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osu1306865559.pdf (4.94 MB)
ETD Abstract Container
Abstract Header
Development Of Cyclic Peptidyl Ligands Through A Combinatorial Library Approach
Author Info
Liu, Tao
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=osu1306865559
Abstract Details
Year and Degree
2011, Doctor of Philosophy, Ohio State University, Biochemistry Program, Ohio State.
Abstract
Cyclic peptides are widely produced in nature and possess a broad range of biological activities. Their enhanced proteolytic stability in vivo and improved receptor binding affinity/specificity makes them excellent drug candidates, molecular probes and targeting agents. In fact, many cyclic peptides are clinically used therapeutic agents. Combinatorial library approaches provide powerful tools for the rapid identification of compounds with desired properties from large pools in biological and biomedical studies. However, the synthesis and screening of cyclic peptide libraries in a combinatorial format has been challenging. To overcome the issue, we have successfully developed one-bead-two-compound (OBTC) libraries with a cyclic peptide displayed on the bead surface accessible for protein targets screening, while the bead interior contains the corresponding linear peptide served as an encoding tag for hit identification. The primary goal of my research is to identify novel biologically active cyclic peptides, beyond what nature has provided us. By applying cyclic peptide library approach, we have successfully identified high affinity ligands against various biological targets, including: extracellular protein receptors (human prolactin receptor), intracellular protein domains (the capsid domain of HIV-1 Gag polyprotein and calcineurin catalytic domain) and enzymes (Pin1 catalytic domains). In the meantime, we have continued to improve the methodologies associated with combinatorial chemistry. To facilitate the process and improve the screening results, such as avoiding false positives, we have developed many cyclic library approaches including libraries on different solid supports, reduced surface density libraries, high diversity libraries with different ring sizes and library compatible with rapid solution phase validation. These new approaches greatly facilitate the ligands discovery process. My final work focused on the intracellular delivery of cyclic peptides. Little is known about how cyclization would affect peptides membrane permeability and the results from existing studies are controversial. With a combination of biophysical approaches and cell based studies, we have found that cyclization has a dramatic effect on the cell permeation of peptides with certain residues. By applying the rules, we were able to design cell permeable cyclic peptide inhibitors against various intracellular protein targets. Our studies provide guiding principles for designing membrane penetrating cyclic peptidyl drugs.
Committee
Dehua Pei, PhD (Advisor)
Peng George Wang, PhD (Committee Member)
Ross E. Dalbey, PhD (Committee Member)
Pages
192 p.
Subject Headings
Biochemistry
;
Biomedical Research
;
Chemistry
Keywords
Cyclic Peptides
;
Combinatorial Chemistry
;
One-Bead-One-Compound (OBOC) Library
;
Prolactin Recepotr
;
Pin1
;
HIV Capsid
;
Calcineurin
;
Cell Penetrating Peptide (CPP)
Recommended Citations
Refworks
EndNote
RIS
Mendeley
Citations
Liu, T. (2011).
Development Of Cyclic Peptidyl Ligands Through A Combinatorial Library Approach
[Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1306865559
APA Style (7th edition)
Liu, Tao.
Development Of Cyclic Peptidyl Ligands Through A Combinatorial Library Approach.
2011. Ohio State University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=osu1306865559.
MLA Style (8th edition)
Liu, Tao. "Development Of Cyclic Peptidyl Ligands Through A Combinatorial Library Approach." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1306865559
Chicago Manual of Style (17th edition)
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Document number:
osu1306865559
Download Count:
573
Copyright Info
© 2011, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.