Regulation of complement and contact system activation via C1 inhibitor potentiation and factor XIIa activity modulation by heparins, glycosaminoglycans and other sulfated glycans

S. Alban, E. Lahrsen, A.-K. Schoenfeld (Kiel, Germany)

Innovation and Novelty
Date: 16.02.2017,
Time: 14:00 - 15:15

Objective: C1 inhibitor (C1-INH) is the only regulator of classical complement activation as well as the major regulator of the contact system. Its importance is demonstrated by hereditary angioedema (HAE), a severe disease with potentially life-threatening attacks due to deficiency or dysfunction of C1-INH. C1 INH replacement is the therapy of choice in HAE. In addition, C1-INH showed to have beneficial effects in other diseases characterized by inappropriate complement and contact system activation. Due to some limitations of its clinical application, there is a need for improving the efficacy of therapeutically applied C1-INH or to enhance the activity of endogenous C1-INH. Given the known potentiating effect of heparin on C1-INH, sulfated glycans (SG) may be such candidates. The aim of this study was to characterize suitable lead structures by investigating structurally distinct SG for their C1-INH potentiation activity as well as their direct effects on the complement factor C1s and on factor FXIIa (FXIIa).

Methods: The effects of SG on the C1INH-mediated inhibition of C1s and FXIIa as well as on C1s and FXIIa activity were measured by chromogenic substrate assays. The > 40 structurally defined SG tested in this study included (1) heparins with molecular weights (MW) ranging from 3 to 15 kDa and fondaparinux, (2) further genuine and chemically modified glycosaminoglycans (GAGs) and danaparoid (3) two series of high-MW and low-MW semisynthetic β 1,3 glucan sulfates, and (4) various algae-derived SG, and (5) two series of successively depolymerized fucoidans.

Results: The SG turned out to potentiate the C1s inhibition by C1-INH without any direct influence on C1s. Their potentiating activity proved to depend on their degree of sulfation, molecular mass as well as glycan structure. In contrast, the SG had no effect on the FXIIa inhibition by C1-INH, but structure-dependently modulated the activity of FXIIa. Among the tested SG, β-1,3-glucan sulfates with MW <= 10 000 were identified as most promising lead candidates for the development of a glycan-based C1-INH amplifier.

Conclusion: In conclusion, the obtained information on structural characteristics of SG favouring C1-INH potentiation represent an useful elementary basis for the development of compounds improving the potency of C1-INH in diseases and clinical situations characterized by inappropriate activation of complement and contact system.