaria.
Young children are most vulnerable to severe infection by malaria parasites, and in 2016, 300,000 died on the African continent from malaria before their fifth birthdays. Of the five Plasmodium species pathogenic to humans, infection by P. falciparum is associated with the most significant morbidity and mortality. Some of the current antimalarial lack pediatric formulations, and there is no vaccine available to prevent malaria. Understanding fundamental biological processes that are essential to parasite survival, but that differ in mammalian cells, could lead to the identification of novel drug targets. Antibiotics that specifically block protein synthesis have long been used to treat bacterial infections, and some have activity against translation in Plasmodium organelles. As an essential step toward the identification of novel treatments for malaria, we aim to target crucial factors involved in the first step of the parasite cytoplasmic protein synthesis – translation initiation, in which mRNAs are recruited to the ribosome. While some of the factors involved in translation initiation are conserved between mammalian cells and P. falciparum, some important factors appear to be missing in the parasite, suggesting the presence of additional factors that have yet to be identified. The ultimate goal is to identify a novel family of antiparasitic agents that disrupt protein-protein interaction during protein synthesis in the parasites, and that could be deployed as part of the armamentarium against malaria.