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Wenlong's dissertation.pdf (4.84 MB)
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DEVELOPMENT AND OPTIMIZATION OF PROTEIN-PROTEIN INTERACTION INHIBITORS BY COMBINATORIAL AND MEDICINAL CHEMISTRY
Author Info
Lian, Wenlong
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=osu1449161031
Abstract Details
Year and Degree
2015, Doctor of Philosophy, Ohio State University, Chemistry.
Abstract
Protein-protein interactions (PPIs) are of central importance in essentially all biochemical pathways, including those involved in disease processes. PPIs therefore represent a large class of new, exciting drug targets. However, PPIs are considered the prototypical “undruggable” or “challenging” targets for the conventional small-molecule approach, because PPIs usually involve large, flat interfaces, with which small molecules usually do not make enough points of contact to impart high affinity or specificity. For some of these PPIs, small-molecule inhibitors have been successfully developed by targeting the so-called “hot spots” at the interaction interface. A more general approach is to develop specific antibodies against the PPI interface. Non-immunoglobulin protein scaffolds have also been engineered into specific binders to target proteins through library screening and/or in vitro evolution. Antibodies and protein binders possess large binding surfaces of their own and are capable of making multiple contacts with a target surface (e.g., those involved in PPIs). Unfortunately, protein-based drugs are impermeable to the mammalian cell membrane; as such they are generally limited to targeting extracellular proteins and are not orally available. Tumor necrosis factor-alpha (TNF-alpha), a pleiotropic inflammatory cytokine of a variety of functions, is responsible for many inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and septic shock and hepatitis. There are two types of marketed biologic drugs that reduced TNF-alpha bioactivity: soluble TNF receptor-Fc fusion protein (etanercept) and anti-TNF mAbs (infliximab). Alternative TNF antagonist agents were also developed, however none of them have been applied clinically. We report here a methodology for chemical synthesis and screening of large combinatorial libraries of bicyclic peptides displayed on rigid small-molecule scaffolds. Screening of a bicyclic peptide library against tumor necrosis factor-alpha identified a potent antagonist (named anticachexin C1) that inhibits the TNF-TNF receptor interaction and protects cells from TNF-induced cell death. TNF antagonist (C1) was also optimized by medicinal chemistry and 2nd generation library screening to get a more potent inhibitor. Protein-tyrosine phosphatase 1B (PTP1B) is a prototypical member of the PTP superfamily and plays numerous roles during eukaryotic cell signaling. Because of its role in negatively regulating insulin and leptin receptor signaling, PTP1B is a valid target for treatment of type II diabetes and obesity. A large number of PTP1B inhibitors have been reported, however, none of them have succeeded in the clinic. Designing PTP inhibitors is challenging because most of the phosphotyrosine (pY) isosteres such as difluorophosphonomethyl phenylalanine (F2Pmp) are impermeable to the cell membrane. Additionally, because all PTPs share a similar active site, achieving selectivity for a single PTP has been difficult. In this work, we report a potentially general approach to designing cell-permeable cyclic peptidyl inhibitors against intracellular proteins such as PTP1B.
Committee
Pei Dehua (Advisor)
Pages
160 p.
Subject Headings
Chemistry
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Citations
Lian, W. (2015).
DEVELOPMENT AND OPTIMIZATION OF PROTEIN-PROTEIN INTERACTION INHIBITORS BY COMBINATORIAL AND MEDICINAL CHEMISTRY
[Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449161031
APA Style (7th edition)
Lian, Wenlong.
DEVELOPMENT AND OPTIMIZATION OF PROTEIN-PROTEIN INTERACTION INHIBITORS BY COMBINATORIAL AND MEDICINAL CHEMISTRY.
2015. Ohio State University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=osu1449161031.
MLA Style (8th edition)
Lian, Wenlong. "DEVELOPMENT AND OPTIMIZATION OF PROTEIN-PROTEIN INTERACTION INHIBITORS BY COMBINATORIAL AND MEDICINAL CHEMISTRY." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449161031
Chicago Manual of Style (17th edition)
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Document number:
osu1449161031
Download Count:
80
Copyright Info
© 2015, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.