Nature 530, 233–236 (2016)

Credit: NATURE

Inhibition of the proteasome has been shown to be toxic for the malaria parasite Plasmodium falciparum. Although inhibitors of the P. falciparum proteasome exist, they have limited utility as therapeutics because they target the human proteasome as well. To find selective inhibitors of the P. falciparum proteasome, Li et al. first compared the substrate specificities of P. falciparum and human 20S proteasomes by testing their activities against 228 diverse synthetic tetradecapeptides and found that P. falciparum exhibited a selective preference for cleaving tryptophan at positions 1 and 3. The authors then modified the canonical trileucine scaffold found in common proteasome inhibitors with tryptophan at the first and third positions to generate three new inhibitor compounds. One, WLW-vs, was highly selective for the parasite proteasome β2-subunit over its β5 subunit and over the human proteasome. A comparison of a cryo-EM structure of WLW-vs bound to the malarial proteasome to that of the human apo proteasome core explains the specificity towards the former over the latter. A second parasite-selective inhibitor identified here had a large therapeutic window against the P. falciparum proteasome and was efficacious in a rodent infection model without toxicity. These proteasome inhibitors were also active against parasites resistant to artemisinin, the current standard of treatment. These results suggest that antimalarial drugs could be made to exclusively target the malarial proteasome.