Introduction and Background of the Project

Introduction

The project will perform the optimization of a novel series of antimalarial compounds with a very attractive therapeutic profile. The series is fast-killing, exhibits high antimalarial potency across all the stages of the parasite lifecycle, including P. vivax hypnozoites (TCP1,3, 4 and 5 potential), has good physicochemical and pharmacokinetic properties and shows high efficacy in mouse models of malaria (treatment and prophylaxis models). The series achieves its antimalarial activity by a novel mode of action, through inhibition of an enzyme critical to the survival of the parasite.

Project objective

The ultimate objective of the project will be to deliver a preclinical candidate, with a novel mode of action, with the potential for single dose treatment and/or prophylaxis of malaria. The 2-year project will aim to identify 1-3 Late Lead compounds, as defined by MMV’s progression criteria, within 18 months and then to profile them in the subsequent 6 months to select a compound which meets MMV’s late lead criteria suitable to progress into preclinical candidate profiling. As an additional objective, the project will endeavor to confirm the proposed mode of action against P. vivax hypnozoites. The project will also assess the potential of the late lead(s) to be developed as a SERCAP for relapsing malaria, which do not cause hemolysis, and thus not requiring G6PD testing.

Project design

A multi-disciplinary drug discovery approach will be used by the project, utilizing the inputs and diverse skills and experiences of medicinal chemists, molecular modelers, parasitologists, pharmacokineticists, toxicologists, formulation and scale-up chemistry. Starting with the identified Lead Series, rational and systematic modifications of the leading compounds will be undertaken to further improve their pharmacological, physicochemical, pharmacokinetic and toxicological properties, based on state-of-the-art capabilities and data generated at MMV, MTPC, UGA and our partners. As the putative target of these molecules is an enzyme that is essential to the growth of the malaria parasite, and structural information is available from analogous bacterial proteins, a structure-based drug design (SBDD) approach will be applied, supported at MTPC. This will provide the opportunity to rapidly and rationally design compounds with a higher likelihood of inhibiting the enzyme potently and selectively and achieving the project goals.

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

Malaria caused approximately 627,000 deaths in 2020, mostly in children under five years of age and pregnant women. Malaria is caused by a parasite from the genus Plasmodium. In humans, five species of Plasmodium are known to cause the disease. Of particular relevance are P. falciparum, which is the most lethal and accounts for 93% of cases in sub-Saharan Africa and P. vivax which is prevalent in Southeast Asia and the Americas and causes post-treatment disease relapse due to a latent liver form of the parasite. Current antimalarial control is highly dependent on artemisinin combination therapies (ACTs), and it is concerning that decreased parasite sensitivity has emerged to all currently-used ACTs, leading to significant failure rates in parts of Southeast Asia where partner drug resistance is evident. If resistance becomes widespread in Africa (where most deaths occur), a major health crisis is feared. In response to this impending crisis and with the eventual aim of eradicating the disease, new drugs with novel modes of action which overcome known resistance associated with existing therapeutics are needed. Development of compounds which can block transmission and be used in chemo-protection/prevention, in addition to acute treatment, and treatment of relapsing malaria are especially valuable to drive eradication. This project, due to the ability of the series to kill P. vivax blood and liver stages, as well as P. falciparum blood, liver and sexual stages, with high potency, has the potential to deliver a Clinical Candidate for P. falciparum or P. vivax malaria (including mixed infections) and has the additional upside of being able to block transmission. This profile would have a major impact on the treatment of malaria.

What sort of innovation are you bringing in your project?

The series is chemically novel, has a novel mode of action and a unique parasitological profile and could be applied to treatment of uncomplicated malaria with the added benefit of preventing transmission. Additionally, the late leads identified would provide a potential treatmet for relapsing malaria without the need for clinical testing of patients for G6PD deficiency, which is required for current therapies. The team will be using modern drug discovery approaches including structure-based drug design and protein crystallography (supported at MTPC), to ultimately identify a preclinical candidate from this project. The UGA team bring their unique, world-leading expertise in the conduct of P. vivax hypnozoite in vitro assays and animal models to the collaboration.  This multidisciplinary team has the necessary expertise and capabilities to deliver on the potential of the series.

Role and Responsibility of Each Partner

The MTPC, UGA and MMV teams will be fully integrated in the running of the project, including design, synthesis and evaluation of new compounds to achieve the project objectives. MTPC will apply their expertise in drug discovery and development, including X-ray crystallography. MMV will apply their malaria drug discovery expertise to ensure the late lead(s) meet the required profile. The UGA team will apply their expertise in in-vitro and in-vivo P. vivax hypnozoite parasitology to guide compound optimization and to demonstrate in-vivo efficacy in P. vivax models.  Many activities will also be conducted at contract research organizations and via academic partners in the MMV network. The overall scientific leadership will be jointly held by representatiaves of all the Collaboration Partner organizations.