gallinamide-a and Malaria--Falciparum

Analogues of the natural product gallinamide A were prepared to elucidate novel inhibitors of the falcipain cysteine proteases. Analogues exhibited potent inhibition of falcipain-2 (FP-2) and falcipain-3 (FP-3) and of the development of Plasmodium falciparum in vitro. Several compounds were equipotent to chloroquine as inhibitors of the 3D7 strain of P. falciparum and maintained potent activity against the chloroquine-resistant Dd2 parasite. These compounds serve as promising leads for the development of novel antimalarial agents.

Topics: Antimalarials; Antimicrobial Cationic Peptides; Cysteine Endopeptidases; HEK293 Cells; Humans; Malaria, Falciparum; Models, Molecular; Molecular Structure; Peptides; Plasmodium falciparum; Structure-Activity Relationship

The marine natural product symplostatin 4 (Sym4) has been recognized as a potent antimalarial agent. However, its mode of action and, in particular, direct targets have to date remained elusive. We report a chemical synthesis of Sym4 and show that Sym4-treatment of P. falciparum-infected red blood cells (RBCs) results in the generation of a swollen food vacuole phenotype and a reduction of parasitemia at nanomolar concentrations. We furthermore demonstrate that Sym4 is a nanomolar inhibitor of the P. falciparum falcipains in infected RBCs, suggesting inhibition of the hemoglobin degradation pathway as Sym4's mode of action. Finally, we reveal a critical influence of the unusual methyl-methoxypyrrolinone (mmp) group of Sym4 for potent inhibition, indicating that Sym4 derivatives with such a mmp moiety might represent viable lead structures for the development of antimalarial falcipain inhibitors.

Topics: Antimalarials; Antimicrobial Cationic Peptides; Cysteine Endopeptidases; Enzyme Inhibitors; Erythrocytes; Hemoglobins; Host-Parasite Interactions; Humans; Malaria, Falciparum; Models, Molecular; Peptides; Plasmodium falciparum