Defense Peptides Engineered from Human Platelet Factor 4 Kill Plasmodium by Selective Membrane Disruption.
Malaria is a serious threat to human health and additional classes of antimalarial drugs are greatly needed. The human defense protein, platelet factor 4 (PF4), has intrinsic antiplasmodial activity but also undesirable chemokine properties. We engineered a peptide containing the isolated PF4 antiplasmodial domain, which through cyclization, retained the critical structure of the parent protein. The peptide, cPF4PD, killed cultured blood-stage Plasmodium falciparum with low micromolar potency by specific disruption of the parasite digestive vacuole. Its mechanism of action involved selective penetration and accumulation inside the intraerythrocytic parasite without damaging the host cell or parasite membranes; it did not accumulate in uninfected cells. This selective activity was accounted for by observations of the peptide's specific binding and penetration of membranes with exposed negatively charged phospholipid headgroups. Our findings highlight the tremendous potential of the cPF4PD scaffold for developing antimalarial peptide drugs with a distinct and selective mechanism of action.
['Lawrence|Nicole|N|', 'Dennis|Adelaide S M|ASM|', 'Lehane|Adele M|AM|', 'Ehmann|Anna|A|', 'Harvey|Peta J|PJ|', 'Benfield|Aurélie H|AH|', 'Cheneval|Olivier|O|', 'Henriques|Sónia Troeira|ST|', 'Craik|David J|DJ|', 'McMorran|Brendan J|BJ|']
D000328:Adult D000962:Antimalarials D015195:Drug Design D004912:Erythrocytes D005260:Female D006801:Humans D016778:Malaria, Falciparum D008297:Male D008875:Middle Aged D008958:Models, Molecular D010456:Peptides, Cyclic D010963:Plasmodium falciparum D010978:Platelet Factor 4
malaria antiplasmodial mechanism of action cyclic peptide drug design host defense membrane lipids structural biology