Abstract

Anemia of chronic inflammation (ACI) is a condition that develops in a setting of chronic immune activation. ACI is characterized and triggered by inflammatory cytokines and the disruption of iron homeostasis. Hepcidin, a small peptide hormone, is the master regulator of iron homeostasis, and rapidly responds to iron supply and demand. Under conditions of chronic inflammation, hepcidin is elevated, and alters the way that iron is absorbed and disrupted throughout the body, resulting in disrupted iron homeostasis through inhibition of the iron exporter protein ferroportin. Anemia arises when insufficient erythropoietic activity combined with inadequate iron supply abrogates the healthy development of mature red blood cells (RBCs). The proprotein convertase (PC) known as furin is a serine protease capable of cleaving peptide precursors into their active state. Furin is critical for normal activation of proteins and enzymes but recently, furin has been implicated in critical roles within cancers, viral and pathogenic infections, and arthritis through activating precursors novel to the disease type. Furin has previously been identified as being the sole PC responsible for generating active hepcidin. Hepcidin is initially synthesized as a larger precursor protein, before undergoing furin cleavage. Furin is known to form mature, bioactive hepcidin, with the removal of this pro-region. Our discovery of a novel regulatory site on Furin has led to potent inhibition using small molecules. This inhibition is shown with the use of in vitro fluorogenic assays, in vivo cell tissue cultures, and within an animal model of ACI. Our results demonstrate that in using these small molecules we can decrease hepcidin levels even in the presence of potent inflammatory cytokines. The inhibition of hepcidin by these small molecules causes an increase in stably expressed ferroportin on cell surfaces and the restoration of the ability to mobilize iron from storage tissues and absorption from the diet. The ability to "fine-tune" inhibition of furin in targeting its allosteric site along with its catalytic domain designates these small-molecule inhibitors as promising therapeutics for treatment of diseases ranging from Alzheimer's and cancer to anthrax and Ebola fever.

Degree

PhD

College and Department

Physical and Mathematical Sciences; Chemistry and Biochemistry

Rights

http://lib.byu.edu/about/copyright/

Date Submitted

2014-07-01

Document Type

Dissertation

Handle

http://hdl.lib.byu.edu/1877/etd7209

Keywords

furin, anemia of chronic inflammation, hepcidin, protease inhibitors, ferroportin

Language

english

Included in

Chemistry Commons

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