- RFP Year2020
- Awarded Amount$4,127,236
- Development StageLead Optimization
- Collaboration PartnersEisai Co., Ltd., International Centre for Genetic Engineering and Biotechnology , The Scripps Research Institute, Broad Institute
- Past Project
Introduction and Background of the Project
Treatment and ultimately elimination of malaria remains a massive challenge due, mainly, to the emergence of drug-resistant strains of Plasmodium falciparum, the most lethal species in humans. It is therefore necessary to discover lead candidates unaffected by existing mechanisms of resistance to traditional antimalarial chemotypes. Additionally, while prophylaxis and transmission-blocking drugs are needed to prevent epidemics and to protect vulnerable populations, standard-of-care antimalarials do not address all of the requirements for pan-lifecycle activity. The Broad Institute, in collaboration with Eisai Ltd., has discovered a series of antimalarial compounds with a novel mechanism of action (targeting Plasmodium falciparum cytosolic phenylalanine tRNA synthetase (PfcPheRS)) (Nature, doi:10.1038/nature19804). Our unique bicyclic azetidine series exhibits potent activity both in vitro and in vivo against blood-, liver- and transmission-stage P. falciparum parasites.
The goal of this proposal is to leverage structural data on the target parasite protein to guide the design of next-generation antimalarials with higher efficacy, with potentially lower costs of treatment, and improved safety profiles.
We will use a combination of structural biology and computational chemistry to guide the design of novel antimalarials, which will be synthesized and profiled in vitro and in vivo. Promising compounds will be advanced to in vivo safety studies with the goal of selecting a preclinical development candidate.
How can your partnership (project) address global health challenges?
While the global public health community has made significant progress in reducing mortality due to malaria, this mosquito-borne parasite still infects over 228 million people per year. Approximately 405,000 deaths were attributed to malaria in 2018, the majority of them in children under the age of five. In order to further decrease the morbidity and mortality associated with malaria, a multi-pronged approach is required, including vector (mosquito) control, effective vaccines, new chemotherapeutics that can target drug-resistant parasites, along with the infectious and transmission stages of the parasites (sporozoites and gametocytes, respectively), and the dormant hypnozoite stages of P. vivax and P. ovale. Medicines for Malaria Venture (MMV) has proposed the development of a Single Exposure Radical Cure and Prophylaxis (SERCaP) for the treatment of uncomplicated malaria in adults and children. The target product profile (TPP) for the ideal SERCaP would include rapid asexual blood-stage parasite reduction, transmission-blocking activity, and targeting of hypnozoites. We anticipate that a candidate from the proposed work would not only meet the requirements of at least one MMV TCP, but due to the known activity against gametocytes and liver-stage parasites, would provide a significant advantage to patients.
What sort of innovation are you bringing in your project?
Effective elimination strategies for malaria have been elusive, primarily due to the complex life cycle of Plasmodium and the emergence of drug-resistant strains of P. falciparum, the most lethal Plasmodium species in humans. The majority of the current antimalarial drugs target the asexual blood stages of Plasmodium in which the parasites invade and replicate within erythrocytes. Even though liver and transmission-stage parasites do not cause malarial symptoms, prophylaxis and transmission-blocking drugs are essential for the proactive prevention of disease epidemics and to protect vulnerable populations. Unfortunately, the current antimalarial drugs do not address all of the requirements for the targeting of pan-life-cycle activity. Our unique bicyclic azetidine series exhibits potent activity both in vitro and in vivo against blood-, liver- and transmission-stage P. falciparum parasites with a novel mechanism of action (via targeting the parasite encoded cytosolic version of phenylalanine tRNA synthetase (PfcPheRS)).
Role and Responsibility of Each Partner
Project members from the Broad Institute, Eisai Co. Ltd., The Scripps Research Institute (Scripps Research), and The International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi will collaborate closely in order to execute on the project plan while taking advantage of each organization’s strengths and expertise.
Broad Institute will contribute to project management and leadership. As the Designated Development Partner, the Schreiber lab at the Broad Institute will be the primary owner/manager of the program. The Broad will serve as a point of contact for all entities participating on this collaborative project team, ensuring the joint progress is coordinated effectively and funds are spent according to the investment agreement. Broad will also work with Scripps, Eisai, and CROs to contract in vitro host cytotoxicity, and in vivo efficacy experiments, as needed.
Eisai will contribute project management and leadership. Additionally, Eisai will contribute advanced synthetic intermediates, chemistry know-how (e.g. synthetic procedures), structural biology, and computational chemistry resources to analyze and design new analogs. Eisai will be responsible for pharmacokinetics and safety studies to identify any key liabilities.
Scripps Research will contribute to project management and leadership. In addition, Scripps will contribute to analog design and planning and supervision of small-molecule synthesis (Objective 1). Scripps Research will also work with Broad, Eisai and CROs to contract in vitro potency (Pf liver- and transmission-stage), and in vivo efficacy experiments, as needed.
ICGEB New Delhi will be responsible the production of recombinant PfcPheRS enzyme for binding assays (TSA, ITC and aminoacylation) and crystallographic studies (Objective 2).
Others (including references if necessary)