Introduction and Background of the Project

1. Introduction

Malaria is one of the most widespread infectious diseases in which over 200 million infections occur annually worldwide. Current antimalarial drugs do not work well against malarial parasite. Antimalarial drugs act by inhibiting a biochemical process in the parasite, for example, an enzyme target, whereas the drug must be specific to the target to prevent toxic side effects. This specificity requirement is an Achilles’ heel as drug-resistant parasites with small genetic changes that prevent the drug from binding. One solution to drug resistance is to develop new drugs against new targets. However, developing new drugs is challenging because there are few suitable drug targets. A new drug design approach is needed to expand the repertoire of antimalarial targets and the drug arsenal to exploit previously untouched vulnerabilities in the parasite. Instead of using drugs that act as inhibitors of target functions, drugs designed as protein degrader, also known as PROteolysis-TArgeting Chimeras or PROTACs, can destroy target proteins. The protein degrader work by hijacking the proteasome (a protein complex present in every cell that naturally breaks down old or damaged proteins) to degrade a target protein. Protein degraders are designed with one “warhead” that binds the target and another that binds ubiquitin E3 ligase, a protein that marks other proteins for degradation. This approach has the advantage that the protein degraders can bind anywhere on the target, without the restriction of binding to sites important for target function. Therefore, the protein degraders can be designed against proteins previously not considered as drug targets. PROTAC antimalarials acting on new targets throughout the parasite life cycle could be important tools for the eradication of malaria. However, no small molecule PROTAC antimalarial currently exists because we lack knowledge of malaria parasite ubiquitin E3 ligases, and no chemical “warhead” is available that can recruit a parasite ubiquitin E3 ligase for hijacking the parasite’s proteasome.

2. Project objective

To identify a chemical warhead(s) that can recruit a parasite ubiquitin E3 ligase(s) to degrade a target parasite protein, which will constitute a platform for the design of protein degrader antimalarials.

3. Project design

We will design and synthesize a library of protein degraders for degradation experiments. The test compounds will be designed with various chemical warheads against a variety of ubiquitin E3 ligases joined to a warhead specific to the Plasmodium parasite bifunctional dihydrofolate reductase-thymidylate synthase, a well-studied parasite protein. The protein degrader that trigger target protein degradation will be used for designing follow-on compounds, including probe compounds for biochemical characterization of Plasmodium ubiquitin E3 ligase(s) that interact with the ubiquitin E3 ligase warhead and those protein degraders for optimizing the degradation of target.

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

There is a growing concern that malaria will become resurgent owing to the evolution and spread of drug-resistant malaria parasites. New drugs with novel mechanisms of action are needed to counter this threat. These new drugs must act against all stages of the parasite life cycle, including stages not targeted by current drugs. Protein degrader antimalarial drugs could fulfill these needs by making many new targets accessible to chemotherapy. If our approach can be demonstrated for antimalarial drugs, the same approach could be applied for other neglected parasitic diseases, such as Leishmaniasis.

What sort of innovation are you bringing in your project?

If successful, we will establish a platform for protein degraders as antimalarial drugs that act by degrading parasite protein targets. This would represent the first small molecule protein degradation platform for drugs against parasitic diseases that target non-human proteins.

Role and Responsibility of Each Partner

The FIMECS company (Japan) will synthesize a library of protein degraders for initial screening. The BIOTEC Institute (Thailand) will perform protein degradation experiments and the protein degrader optimization of follow-on compounds. 

Others (including references if necessary)