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

doi:10.1016/j.chom.2012.10.017

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Platelet Factor 4 Activity against P. falciparum and Its Translation to Nonpeptidic Mimics as Antimalarials

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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, …

Cell host & microbe, v 12(6), pp 815-823

13 Dec 2012

DOI: https://doi.org/10.1016/j.chom.2012.10.017

PMID: 23245326

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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. [Display omitted] ► The human HDP-containing protein, PF4, is an antimalarial component of platelets ► PF4 kills malaria parasites via lysis of the parasite digestive vacuolar membrane ► Drug-like HDP mimics (smHDPs) have the same antimalarial mechanism as PF4 ► Lead smHDPs show potency in murine models of malaria

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Title: Platelet Factor 4 Activity against P. falciparum and Its Translation to Nonpeptidic Mimics as Antimalarials
Creators: Melissa S Love - Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
Melanie G Millholland - Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
Satish Mishra - Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Swapnil Kulkarni - Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
Katie B Freeman - PolyMedix, Inc., Radnor, PA 19087, USA
Wenxi Pan - PolyMedix, Inc., Radnor, PA 19087, USA
Robert W Kavash - PolyMedix, Inc., Radnor, PA 19087, USA
Michael J Costanzo - PolyMedix, Inc., Radnor, PA 19087, USA
Hyunil Jo - Department of Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA
Thomas M Daly - Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA
Dewight R Williams - Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
M. Anna Kowalska - Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Lawrence W Bergman - Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA
Mortimer Poncz - Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
William F DeGrado - Department of Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA
Photini Sinnis - Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Richard W Scott - PolyMedix, Inc., Radnor, PA 19087, USA
Doron C Greenbaum - Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
Publication Details: Cell host & microbe, v 12(6), pp 815-823
Publisher: Elsevier
Resource Type: Journal article
Language: English
Academic Unit: Microbiology and Immunology; [Retired Faculty]
Web of Science ID: WOS:000313406600012
Scopus ID: 2-s2.0-84870988912
Other Identifier: 991014878416704721

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Collaboration types: Domestic collaboration
Web of Science research areas: Microbiology; Parasitology; Virology