Purine Analogues as anti-Malarial Drug – PAMalaD
The aim of the PAMalaD project is twofold: to develop this compound (purine analogue) from a lead to a drug candidate status and to decipher its mechanism of action at the cellular and molecular level.
- To improve oral bioavailability in order to select a drug candidate; and
- To validate the therapeutic target of the lead compound and to decipher its mechanism of action.
The PAMalaD project concerns the development of innovative antimalarial agents belonging to the family of AcycloNucleoside Phosphonates (ANPs). A discovery of a novel class of ANPs whose lead compound is a purine analogue and 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. This compound is also active against sexual stages of the parasite, and therefore likely able to stop the transmission between humans and mosquitoes. This study's 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 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.