Platelet factor 4 activity against P. Falciparum and its translation to nonpeptidic mimics as antimalarials

Melissa S. Love, Melanie G. Millholland, Satish Mishra, Swapnil Kulkarni, Katie B. Freeman, Wenxi Pan, Robert W. Kavash, Michael J. Costanzo, Hyunil Jo, Thomas M. Daly, Dewight R. Williams, M. Anna Kowalska, Lawrence W. Bergman, Mortimer Poncz, William F. Degrado, Photini Sinnis, Richard W. Scott, Doron C. Greenbaum

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)815-823
Number of pages9
JournalCell Host and Microbe
Volume12
Issue number6
DOIs
StatePublished - Dec 13 2012

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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