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Complement System

The complement system is a sophisticated part of the immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells, promotes inflammation, and attacks the pathogen's cell membrane. This system is named for its capacity to "complement" the killing of pathogens by antibodies.

Comprising over 30 small proteins produced by the liver, the complement system circulates in the blood serum and within tissues throughout the body. These proteins are normally inactive but become sequentially activated in response to a pathogen. Activation can occur via three pathways: the classical pathway, which is triggered by antibodies bound to a pathogen; the lectin pathway, which is activated by mannose-binding lectin attaching to the pathogen surface; and the alternative pathway, which can be initiated directly by pathogen surfaces.

Each pathway leads to the cleavage of the protein C3, generating C3a and C3b fragments. C3b binds to the pathogen surface and can lead to direct opsonization—tagging the pathogen for destruction by phagocytes. C3a, along with other small fragments released during complement activation, acts as a chemoattractant to recruit immune cells to the site of infection and promote inflammation.

The final common step of the complement activation pathways is the assembly of the membrane attack complex (MAC). This complex forms a pore in the membrane of the target cell, leading to cell lysis and death. The MAC is particularly effective against gram-negative bacteria.

Regulation of the complement system is crucial, as overactivation can damage host cells. Regulators are present in blood plasma and on cell surfaces, ensuring the system is directed only at pathogens or damaged cells.

The complement system plays a crucial role not only in innate immunity but also as a bridge to adaptive immunity. It assists in clearing immune complexes and apoptotic cells, and in enhancing the humoral response and immune memory.

Understanding and manipulating the complement system has therapeutic potential for numerous diseases, including those that involve excessive or inappropriate activation of the complement pathways.

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  1. A18609
    Danicopan

    Factor D inhibitor

    Danicopan (ACH-4471), a selective and orally active small-molecule factor D inhibitor, shows high binding affinity to human Factor D with Kd value of 0.54 nM.
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  2. A18864
    Complement C5-IN-1

    C5 inhibitor

    Complement C5-IN-1 (Compound 7) is a small-molecule inhibitor of complement component 5 protein (C5).
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  3. A18905
    Iptacopan (LNP023)

    Factor B inhibitor

    LNP023 is a highly potent factor B (FB) inhibitor with an IC50 value of 10 nM. LNP023 shows direct, reversible, and high-affinity binding to human FB (KD=7.9 nM).
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  4. A20253
    Complement factor D-IN-1

    factor d inhibitor

    Complement factor D-IN-1 is a potent and selective small-molecule reversible factor d inhibitor, with IC50s of 0.006 and 0.05 μM in FD Thioesterolytic Fluorescent Assay and a MAC Deposition Assay, respectively.
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  5. A22732
    Compstatin

    Primates' C3 Inhibitor

    Compstatin, a 13-residue cyclic peptide, is a potent inhibitor of the complement system C3 with species specificity. Compstatin binds to baboon C3 and is resistant to proteolytic cleavage in baboon blood (similar to humans). Compstatin inhibits only the activation of primates' complement system. Compstatin exhibits IC50 values of 63 μM and 12 μM for classical and alterative complement pathway, respectively.

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  6. A22799
    POT-4 (AL-78898A)

    Complement factor C3 inhibitor

    POT-4 (AL-78898A), a Compstatin derivative, is a potent inhibitor of complement factor C3 activation. POT-4 can be used for age-related macular degeneration research
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