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Full text release has been delayed at the author's request until May 06, 2024
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Discovery and Optimization of Cell-Penetrating Peptidyl Therapeutics through Computational and Medicinal Chemistry
Author Info
Dougherty, Patrick G
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=osu1555576605800362
Abstract Details
Year and Degree
2019, Doctor of Philosophy, Ohio State University, Chemistry.
Abstract
The development of new modalities to target biologically relevant, but conventionally undruggable interactions, serves as the foundation for a new frontier of therapeutic intervention. This work focuses specifically on the development of entities that can target protein-protein interactions (PPIs), a class of interactions that serve as important modulators for a diverse range of biological functions. Development of agents that can successfully inhibit PPIs is an area of intense research within drug discovery as they are not amenable to targeting using conventional small molecule therapeutics. Alternative moieties, such as biological drugs, are capable of PPI inhibition, but lack the ability to cross the cell membrane to engage with intracellular targets. Peptides serve as an attractive intermediate, offering small molecule-like pharmacokinetics combined with high affinity and specificity observed with biological drugs (e.g. antibodies). Fusion of a peptide with a cell-penetrating peptide (CPP), a short sequence motif that confers cellular uptake, results in compounds possessing a highly desirable synergy of pharmacokinetic and pharmacodynamic characteristics. In this work, highly potent peptidyl inhibitors have been developed through synergizing medicinal, combinatorial, and computational chemistry and evaluated for biological efficacy both in vitro and in vivo. In this work, the synergistic application of medicinal, computational, and combinatorial chemistry inhibitors has been employed to identify highly-potent inhibitors of the calcineurin (CN)-NFAT interaction. Nuclear factor of activated T-cells (NFAT) is a key transcriptional mediator of inflammatory response and the CN-NFAT PPI is a well-established therapeutic target for a range of inflammatory and autoimmune disorders. Computational optimization of the N-terminal residues of a previously identified peptidyl CN-NFAT inhibitor yielded a lead compound with improved binding affinity and proteolytic stability. Combinatorial optimization of the C-terminal region resulted in a lead compound with single-digit nanomolar binding affinity to CN. Conjugation with a cyclic CPP rendered a lead compound that has demonstrated potent in vivo activity as a CN-NFAT inhibitor in a murine model of acute respiratory distress syndrome. This approach was also applied to a disulfide-cyclized inhibitor of the CAL-PDZ-CFTR interaction. CAL, cystic fibrosis receptor associated ligand, interacts with the cystic fibrosis transmembrane regulator (CFTR) through a PDZ domain. Beginning from a previously identified ligand, iterative medicinal chemistry and computational optimization yielded a final lead compound with exceptionally improved binding affinity, target binding specificity and proteolytic stability. In vitro activity assays confirmed potent and successful rescue of CFTR function as a potential therapeutic to aid CF patients. Finally, a general methodology for the delivery of lactam-stapled peptides using cyclic CPPs was developed. Stapled peptides are a class of PPI inhibitors based around linear peptides preorganized into an α-helical conformation through side-chain cyclization or “stapling”. The ubiquity of PPI’s mediated by α-helices makes a robust strategy for their effective intracellular delivery valuable for their future application as potential therapeutics. Proof-of-concept examples were designed and evaluated in vitro for both the p53-MDM2 and β-catenin-Wnt signaling pathways.
Committee
Dehua Pei (Advisor)
Christopher Hadad (Committee Member)
Thalil Rajanbabu (Committee Member)
Steffen Lindert (Committee Member)
Pages
215 p.
Subject Headings
Chemistry
Keywords
Cell-penetrating peptide
;
calcineurin
;
protein-protein interaction
;
cystic fibrosis
;
CFTR
;
NFAT
;
MDM2
;
p53
;
drug discovery
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Citations
Dougherty, P. G. (2019).
Discovery and Optimization of Cell-Penetrating Peptidyl Therapeutics through Computational and Medicinal Chemistry
[Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555576605800362
APA Style (7th edition)
Dougherty, Patrick.
Discovery and Optimization of Cell-Penetrating Peptidyl Therapeutics through Computational and Medicinal Chemistry.
2019. Ohio State University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=osu1555576605800362.
MLA Style (8th edition)
Dougherty, Patrick. "Discovery and Optimization of Cell-Penetrating Peptidyl Therapeutics through Computational and Medicinal Chemistry." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555576605800362
Chicago Manual of Style (17th edition)
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Document number:
osu1555576605800362
Copyright Info
© 2019, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.