With the accumulation of experience in the past years, Creative Biolabs is dedicated to providing a full range of biotherapeutics development services. Based on our well-established antibody engineering platform, protease inhibitor platform, and drug discovery platform, we are fully equipped to partner with our clients who are doing or may have the desire to work on complement systems for drug discovery and validation.
The immune system is the defense system that detects a broad range of agents (virus, parasitic worm and bacteria etc.) and protects against diseases. As part of the immune system, the complement system plays an important role in defending people’s health. The complement system consists of approximately 30 fluid-phase and cell-membrane proteins and can be activated essentially by three pathways including the classical pathway, mannose-binding lectin pathway, and alternative pathway. The classical pathway is initiated by the C1 complex recognizing the antigen-antibody complex. C1r is a component of C1 complex. Encoded by C1R gene in humans, C1r functions as an esterase, selectively cleaving Lys (or Arg)-Ile bond in complement subcomponent C1s to form the activated C1s. The active form of C1s cleaves complement component C4, releasing C4a and initiating covalent attachment of C4b to the activating surface. The activated C1s cleaves complement component C2 as well, transforming C2 into C2a and C2b. C2a binds C4b to form C3 convertase leading to the formation of the membrane attack complex and the elimination of the target.
Fig. 1 The 3D model of human C1r.1
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Function
In the classical pathway of the complement system, C1r enzyme is used to activate C1s proenzyme, an inactivated form of C1s. With the presence of calcium, C1r is capable of binding another C1r molecule. Thus these, together with two C1s molecules bind to C1q. It occurred that the activated C1r rapidly activates the two C1s proenzymes to form C1s enzymes and the resulting C1q-C1r2-C1s2 complex is a fully active C1 molecule.
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Regulation
C1-inhibitor (C1-INH) acts as a protease inhibitor, whose main function is to inhibit the complement system in an attempt to prevent the spontaneous activation. The spontaneous activation of C1r is minimized by the presence of C1-INH which rapidly inactivates spontaneously activated C1r. Stabilization of the proenzyme results from the existence of a weak complex between C1-INH and C1r proenzyme. This association apparently stabilizes C1 thus preventing spontaneous activation in serum. Separation of C1-INH from C1 during purification is one of the reasons that isolated C1 and C1r proenzyme is unstable and prone to spontaneous activation.
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C1r Related Disease
C1r gene is linked to the periodontal Ehlers-Danlos syndrome and the mechanism underlies its related pathway including Creation of C4 and C2 activators and complement and coagulation cascades. In general, Ehlers-Danlos syndrome is a clinically and genetically heterogeneous group of connective tissue disease defined by joint laxity and skin alterations. Periodontal Ehlers-Danlos syndrome, once designated Ehlers-Danlos syndrome VIII, is one specific subtype of Ehlers-Danlos syndrome with autosomal dominant inheritance. Its defining feature is an Ehlers-Danlos syndrome phenotype with several periodontal inflammations.
As a global leader in the drug discovery and complement therapeutic field, Creative Biolabs' outstanding crew are confident in providing high-quality biotherapeutics development services based on the complement system. We offer turn-key or ala carte services customized to our client’s needs. If you are interested in our platform or you are calling for our services, please contact us for detailed information.
Reference
1. From Wikipedia: By Emw - Own work, CC BY-SA 3.0 https://commons.wikimedia.org/wiki/File:Protein_C1R_PDB_1apq.png
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Questions & Answer
A: Researchers have employed strategies like structure-based drug design, high-throughput screening, virtual screening, peptide-based inhibitors, antibody-based inhibition, combinatorial chemistry, fragment-based drug design, rational design, allosteric inhibition, and natural product-based screening to design C1r-specific inhibitors. These approaches involve targeting the enzyme's active site, using computational methods, creating peptides or antibodies, optimizing chemical compounds, and exploring diverse chemical libraries or natural products to disrupt C1r activity in the complement system.
A: Developing C1r-targeted therapeutics faces challenges such as achieving specificity without affecting related enzymes, addressing potential off-target effects, ensuring effective delivery to target tissues, and overcoming the potential for resistance. Additionally, navigating the complex regulatory pathways and safety considerations associated with modulating the complement system poses a challenge.
A: Before advancing C1r-targeted therapies to clinical trials, essential preclinical studies involve assessing compound toxicity, pharmacokinetics, and pharmacodynamics in animal models. Investigating potential off-target effects, immunogenicity, and dose-response relationships is crucial. Comprehensive safety and efficacy data generated from our preclinical investigations inform decision-making, optimizing the likelihood of success and safety in subsequent clinical trials for C1r-targeted therapies.
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