Introduction and Background of the Project

Introduction

Drug resistance continues to hinder malaria eradication efforts, and the discovery of new drug targets is critical to further combat this disease. Plasmodial serine hydroxymethyltransferase (SHMT) is a key enzyme in the folate biosynthesis pathway of malaria parasites, which is required to maintain vital cellular functions by providing essential products for amino acid metabolism, nucleotide biosynthesis and methylation reactions. Antifolate inhibitors have been reported for Plasmodium dihydrofolate reductase (DHFR), thymidylate synthase (TS) and SHMT, validating that the folate cycle is a druggable pathway in malaria. Recently, Plasmodium serine hydroxymethyltransferase (PfSHMT) was further designated as a high priority candidate for target-based drug discovery based on a comprehensive data mining study¹. However, the SHMT target remains understudied and thus far only small libraries of known antifolate inhibitors have been screened.

Project objective

The primary objective of the project is to identify validated hit compounds that selectively inhibit the activity of plasmodial SHMT.

Project design

TropIQ Health Sciences (TropIQ) will lead a primary screen of compounds from Eisai Co., Ltd.’s (Eisai) compound library using a probe-based biochemical assay.

To confirm target selectivity of actives, counter-screening against human SHMT will subsequently be performed in the early stage of the project. Hits showing reproducible inhibition and selectivity of plasmodial SHMT over human SHMT will be further assessed using secondary assays.

Confirmed hits will be further assessed by a series of secondary assays. Biochemical assays will be used to further validate actives and generate dose-response curves. To assess biological relevance, compounds will be tested against multiple malaria life cycle stages, including whole parasite asexual blood stage replication, gametocyte and liver stage assays. To exclude toxic compounds, cytotoxicity will be evaluated. All assays will be performed according to TropIQ’s established protocols.

Eisai, Medicines for Malaria Venture (MMV), and TropIQ will review the top hits and assess for clusters of structurally related chemotypes to define chemical series for future work and to establish an early structure-activity relationship.

How can your partnership (project) address global health challenges?

Malaria remains a serious global health challenge. Despite recent advances in malaria control and elimination efforts, the World Health Organization estimates 263 million malaria cases and 597,000 malaria deaths occurred globally in 2023². Antimalarial drug resistance is a major threat and the development of next-generation antimalarial drugs is critical for malaria control and elimination. Our project aims to address this need for new antimalarial drugs by conducting a comprehensive screening effort to identify compounds that could inhibit plasmodial SHMT, a novel malaria drug target. 

What sort of innovation are you bringing in your project?

Our project will utilize Eisai’s compound library to screen against plasmodial SHMT, an unprecedented top candidate for target-based antimalarial drug discovery¹. Our project will also employ a validated probe-based screening method that utilizes purified recombinant SHMT from multiple malaria parasite species and humans to help identify SHMT inhibitors.

Role and Responsibility of Each Partner

As the designated development partner for this project, Eisai is responsible for delivering the work plan within the agreed timeline and budget, as well as for GHIT reporting. 

The project will be carried out by a team consisting of scientists and project managers from Eisai, MMV and TropIQ Health Sciences. Eisai will provide a library of compounds that have not yet been tested against the plasmodial SHMT target. TropIQ will lead a primary screen of these compounds and identify primary hits that will be further screened to identify compounds that meet defined criteria for progression. TropIQ will assess confirmed hits in a series of secondary assays for validation. Eisai will supply additional compounds to TropIQ as needed to conduct secondary assays.  Eisai, MMV and TropIQ will review the top compounds, identify potential chemical series for future work and establish an early structure-activity relationship.

Others (including references if necessary)

(1) Godinez-Macias, K.P., Chen, D., Wallis, J.L. et al. Revisiting the Plasmodium falciparum druggable genome using predicted structures and data mining. npj Drug Discov. 2, 3 (2025).

(2) World malaria report 2024: addressing inequity in the global malaria response. Geneva: World Health Organization; 2024.