cellular thermal shift protein assays (CETSA) has recently emerged as a powerful tool for identifications of direct protein targets of a wide range of drugs.
In our work, we adopted CETSA to study the intracellular parasite of human malaria, Plasmodium falciparum. At first we wished to identify drug targets of antimalarial drugs that were in clinical use for over a half century but until now no clear factors of their MOA are known.
Contrary to the general believe that most antimalarial drugs have a pluripotent effect within the parasite cell, we identified several clear protein targets. These include a purine nucleoside phosphorylate for quinine and a metaloprotease, falcilysin, for chloroquine.
Based on these results falcilysin is emerging as a highly potent antimalarial target with a promiscuous binding pocket for several classes of antimalarial drug including other clinically relevant quinolines as well as several new novel drug candidates. Although CETSA is emerging as a powerful method to decipher antimalarial drugs MOA, many challenges still remain for its full-fledged applications for (other) malarials and antimicrobials in general. Some of the challenges and future perspectives will be discussed.