Low‐molecular weight inhibitors of the alternative complement pathway

Abstract

The complement system, a major arm of the humoral innate immune system, comprises a cascade of sequentially activated proteases directed at the elimination of pathogens. Deposition of complement components on pathogen surfaces, either directly, or via surfacebound antibodies induces a proteolytic cascade that generates multiple pro-inflammatory protein fragments with diverse functions: Direct cell lysis, chemoattraction and activation of innate immune effector cells, and opsonization, that is, facilitation of pathogen removal by phagocytic cells. As the complement system is a rapid and amplified pro-inflammatory effector system, it needs to be tightly controlled to prevent aberrant and destructive activation. Primary failure of these control mechanisms due to mutations of complement regulators, gain-of function mutations in components of the protease cascade or secondary activation of the complement system due to autoantibodies that stabilize activating complement proteases or neutralize complement regulators or are directed at "self" antigens, all lead to devastating auto-inflammatory diseases.

Targeted genotyping of COVID-19 patients reveals a signature of complement C3 and factor B coding SNPs associated with severe infection

“…Some of the comorbidities reported for this study group, may influence the severity of the disease and aspects of the responses to medication through epigenetic gene regulatory mechanisms, but herein we decided to keep our study focused on the findings of germline genetic variation. Moreover, our findings further support the notion behind complement therapeutics in COVID-19, especially the ones targeting the components of the AP, primarily C3 ( Sim et al, 2022 )( Skendros et al, 2022 ), CFB as well as CFD ( Schubart et al, 2022 )( Dreismann et al, 2023 ). In particular, safety and efficacy has been shown for terminal complement inhibition with the anti-C5 eculizumab ( Diurno et al, 2020 ), C3 inhibition with the AMY-101 ( Mastaglio et al, 2020 ), C1 inhibition with conestat alpha ( Urwyler et al, 2020 ), and lectin pathway inhibition with the anti-MASP-2 narsoplimab ( Rambaldi et al, 2020 ).…”

The complement alternative pathway in health and disease—activation or amplification?

“…These include LMW inhibitors of FB and FD. Schubart et al 52 eloquently take us through the rationale for specific blockade of the amplification loop and the evolution of the small molecule inhibitors.…”

Large‐scale separation of alkaloids from Corydalis decumbens by pH‐zone‐refining centrifugal partition chromatography and their anticomplement activity

“…However, excessive complement activation can lead to various inflammatory diseases such as rheumatoid arthritis [1], systemic lupus erythematosus [2, 3], membranous nephropathy [4], and asthma [5]. Complement inhibitors are thus in high demand and have begun to emerge in the clinical setting [6].…”

“…[2,3], membranous nephropathy [4], and asthma [5]. Complement inhibitors are thus in high demand and have begun to emerge in the clinical setting [6].…”