Regioselectively modified sulfated cellulose as prospective drug for treatment of malaria tropica
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Regioselectively modified sulfated cellulose as prospective drug for treatment of malaria tropica. / Schwartz-Albiez, Reinhard; Adams, Yvonne; Von Der Lieth, Claus W.; Mischnick, Petra; Andrews, Katherine T.; Kirschfink, Michael.
I: Glycoconjugate Journal, Bind 24, Nr. 1, 01.2007, s. 57-65.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Regioselectively modified sulfated cellulose as prospective drug for treatment of malaria tropica
AU - Schwartz-Albiez, Reinhard
AU - Adams, Yvonne
AU - Von Der Lieth, Claus W.
AU - Mischnick, Petra
AU - Andrews, Katherine T.
AU - Kirschfink, Michael
N1 - Funding Information: Acknowledgment This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG) SFB 544 “Control of Tropical Infectious Diseases.”
PY - 2007/1
Y1 - 2007/1
N2 - Adhesion of Plasmodium falciparum infected erythrocytes (IE) to placental chondroitin-4-sulfate (CSA) has been linked to the severe disease outcome of pregnancy-associated malaria. Consequently, sulfated polysaccharides with inhibitory capacity may be considered for therapeutic strategies as anti-adhesive drugs. During in vitro screening a regioselectively modified cellulose sulfate (CS10) was selected as prime candidate for further investigations because it was able to inhibit adhesion to CSA expressed on CHO cells and placental tissue, to de-adhere already bound infected erythrocytes, and to bind to infected erythrocytes. Similar to the undersulfated placental CSA preferred by placental-binding infected erythrocytes, CS10 is characterized by a clustered sulfate pattern along the polymer chain. In further evaluation of its effects on P. falciparum interactions with host erythrocytes, we now show that CS10 inhibits the in vitro asexual growth of parasites in erythrocytes. Furthermore, we show that CS10 interferes with C1 of the classical complement pathway but not with MBL of the lectin pathway. In order to gain insights into the possible interactions of CS10 with known parasite receptors at the molecular level, we designed 3D-structures of characteristic stretches of CS10. CS10 fragments with clustered sulfate groups showed complex patterns of hydrophobic and hydrophilic patches most likely suitable for interactions with protein binding partners. The significance of CS10 interactions with the complement system as well as its anti-malarial effect for prospective drug application are discussed.
AB - Adhesion of Plasmodium falciparum infected erythrocytes (IE) to placental chondroitin-4-sulfate (CSA) has been linked to the severe disease outcome of pregnancy-associated malaria. Consequently, sulfated polysaccharides with inhibitory capacity may be considered for therapeutic strategies as anti-adhesive drugs. During in vitro screening a regioselectively modified cellulose sulfate (CS10) was selected as prime candidate for further investigations because it was able to inhibit adhesion to CSA expressed on CHO cells and placental tissue, to de-adhere already bound infected erythrocytes, and to bind to infected erythrocytes. Similar to the undersulfated placental CSA preferred by placental-binding infected erythrocytes, CS10 is characterized by a clustered sulfate pattern along the polymer chain. In further evaluation of its effects on P. falciparum interactions with host erythrocytes, we now show that CS10 inhibits the in vitro asexual growth of parasites in erythrocytes. Furthermore, we show that CS10 interferes with C1 of the classical complement pathway but not with MBL of the lectin pathway. In order to gain insights into the possible interactions of CS10 with known parasite receptors at the molecular level, we designed 3D-structures of characteristic stretches of CS10. CS10 fragments with clustered sulfate groups showed complex patterns of hydrophobic and hydrophilic patches most likely suitable for interactions with protein binding partners. The significance of CS10 interactions with the complement system as well as its anti-malarial effect for prospective drug application are discussed.
KW - Adhesion
KW - Cellulose sulfate
KW - Complement system
KW - Molecular modelling
KW - Plasmodium falciparum
KW - Pregnancy associated malaria
KW - Sulfated polysaccharides
UR - http://www.scopus.com/inward/record.url?scp=33845578301&partnerID=8YFLogxK
U2 - 10.1007/s10719-006-9012-1
DO - 10.1007/s10719-006-9012-1
M3 - Journal article
C2 - 17115275
AN - SCOPUS:33845578301
VL - 24
SP - 57
EP - 65
JO - Glycoconjugate Journal
JF - Glycoconjugate Journal
SN - 0282-0080
IS - 1
ER -
ID: 340559721