Discovery and characterization of tubulin-interactive peptides

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Title Discovery and characterization of tubulin-interactive peptides
Publication Type dissertation
School or College College of Pharmacy
Department Pharmacology & Toxicology
Author Edler, Michael Charles, Jr.
Date 2003-05
Description Tubulin is a heterodimer composed of an ? and a ? subunit. Polymerization of these dimers results in the formation of microtubules that are important in many cellular functions, such as cell division. Rapidly dividing cells, such as cancer cell, are very sensitive to compounds that disrupt microtubule biochemistry. Natural products have yielded several tubulin active poisons used in the clinic today. Recent exploration into marine natural products has produced several new molecules with tubulin activity. One such compound is vitilevuamide, a bicyclic 13 amino acid peptide, isolated from marine ascidians. Phage display is a combinatorial technique used to find short peptides that bind a desired target. We have isolated several peptides from a phage display library that bind tubulin. The focus of this study is to compare the natural product vitilevuamide and the peptides found by screening phage libraries. Although phage display may select some cytotoxic peptides, we hypothesized that many others would bind motifs that modulate tubulin function in a noncytotoxic fashion. The effect of the peptides on tubulin polymerization, aggregation, quenching of tubulin fluorescence and prevention of time- and temperature-dependent denaturation of tubulin was determined. The ability of these peptides to prevent drug-induced aggregation was also examined. Sequence similarity analysis was used to generate possible explanation for characteristics displayed by the phage-derived peptides. One phage display peptide isolated was found to have sequence similarity to a conserved region of tau protein. Another peptide had similarities to regions on tubulin that play roles in both lateral and longitudinal contacts in polymerization of microtubules. These studies have shown that phage display can produce peptides that have affinity for tubulin, but do not function like traditional cytotoxic natural product peptides.
Type Text
Publisher University of Utah
Subject Peptide Drugs; Tubulins; Antineoplastic Agents
Subject MESH Antineoplastic Agents; Tubulin; Peptide Hydrolases
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Discovery and characterization of tubulin-interactive peptides." Spencer S. Eccles Health Sciences Library. Print version of "Discovery and characterization of tubulin-interactive peptides." available at J. Willard Marriott Library Special Collection. RS43.5 2003 .E35.
Rights Management © Michael Charles Edler, Jr.
Format application/pdf
Format Medium application/pdf
Format Extent 2,611,912 bytes
Identifier undthes,4952
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 2,611,963 bytes
ARK ark:/87278/s6w95c1k
Setname ir_etd
ID 191405
Reference URL https://collections.lib.utah.edu/ark:/87278/s6w95c1k
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