INNOVATIVE DISCOVERY AND TARGETING OF NOVEL POINTS OF INTERVENTION TO KILL RESISTANT LIFE-THREATENING PARASITES

Neglected tropical diseases (NTDs) due to parasitic infections are chronic, debilitating, and poverty-promoting maladies. Current treatments are failing due to the spread of resistant strains, high host toxicity, and lack of suitability for rural health systems. Among NTDs, pathogenic trypanosomatids T. cruzi (Chagas disease), Leishmania spp. and T. brucei (Human African Trypanosomiasis) are responsible for the most dramatic figures.

The gravity of the NTD situation necessitates a new mindset to provide effective therapy. Armed by new biomedical technology and a collaborative approach designed to seize upon new leads and new strategies for target validation, we propose to focus on two fundamental objectives: 1) identification of new points of intervention for therapeutic discovery. Employing promising prototypes as probes, we will characterize primary and secondary targets, binding patterns, modes of action and mechanisms of drug resistance. 2) Targeting vital parasite functions with novel molecules, we will pursue new agents to disrupt glycosome and ribosome function. Novel drugs against resistant NTDs will be developed with enhanced potential to improve potency, selectivity and drug-like properties. 

Our interdisciplinary team is strategically composed of international leaders in the fields of chemistry, molecular and medical parasitology, and structural biology.  To identify and target novel points of intervention, our team has mastery of state-of-the-art approaches, including unique CRISPR-based pathway screening, ground-breaking in vitro and in vivo models, NG proteomics, RNA-mRNA foot printing, single particle cryo-EM methods to discover the molecular details underlying death or survival, whole-genome approaches for the discovery of drug resistance mechanisms, and in-house peptide and small molecule leads.

This program represents a first in-kind international effort to curtail the threat of resistant life-threatening parasites. Our fusion of medical chemistry, structural biology and parasitology offers a novel foundation for training highly qualified personnel in the identification and targeting of new points of intervention against parasites.  Fueled by our individual track records for success and our promising collaborative results, our team is positioned to pioneer discovery of new intellectual property, original tactics for controlling parasitic infection and novel therapy to relieve the socioeconomic burden of neglected tropical diseases.

Team:

 

Martin Olivier (McGill University, Canada)

William Lubell (University of Montreal, Canada)

Ada Yonath (Weizmann Institute, Israel)

Anat Bashan (Weizmann Institute, Israel)

Javier Moreno (National Center of Microbiology-ISCIII, Spain)

Eugenia Carrillo (National Center of Microbiology-ISCIII, Spain)

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