Dissertation
Caspase-7 allostery and drug targeting
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2023
DOI: 10.25820/etd.007284
Abstract
Caspase-7 (C7) is a cysteine protease involved in apoptosis. C7 has also been shown to play a role in the etiopathogenesis of several human diseases including neurodegenerative diseases (e.g. Parkinson’s disease and Alzheimer’s disease) and inflammatory conditions. Despite the substantive therapeutic value and high degree of interest in drugs targeting C7, there are currently no pharmaceutical inhibitors of C7 or any other caspase. My research approach used fragment-based drug discovery (FBDD) and natural products screening in order to identify novel caspase-7 effectors, which may serve as drug leads. I used a biochemical, structural, and computational workflow to gain insight into the mechanism of inhibition of a developing pharmacophore targeting the C7 allosteric site identified by FBDD. Additionally, I attempted to streamline the characterization of hits from screening of fractionated natural products libraries, a major obstacle currently limiting their utility in the broader landscape of drug discovery research, using an integrated analytical chemistry and computational approach. Here I present novel fragment-based inhibitors targeting the C7 allosteric site, elucidate how these inhibitors affect C7 structure and catalysis, and demonstrate the value of continued investigation of natural products to identify novel C7 inhibitors. Additionally, I develop a novel process for structural characterization of samples from fractionated natural products libraries reducing i) the amount of material needed for structure determination and ii) the number of assays needed to identify a hit. My work advances drug targeting efforts for C7 and provides valuable insight into the mechanism of allosteric inhibition of C7. This provides a springboard for future drug discovery efforts targeting C7, as well as allosteric drug discovery efforts in similar proteins. My work also puts forth a significant innovation to screening natural products, which can be used to reduce the cost and improve the accessibility of natural products screening for drug discovery.
Details
- Title: Subtitle
- Caspase-7 allostery and drug targeting
- Creators
- Kathryn Fern Hobbs
- Contributors
- Ernesto Fuentes (Advisor)Charles Brenner (Committee Member)Jonathan A Doorn (Committee Member)Lori Wallrath (Committee Member)M. Todd Washington (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biochemistry and Molecular Biology
- Date degree season
- Spring 2023
- DOI
- 10.25820/etd.007284
- Publisher
- University of Iowa
- Number of pages
- xix, 173 pages
- Copyright
- Copyright 2023 Kathryn Fern Hobbs
- Comment
This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/.
- Language
- English
- Date submitted
- 04/24/2023
- Date approved
- 06/30/2023
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 126-135).
- Public Abstract (ETD)
Cells have numerous mechanisms regulating their function to maintain a healthy biological system. Apoptosis is the process of programmed cell death, which is a normal part of an organism’s development and can also be used to rid the body of abnormal cells. However, dysregulated or inappropriately increased apoptosis can exacerbate neurodegenerative diseases like Alzheimer's disease and Parkinson’s disease, as well as inflammatory conditions. An important protein involved in orchestrating apoptosis is caspase-7, which breaks down proteins involved in a number of critical cellular functions. Thus, a drug inhibiting caspase-7 activity has therapeutic value for treating neurodegenerative and inflammatory diseases. However, there are currently no FDA approved drugs known to target caspase-7. I employ several strategies to find new caspase-7 inhibitors and understand how they work to disrupt caspase-7 functioning. Here I present several new and improved inhibitors of caspase-7 and shows how they affect caspase-7 activity. This provides a better starting point for future drug discovery efforts targeting caspase-7 and other similar targets.
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984425314502771
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