A mechanistic model of in vitro plasma activation to evaluate therapeutic kallikrein-kinin system inhibitors.

Autor: Alireza Rezvani-Sharif, Hadi Lioe, Steven K Dower, Matthias Pelzing, Con Panousis, Dalton J E Harvie, Ineke L Muir
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: PLoS Computational Biology, Vol 20, Iss 11, p e1012552 (2024)
Druh dokumentu: article
ISSN: 1553-734X
1553-7358
DOI: 10.1371/journal.pcbi.1012552
Popis: BackgroundThe kallikrein-kinin system (KKS) is a complex biochemical pathway that plays a crucial role in regulating several physiological processes, including inflammation, coagulation, and blood pressure. Dysregulation of the KKS has been associated with several pathological conditions such as hereditary angioedema (HAE), hypertension, and stroke. Developing an accurate quantitative model of the KKS may provide a better understanding of its role in health and disease and facilitate the rapid and targeted development of effective therapies for KKS-related disorders.ObjectivesHere, we present a novel, detailed mechanistic model of the plasma KKS, elucidating the processes of Factor XII (FXII) activation, the kallikrein feedback loop, cleavage of high molecular weight kininogen leading to bradykinin (BK) production, and the impact of inhibitors.MethodsThe model incorporates both surface and solution-phase reactions of all proteins in the KKS, describing how binding site concentration affects the rate of surface reactions. The model was calibrated and validated using a variety of published and in-house experimental datasets, which encompass a range of dextran sulphate (DXS) concentrations to initiate contact activation and various KKS inhibitors to block bradykinin production.ResultsOur mathematical model showed that a trace amount of activated FXII is required for subsequent FXII activation. The model also reveals a bell-shaped curve relationship between the activation of the KKS and the number of DXS surface binding sites. Simulations of BK generation in healthy and HAE plasma demonstrated the impact of C1 esterase inhibitor (C1inh) deficiency via increased peak BK levels and accelerated formation in HAE plasma. The efficacy of KKS inhibitors, such as CSL312, ecallantide, and C1inh, was also evaluated, with CSL312 showing the most potent inhibition of BK generation.ConclusionsThe present model represents a valuable framework for studying the intricate interactions within the plasma KKS and provides a better understanding of the mechanism of action of various KKS-targeted therapies.
Databáze: Directory of Open Access Journals
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