Inhibition ofPlasmodium falciparumGrowth In Vitro and Adhesion to Chondroitin-4-Sulfate by the Heparan Sulfate Mimetic PI-88 and Other Sulfated Oligosaccharides

Abstract

A panel of sulfated oligosaccharides was tested for antimalarial activity and inhibition of adhesion to the placental malaria receptor chondroitin-4-sulfate (CSA). The heparan sulfate mimetic PI-88, currently undergoing phase II anticancer trials, displayed the greatest in vitro antimalarial activity against Plasmodium falciparum (50% inhibitory concentration of 7.4 M) and demonstrated modest adhesion inhibition to cell surface CSA.Some of the severe pathophysiological symptoms of Plasmodium falciparum infection, the causative agent of the most lethal form of human malaria, involve carbohydrate interactions. For example, infected erythrocytes (IEs) can adhere to the glycosaminoglycans chondroitin-4-sulfate (CSA) and hyaluronic acid (6,7,14) in the placenta during pregnancy, and heparan sulfate may be involved in the formation of P. falciparum rosettes (5, 9, 10). Negatively charged polysaccharides, such as heparin, CSA, dextran sulfates, cellulose sulfates, fucoidan, and the nonsulfated glycosaminoglycan hyaluronic acid, have been shown experimentally to inhibit the in vitro invasion of P. falciparum merozoites into erythrocytes, block cytoadhesion of IEs to various host receptors (3,11,26), or disrupt P. falciparum rosettes (8,24). In this study, we have examined a panel of sulfated oligosaccharides, including the heparan sulfate mimetic PI-88 (17), which is currently undergoing phase II clinical trials as an anticancer agent, both for their in vitro antimalarial activities and for their effects on adhesion to the host receptor CSA.A series of hypersulfated oligosaccharides (di-to hexasaccharide, varying in sugar unit, linkage between sugars, and structure of the reducing terminus sugar) were used (Sigma, MO) (Table 1) (20). Each of the prepared sulfated oligosaccharides, along with dextran sulfate (5 kDa) and PI-88 (average molecular mass of ϳ2.4 kDa; composed predominately of penta-and tetrasaccharides), possesses between three and five hydroxyl groups per saccharide unit available for sulfation, while pentosan polysulfate (5 kDa) has two. The in vitro antimalarial activities of this panel of sulfated saccharides were examined using the multidrug-resistant P. falciparum clone Dd2 and [ 3 H]hypoxanthine incorporation, as previously described (4, 13). Early-ring-stage IEs were incubated with various concentrations of each substance for 48 h before adding

Marine organism sulfated polysaccharides exhibiting significant antimalarial activity and inhibition of red blood cell invasion by Plasmodium

“…Negatively charged polysaccharides, such as heparin, chondroitin and dextran sulfates, fucoidan, and the nonsulfated glycosaminoglycan (GAG) hyaluronan, block cytoadhesion of pRBCs to various host receptors 7 8 9 10 and disrupt P. falciparum rosettes 11 12 . Heparin and related sulfated polysaccharides possess antimalarial activity that has been described to operate through inhibition of RBC invasion by merozoites 9 13 14 15 16 .…”

New approaches to studying Plasmodium falciparum merozoite invasion and insights into invasion biology

“…Polysulphated heparin-like-molecules (HLMs) are inhibitory to invasion (Boyle et al, 2010a) and may have potential as antimalarial agents (Havlik et al,1994(Havlik et al, , 2005Clark et al, 1997;Evans et al, 1998;Adams et al, 2006;Boyle et al, 2010a). From testing a number of modified HLMs and semi-synthetic carbohydrates based on K5 polysaccharides that have different compositions, it has been previously shown that the invasion-inhibitory activity of these compounds is specific and dependent on the level and degree of sulphation, as well as backbone structure and chain length (Boyle et al, 2010a).…”

A microfluidic platform to isolate avian erythrocytes infected with Plasmodium gallinaceum malaria parasites based on surface morphological changes

“…A small amount of the anticoagulent agent, heparin, was introduced into the diagnostic channel from the heparin-coated capillary tube used for collecting blood sample. This was done to suppress blood coagulation before loading the blood into the diagnostic channel (Adams et al 2006;Xiao et al 1996). Removing heparin from the sample was necessary because it could alter the surface morphology of the cell membranes (Freidlin 1985).…”