TY - JOUR
T1 - Platelet factor 4 activity against P. Falciparum and its translation to nonpeptidic mimics as antimalarials
AU - Love, Melissa S.
AU - Millholland, Melanie G.
AU - Mishra, Satish
AU - Kulkarni, Swapnil
AU - Freeman, Katie B.
AU - Pan, Wenxi
AU - Kavash, Robert W.
AU - Costanzo, Michael J.
AU - Jo, Hyunil
AU - Daly, Thomas M.
AU - Williams, Dewight R.
AU - Kowalska, M. Anna
AU - Bergman, Lawrence W.
AU - Poncz, Mortimer
AU - Degrado, William F.
AU - Sinnis, Photini
AU - Scott, Richard W.
AU - Greenbaum, Doron C.
N1 - Funding Information:
We thank Michael Betts, Morgan Reuter, and Johanna Daly for helpful discussions and the following funding sources for this work: NIH R44 AI090762-0 (D.C.G., R.W.S.), NIHT32GM08076 (M.S.L.), NIHT32AI007532 (M.G.M.), NIH R01 AI056840 (P.S.), University of Pennsylvania TAPITMAT Pilot Program (D.C.G.), Penn Genome Frontiers Institute (D.C.G.), and Gates Grand Challenges Exploration Program (D.C.G.).
PY - 2012/12/13
Y1 - 2012/12/13
N2 - Plasmodium falciparum pathogenesis is affected by various cell types in the blood, including platelets, which can kill intraerythrocytic malaria parasites. Platelets could mediate these antimalarial effects through human defense peptides (HDPs), which exert antimicrobial effects by permeabilizing membranes. Therefore, we screened a panel of HDPs and determined that human platelet factor 4 (hPF4) kills malaria parasites inside erythrocytes by selectively lysing the parasite digestive vacuole (DV). PF4 rapidly accumulates only within infected erythrocytes and is required for parasite killing in infected erythrocyte-platelet cocultures. To exploit this antimalarial mechanism, we tested a library of small, nonpeptidic mimics of HDPs (smHDPs) and identified compounds that kill P. falciparum by rapidly lysing the parasite DV while sparing the erythrocyte plasma membrane. Lead smHDPs also reduced parasitemia in a murine malaria model. Thus, identifying host molecules that control parasite growth can further the development of related molecules with therapeutic potential.
AB - Plasmodium falciparum pathogenesis is affected by various cell types in the blood, including platelets, which can kill intraerythrocytic malaria parasites. Platelets could mediate these antimalarial effects through human defense peptides (HDPs), which exert antimicrobial effects by permeabilizing membranes. Therefore, we screened a panel of HDPs and determined that human platelet factor 4 (hPF4) kills malaria parasites inside erythrocytes by selectively lysing the parasite digestive vacuole (DV). PF4 rapidly accumulates only within infected erythrocytes and is required for parasite killing in infected erythrocyte-platelet cocultures. To exploit this antimalarial mechanism, we tested a library of small, nonpeptidic mimics of HDPs (smHDPs) and identified compounds that kill P. falciparum by rapidly lysing the parasite DV while sparing the erythrocyte plasma membrane. Lead smHDPs also reduced parasitemia in a murine malaria model. Thus, identifying host molecules that control parasite growth can further the development of related molecules with therapeutic potential.
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U2 - 10.1016/j.chom.2012.10.017
DO - 10.1016/j.chom.2012.10.017
M3 - Article
C2 - 23245326
AN - SCOPUS:84870988912
SN - 1931-3128
VL - 12
SP - 815
EP - 823
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 6
ER -