title: Disruption of rosetting in Plasmodium falciparum malaria with chemically modified heparin and low molecular weight derivatives possessing reduced anticoagulant and other serine protease inhibition activities.
abstract: Severe malaria has been, in part, associated with the ability of parasite infected red blood cells to aggregate together with uninfected erythrocytes to form rosettes via the parasite protein PfEMP-1. In this study, inhibitors of rosetting by the Plasmodium falciparum strain R-29, based on chemically modified heparin polysaccharides (IC 50 = 1.97 x 10 (-2) and 3.05 x 10 (-3) mg.mL (-1)) and their depolymerized, low molecular weight derivatives were identified with reduced anticoagulant and protease (renin, pepsin, and cathepsin-D) activities. Low molecular weight derivatives of the two most effective inhibitors were shown to have distinct minimum size and strain-specific structural requirements for rosette disruption. These also formed distinct complexes in solution when bound to platelet-factor IV.
authors.affiliation: The University of Liverpool, Liverpool, England.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Skidmore
authors.forename: Audrey F
authors.initials: AF
authors.lastname: Dumax-Vorzet
authors.forename: Scott E
authors.initials: SE
authors.lastname: Guimond
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rudd
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Edwards
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Turnbull
authors.forename: Alister G
authors.initials: AG
authors.lastname: Craig
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Yates
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology / Q000502:physiology; D006493:Heparin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016778:Malaria, Falciparum / Q000097:blood* / Q000469:parasitology; D008970:Molecular Weight; D010963:Plasmodium falciparum / Q000502:physiology*; D010978:Platelet Factor 4 / Q000737:chemistry; D011108:Polymers; D011485:Protein Binding; D011487:Protein Conformation; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000925:Anticoagulants; D011108:Polymers; D015842:Serine Proteinase Inhibitors; D010978:Platelet Factor 4; D006493:Heparin