Honors Theses

Date of Award

2018

Document Type

Undergraduate Thesis

Department

Biomolecular Sciences

First Advisor

Ziaeddin Shariat-Madar

Relational Format

Dissertation/Thesis

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.

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