Development of a Highly Selective <i>Plasmodium falciparum</i> Proteasome Inhibitor with Anti‐malaria Activity in Humanized Mice

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against at multiple stages—erythrocytic, gametocyte, liver, and gamete activation stages—indicating that selective Pf20S possess the potential to be therapeutic, prophylactic, transmission-blocking antimalarials. Starting from a reported compound, we developed noncovalent, macrocyclic peptide inhibitor of malarial with high species selectivity improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition β5 subunit Pf20S, kills artemisinin-sensitive artemisinin-resistant P. isolates in vitro reduces parasitemia humanized, falciparum-infected mice.