Abstract
The serpin 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 SG by evaluating structure-activity relationships. For this, more than 40 structurally distinct SG were examined for their effects on C1-INH, C1s and FXIIa. 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 a Mr ≤ 10 000 were identified as most promising lead candidates for the development of a glycan-based C1-INH amplifier. In conclusion, the obtained information on structural characteristics of SG favoring 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.
Highlights
C1 inhibitor (C1-INH) is a member of the serpin family of protease inhibitors and the major regulator of several serine proteases of the human complement, contact and coagulation system [1,2]
C1-INH is one of several soluble and membrane-bound regulatory proteins, the only one inhibiting the initial activation of the complement system that can occur via three different pathways, i.e. (1) the classical pathway (CP) mainly initiated by antibody complexes, (2) the lectin pathway (LP), that is activated by carbohydrates or N-acetylated groups on microbial surfaces, and (3) the alternative pathway (AP) which is triggered by foreign surfaces and functions as so-called amplification loop [5]
After a preincubation of C1-INH in absence and presence of PS3 for 0, 2, 5, 10 or 15 min at 37°C the residual C1s activity was determined as described in materials and methods
Summary
C1 inhibitor (C1-INH) is a member of the serpin family of protease inhibitors and the major regulator of several serine proteases of the human complement, contact and coagulation system [1,2]. These plasmatic cascade systems are closely linked to each other and as part of the innate immunity indispensable for an adequate immune response [2]. C1-INH, diminishes the consequences of complement activation, including the generation of pro-inflammatory anaphylatoxins, especially C5a, and the formation of a membrane attack complex (MAC) that leads to lysis of foreign cells
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