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Small Molecule Inhibition of microRNA-21 & Chemical Approaches to Manipulating the Ubiquitin-Proteasome System

Naro, Yuta (2019) Small Molecule Inhibition of microRNA-21 & Chemical Approaches to Manipulating the Ubiquitin-Proteasome System. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The nature of cellular functions involves a complex system of interactions between numerous small molecules and macromolecules. New approaches to discreetly dissect these interactions are vital to understanding how individual interactions contribute to the global function of cells and organisms. The use of selective chemical probes has provided discreet control over many cellular processes and has permitted the investigation of many unanswered questions in chemical biology. Herein, I am describing my contributions to the discovery and application of new chemical tools for the fields of: (a) microRNA biology, (b) targeted protein degradation, (c) HPV-related cancers, and (d) the genetic incorporation of unnatural amino acids.
In the case of targeting microRNA biology, my contributions include the identification and validation of selective small molecule inhibitors of microRNA-21 through the use of chemical optimization, biochemical assays, and cell-based functional assays. These small molecule inhibitors provide valuable tools and potential therapeutics for treating miR-21 related diseases. In the field of targeted protein degradation, I have developed a strategy to control the activity of small molecule protein degradation agents using light as an external stimulus. This approach provides unprecedented spatiotemporal control over protein degradation. Also in this work, I describe the rational design of a protein-mimetic covalent peptide inhibitor of the HPV E6 as a means to combat HPV-related cancers. This peptide represents a novel approach to targeting a protein previously deemed ‘undruggable’. Lastly, computational investigations into the molecular interactions between bioorthogonal tRNA synthetases and their respective unnatural amino acids (UAAs) is explored. These studies provide insight into the electronic and steric interactions that are vital to UAA recognition, while also providing a means to computationally design new tRNA synthetases which can incorporate UAAs with diverse structures and functions.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Naro, Yutayrn1@pitt.eduyrn1
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeiters,
Committee MemberHorne,
Committee MemberFloreancig,
Committee MemberVlad,
Date: 27 September 2019
Date Type: Publication
Defense Date: 6 December 2018
Approval Date: 27 September 2019
Submission Date: 15 May 2019
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 320
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: HPV-16 E6 E6AP stapled peptide miR-21
Date Deposited: 27 Sep 2020 05:00
Last Modified: 27 Sep 2020 05:00


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