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.
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.
Skidmore
Mark A
MA
The University of Liverpool, Liverpool, England.
Dumax-Vorzet
Audrey F
AF
Guimond
Scott E
SE
Rudd
Timothy R
TR
Edwards
Elizabeth A
EA
Turnbull
Jeremy E
JE
Craig
Alister G
AG
Yates
Edwin A
EA
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
D000925:Anticoagulants; D011108:Polymers; D015842:Serine Proteinase Inhibitors; D010978:Platelet Factor 4; D006493:Heparin