Inhibition of Blood Coagulation Factor XII: Evaluation of Flavonoids as a Drug Candidate

Crosswhite, Betsy (2018) Inhibition of Blood Coagulation Factor XII: Evaluation of Flavonoids as a Drug Candidate. Undergraduate thesis, under the direction of Ziaeddin Shariat-Madar from BioMolecular Sciences, University of Mississippi.

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Abstract

This study investigated natural product inhibitors of blood coagulation Factor XII (FXII). FXII initiates the Kallikrein Kinin-System (KKS) within the intrinsic coagulation pathway. Increased expression of this system leads to proinflammatory and procoagulant activities. Inflammation occurs through downstream activation in the KKS. Following the activation of FXII-dependent pathway, bradykinin (BK) binds to the BK receptor 2 (B2) and produces inflammatory signaling. Abnormally increased BK can result in life threatening Hereditary Angioedema (HAE), characterized by severe reoccurring swelling. FXII is critical for pathogenic thrombosis, but is dispensable for hemostasis. This unique property of FXII makes it an attractive drug target. We hypothesized that the identification of a specific inhibitor for activated FXII could lead to the reduction of Hereditary Angioedema Type III (HAE III) symptoms and hinder thrombosis formation without an increased risk for bleeding. In this study, we presented an extension of our previous work, which dealt with high-throughput screening of plant extracts and a large compound collections to target FXIIa. We identified myricitin as a candidate compound via a systemic experimental screening. Chromogenic activated FXII activity assays were preformed to test the effects of myricitrin analogues on plasma enzymes (FXIIa, FXIa, and kallikrein). To assess the inhibitory effects of candidate compounds on these proteases, the release of paranitrianalide from the chromogenic substrates were measured as an indicator of FXIIa, FXIa, or kallikrein activity. The results of this study showed that myricetin, an analogue of myricitrin, significantly inhibited FXIIa at the sub-micromolar to the low micromolar concentration range. Overall, myricetin has the potential to be a useful multifunctional therapeutic drug in patients with HAE and thrombolytic diseases.

Item Type: Thesis (Undergraduate)
Creators: Crosswhite, Betsy
Student's Degree Program(s): B.A. in Biology
Thesis Advisor: Ziaeddin Shariat-Madar
Thesis Advisor's Department: BioMolecular Sciences
Institution: University of Mississippi
Subjects: R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Depositing User: Miss Betsy Crosswhite
Date Deposited: 04 Apr 2018 13:11
Last Modified: 04 Apr 2018 13:11
URI: http://thesis.honors.olemiss.edu/id/eprint/1007

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