Introduction and Background of the Project

1.Introduction

Malaria continues to inflict an enormous healthcare burden. In 2020, 241 million cases of malaria and 627,000 deaths were recorded, mostly in Africa, and half of the world’s population in 91 countries are at risk of the disease (World Malaria Report, WHO, 2017-2021). Existing antimalarial drugs have limitations due to their dosing regimens and side effects, and resistance to frontline therapies is rapidly emerging. There is therefore a critical need for development of new drugs with improved properties, particularly antimalarials with new mechanisms of action (MoA) to combat resistance, and the ability to clear infection with a single dose.
Our collaborative team has pioneered the development of antimalarials inhibiting P. falciparum cytosolic phenylalanyl-tRNA synthetase (PfcPheRS), a high-priority novel antimalarial target (Forte et al., ACS Infect. Dis. 2021, 7, 2764–2776). This has resulted in a clinical candidate with a novel MoA, multi-stage activity and the potential for single-dose efficacy. Recently, our team has employed a structure-based approach to identify next-generation PfcPheRS inhibitors.

2.Project objective

The goal of this proposal is to evaluate the safety, pharmacokinetic and efficacy profiles of next-generation cPheRS-inhibitor antimalarials, with potentially lower cost of treatment and improved safety profiles.

3.Project design

Promising, recently generated novel antimalarial compounds will be synthesized and profiled in in vivo efficacy studies, exploratory safety studies and multi-species pharmacokinetic 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 241 million people per year. Approximately 627,000 deaths were attributed to malaria in 2020, the majority of them in children under the age of five. In order to decrease the morbidity and mortality associated with malaria with the ultimate goal of eradication, a multi-pronged approach is required, including vector (mosquito) control, effective vaccines and new chemotherapeutics. These new drugs are urgently needed to combat emerging resistance to frontline antimalarials, and provide improved properties such as single-dose efficacy and activity against multiple stages of the parasite lifecycle that will contribute to effective malaria control. A candidate from our project has the potential to meet these criteria as a next-generation PfcPheRS inhibitor with single-dose efficacy, multi-stage activity, a favorable safety profile and affordable cost-of-treatment.

What sort of innovation are you bringing in your project?

Our project leverages a structure-based approach that has enabled identification of next generation inhibitors of a high-priority antimalarial target, PfcPheRS. This builds on and is informed by the pioneering work of our collaborative project team to develop the first clinical candidate against this target. The next-generation program is expected to retain the key advantages of that frontrunner program – namely a novel MoA, multi-stage activity and predicted single-dose efficacy – with the potential for improvements in safety profile and cost of treatment.
The project also represents the synergy of leading academic institutions with a large pharmaceutical company, all with longstanding commitment to addressing the urgent need for new antimalarials.

Role and Responsibility of Each Partner

Project members from 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 the project plan while taking advantage of each organization’s strengths and expertise.
As the Designated Development Partner, Eisai will have overall responsibility for the program, including scientific leadership and project management. Eisai will lead the compound scale-up, in vivo efficacy studies, exploratory safety studies, multi-species pharmacokinetic studies and human dose prediction. Additionally, Eisai will contribute advanced synthetic intermediates and chemistry know-how.
Scripps Research will contribute to project management and leadership. In addition, Scripps will contribute to planning and management of compound scale-up. Scripps Research will also work with Eisai and CROs to contract in vivo efficacy experiments, as needed.
ICGEB New Delhi will be responsible for the generation of crystallographic information that will support advancement of the candidate compound. The ICGEB team will also contribute their perspective as researchers in a malaria-endemic country.

Others (including references if necessary)

Nature, doi:10.1038/nature19804