Purine Analogues as anti-Malarial Drug – PAMalaD

Malaria, which remains one of the deadliest infectious diseases, is caused by a parasite of the genus Plasmodium and is spread by the bite of Anopheles mosquitoes. The emergence of parasites resistant to all current antimalarial drugs including artemisinin-based combination therapies (ACTs) highlights the urgency of obtaining new molecules with novel mechanisms of action.

The PAMalaD project concerns the development of innovative antimalarial agents belonging to the family of AcycloNucleoside Phosphonates (ANPs). We have discovered a novel class of ANPs whose lead compound is a purine analogue. It presents unprecedented features: 1) strong antiplasmodial activities (high efficacy both in vitro in the nanomolar range and in vivo in a malaria mouse model), 2) no effect on mammalian cells (up to the millimolar range, resulting in a selectivity index > 10 000), 3) a chemical structure unrelated to the antimalarial drugs currently on the market or in (pre-) clinical development, and 4) a novel mechanism of action targeting a crucial enzyme involved in several stages during the parasite’s life cycle. Our compound is also active against sexual stages of the parasite, and therefore likely able to stop the transmission between humans and mosquitoes.

The aim of the PAMalaD project is twofold: to develop this compound from a lead to a drug candidate status and to decipher its mechanism of action at the cellular and molecular level.
- Our first objective is to improve oral bioavailability in order to select a drug candidate. All future treatments for uncomplicated malaria are expected to be administered orally. We will therefore develop efficient prodrug strategies to increase the oral bioavailability of the lead compound. We will design molecules that are able to cross the intestinal barrier before being converted to the active compound. In parallel, backup molecules will be synthesized to circumvent any unanticipated effect of the compound in vivo.
- Our second objective is to validate the therapeutic target of the lead compound and to decipher its mechanism of action. Our recent results show that parasite growth is stopped because the compound blocks the egress of the parasite from the erythrocyte. In addition, at the sexual stages, it inhibits the exflagellation of male gametocytes. We will extend the phenotypic analyses by studying the other stages of the parasite’s life cycle (mosquito and liver stages). The potential molecular target of the compound has recently been identified. We will validate the target by genetic and biochemical studies.

Our methodology combines medicinal chemistry, pharmacology, molecular and cellular biology and biochemistry. This project is original in terms of the chemical entities that will be developed and in terms of the antimalarial target, which has so far not been targeted by commercial antimalarial drugs. The PAMalaD project is strengthened by a well-established collaboration between two academic teams relying on a strong synergy and their complementary expertise in medicinal chemistry and malaria research.

The expected outcome is an antimalarial drug candidate for pre-clinical phases that will meet the criteria established by the World Health Organization and Medicines for Malaria Venture (the leading non-profit organization involved in malaria eradication) in terms of pharmacological activity, novelty of the mechanism of action, oral bioavailability and cost.