- RFP Year2019
- Awarded Amount$1,016,129
- Development StageLead Identification
- Collaboration PartnersTakeda Pharmaceutical Company Limited, Medicines for Malaria Venture (MMV), The University of Melbourne’s Bio21 Molecular Science and Biotechnology Institute
Introduction and Background of the Project
Malaria is a debilitating disease caused by Plasmodium parasites. Every year ~200 million new infections are established, causing more than 400,000 deaths. There is an urgent need to develop new antimalarial drugs that are safe, fast-acting, active against different stages and all strains, effective as a single dose and suitable for both treatment and prophylaxis. We have identified a class of nucleoside sulfamates that show potential to meet these demanding criteria. Our front-runner compounds exhibit long in vivo half-lives, very high potency against malaria parasite cultures and very low toxicity against mammalian cell lines. We have demonstrated single dose efficacy in a mouse model of human malaria.
This project seeks to undertake Hit-to-Lead studies on our nucleoside sulfamates series to identify compounds which meet MMV’s early lead criteria for entry into lead optimization.
Specifically, the Project aims:
i) To undertake a medicinal chemistry program to improve oral bioavailability of the nucleoside sulfamate series, while maintaining selectivity and potent anti-parasitic activity.
ii) To undertake a detailed analysis of the activity of orally bioavailable nucleoside sulfamates in a testbed of assays against different life stages of Plasmodium to define the potential product profile (i.e. treatment and/or chemoprotection).
iii) To demonstrate efficacy and tolerability of orally bioavailable nucleoside sulfamates in a SCID mouse model of P. falciparum malaria.
iv) To confirm the mode of action and to understand the potential for resistance generation.
The target of the nucleoside sulfamate front-runner compound has been identified as an important protein synthesis enzyme, called tyrosine tRNA synthetase. The target enzyme is divergent from its human homologue, consistent with good selectivity of the inhibitors. We will establish biochemical assays and a well-defined test cascade to support a medicinal chemistry program to improve oral availability and deliver nucleoside sulfamates with drug-like properties that maintain potency and selectivity. We anticipate that good pharmacokinetic properties (oral bioavailablity, low clearance and long half-lives, good solubility and suitable LogP) can be obtained. Within one year of project funding, we will identify nucleoside sulfamate compounds that inhibit the growth of 3D7 P. falciparum with an IC50 value less than 100 nM and show more than 25% bioavailability in rats.
How can your partnership (project) address global health challenges?
Current antimalarial control is highly dependent on artemisinin combination therapies (ACTs). Artemisinins have very short in vivo half-lives. As a consequence, ACTs are delivered as a 3-day regimen that suffers poor compliance - driving the emergence of resistant strains. Reistance is also emerging to each of the partner drugs used in ACTs. As a consequence, high levels of treatment failure are observed  and there is a significant risk of contracting malaria infections that are resistant to all available drugs. Our Project aims to develop a new antimalarial drug that is safe and efficacious and suitable for both treatment and prophylaxis.
What sort of innovation are you bringing in your project?
An exciting aspect of this project is that it brings together pharmaceutical industry experts (Gould, Dick; with many years of experience in developing nucleoside sulfamates as potential anti-cancer agents), an academic malaria expert (Tilley, with structural biology and biochemistry expertise) and a Product Development Partner (Brand, Baud MMV).
A particularly innovative aspect of this work is that it will explore a novel target that is essential at all stages of parasite growth. Thus, we anticipate that a nucleoside sulfamate antimalarial has the potential to meet the MMV criterion of inhibiting all stages, all strains and all species of plasmodium.
Role and Responsibility of Each Partner
Dr Sandy Gould (Lead PI), Takeda Pharmaceuticals, will co-ordinate activties across the Project. She will also lead and coordinate the activities of a team of Takeda medicinal chemists and biochemists who will be designing and analysing new nucleoside sulfamates for this hit to lead effort.
Prof Leann Tilley (PI and Designated Development Partner representative), University of Melbourne, and her team, including Dr Stanley Xie, will contribute relevant test cascade assays, provide recombinant P. falciparum tRNA synthetase, conduct mechanism of action studies, and develop key tools, such as nucleoside sulfamate resistant parasites.
Dr Stephen Brand (PI), MMV, will provide drug discovery expertise and strategic input and will connect the team with partners in the MMV network to provide access to state-of-the-art assays and expert advice.
Dr Larry Dick, MMV consultant, will provide expert biochemcial and drug development expertise, based on his many year in the Pharmaceutical industry.
Ms Delphine Baud, MMV, will coordinate logisitics, compound management and testing in the MMV platform of assays.
The assembled international team of researchers has the necessary expertise to deliver a chemical entity from this compound class into a Lead Optimization program.
Others (including references if necessary)
 van der Pluijm RW, Imwong M, Chau NH, Hoa NT, Thuy-Nhien NT, Thanh NV, et al. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet Infect Dis 2019 Jul 22.