Developing inhibitors of Plasmodium Acetyl CoA Synthetase as new multistage antimalarials

There were approximately 241 million cases of malaria and 627,000 deaths worldwide in 2020. Africa carries a disproportionally high share of the global malaria burden. In 2020, the African continent accounted for 95% of malaria cases and 96% of malaria deaths. Children under 5 years of age, pregnant women, patients with HIV/AIDS and people with low immunity moving to areas with high level of transmission are a higher risk of contracting malaria and developing severe disease. Among those, children under 5 years account for 80% of all malaria deaths in Africa. In addition, malaria has a negative impact in the economy of countries where is endemic, keeping children out of school and adults out or work, contributing the cycle of poverty and increasing pressure in fragile health systems. In the past five years the reduction in malaria incidence and mortality has stalled and resistance to the current standard of care is rising in southeast Asia and Africa. There is an urgent need for new antimalarial agents for treatment and prophylaxis.

Our group, in collaboration with other members of the Malaria Drug Accelerator (MalDA), have recently demonstrated that the enzyme P. falciparum acetyl-CoA synthetase is essential for the survival of malaria parasites. We identified two molecules that interfere with the function of this enzyme and have the potential to be developed into new medicines for the treatment and prevention of malaria infections. However, these two molecules are not sufficiently potent and do not have the properties required for an oral drug. We selected for optimisation one of these molecules, MMV019721. We have now developed more potent molecules with improved properties that can be dosed orally, and we are confident of the potential for further optimisation towards a new treatment for malaria. The aim of this proposal is to improve the properties of this class of molecules to deliver a declared late lead according to the Medicines for Malaria Venture (MMV) Late Lead Criteria. This will require us to optimise multiple features of the molecule including its ability to kill the malaria parasite, its ability to reach the site of the body where the parasite resides without being broken down and its safety. At the end of the project the late lead will be ready to enter more advance toxicological studies before moving into human clinical trials.

Technical Summary

There were approximately 241 million cases of malaria and 627,000 deaths worldwide in 2020. The reduction in malaria incidence and mortality has stalled in the past five years and resistance to the current standard of care is rising in southeast Asia and Africa. There is an urgent need for new antimalarial agents with novel modes of action for treatment and prophylaxis. We have recently shown that P. falciparum acetyl-CoA synthetase is essential for the survival of malaria parasites and we reported two inhibitors of this enzyme with activity in multiple life-cycle stages of the parasite, giving potential for treatment and chemoprotection. However, these P. falciparum acetyl-CoA synthetase inhibitors are not sufficiently potent and do not have the properties required for an oral drug. We selected for optimisation one of these PfACS inhibitors, MMV019721 a fast-acting compound with moderate activity against the malaria parasite. We have identified more potent analogues with improved properties that can be dosed orally, and we are confident that the series has potential for further optimisation towards a preclinical candidate. Further, the project is now structurally enabled, using a homologue of the parasite enzyme, which should greatly facilitate optimisation. The aim of this proposal is to develop compounds with the potency, pharmacokinetics and predicted human dose and exposure required for the treatment of malaria (milestone 1). We will then scale up the synthesis of two lead compounds and profile them through more detailed efficacy, pharmacokinetic and solid-state characterisation studies and assess their resistance risk (milestone 2). At the end of this project, we aim to deliver a declared late lead compound according to the Medicines for Malaria Venture (MMV) Late Lead Criteria. A fast-acting inhibitor of acetyl CoA synthetase with blood and liver stage activity meets the requirements for the MMV target candidate profiles for blood stage killer (TCP1).