Aug 29, 2019

Sulfated Dendritic Polyglycerol Is a Potent Complement Inhibitor

Biomacromolecules
Kim SilberreisJens Dernedde

Abstract

The complement system is a powerful mechanism of the innate immune defense system. Dysregulation may contribute to several diseases. Heparin is a known regulator of the complement system, but its application is limited due to its anticoagulative activity. A promising alternative is the synthetic analogue dendritic polyglycerol sulfate (dPGS). Although dPGS-mediated inhibition of the classical and alternative pathway has been roughly described previously, here we analyzed the effects of dPGS regarding the three pathways at different levels of the proteolytic cascades for the first time. Regarding the final outcome (membrane attack complex formation), IC50 values for dPGS varied between the alternative (900 nM), the classical (300 nM), and the lectin pathway (60 nM). In a backward approach, processing of proteins C5 and C3 via the respective convertase was analyzed by ELISA to narrow down dPGS targets. A dose-dependent reduction of C5a and C3a levels was detected. Further, the analysis via surface plasmon resonance revealed novel dPGS binding proteins; the pro-inflammatory anaphylatoxins C3a and C5a and the classical pathway activator C1q showed down to nanomolar binding affinities. The fully synthetic multivalent polymer dPGS se...Continue Reading

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Mentioned in this Paper

Complement System Proteins
Heparin
Complement C5a
Magnetic Resonance Imaging
C3a-derived anaphylatoxin receptor, mouse
Deep Gray Layer of the Superior Colliculus
Complement C1q Antibody
Activation of Membrane Attack Complex
Binding Protein
Binding (Molecular Function)

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