Malaria is endemic in tropical zones, where two billion people are at risk. Over 700,000 people die every year from this parasitic disease caused by Plasmodium, many strains of which have become resistant to conventional antimalarial drugs. Most deaths are due to Plasmodium falciparum (the "neuro-palu"). In the erythrocytic phase, the parasite uses hemoglobin as a source of amino acids, leaving the residual heme in the form of an inert polymer, hemozoin. Natural (quinine) or bio-inspired (chloroquine) antimalarial molecules act as inhibitors of this polymerization. Artemisinin, a Chinese pharmacopoeia drug, alkylates the heme after homolytic disruption of the O-O bond in the molecule's central trioxane. Understanding artemisinin's mode of action has led to the development of new hybrid antimalarial molecules with dual activity. One of these molecules, PA1103, was the subject of preclinical development by the young company Palumed in collaboration with the pharmaceutical group Sanofi from 2002 to 2010.
It should be noted that more than half of artemisinin is now produced using a modified yeast, containing the six key enzymes in the biosynthesis of this molecule and enabling access to artemisinic acid at 25 g/l. Three chemical steps lead to the synthesis of the active ingredient. This new synthesis is a successful example of the combination of synthetic biology and chemical synthesis to produce large quantities of a molecule with a sophisticated structure, difficult to access by total chemical synthesis.
Trioxaquine PA1647 has also proved highly effective in the treatment of schistosomes responsible for bilharzia, a parasitic disease affecting people working in Schistosoma-infested rivers or lakes. This molecule has a synergistic action with praziquantel, the only molecule currently used in the field.
