Sequence-controlled synthesis of beta3-peptides: Solid-phase synthesis and DNA-templated synthesis.

Format:

Book

Thesis/Dissertation

Author/Creator:

Chiang, Ying-Ling.

Contributor:

Percec, Virgil, committee member.

Chenoweth, David M., committee member.

Petersson, E. James, committee member.

Bode, J. W. (Jeffrey W.), advisor.

University of Pennsylvania. Chemistry.

Language:

English

Subjects (All):

Biochemistry.

0487.

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Local Subjects:

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

0487.

Physical Description:

233 pages

Contained In:

Dissertation Abstracts International 74-10B(E).

System Details:

Mode of access: World Wide Web.

text file

Summary:

The discovery of beta3-peptides as foldamers has attracted substantial interest in their synthesis, analysis and application. The advantages of using beta3-peptides as structural and functional mimics of natural peptides derives from their resistance to proteolysis, metabolic stability and ability to fold into discrete, stable and defined structures at shorter chain lengths than their alpha-peptide counterparts. Since the interaction between beta3-peptides and biomolecules depends on precise substituent sequence of beta3-peptides, we decided to use two different strategies to achieve the sequence-controlled synthesis of beta3-peptides: solid phase peptide synthesis (SPPS) and DNA-templated synthesis (DTS).

Although the SPPS of beta3-peptides has been developed, it was hampered by the difficulties of deprotection and sluggish reactivity of beta3-amino acids. Based on the alpha-ketoacid-hydroxylamine (KAHA) ligation discovered by our group, we have developed a new iterative alpha-ketoacid-isoxazolidine approach for beta3-peptide synthesis. A versatile synthesis of enantiopure isoxazolidine monomers has also been developed. Isoxazolidine monomers with side chains of diverse functionalities (proteinogenic and non-proteinogenic) and different configurations have been synthesized. With the availability of different isoxazolidine monomers, we have developed a three-step procedure to synthesize beta3-peptides, including coupling, hydrolysis and neutralization, for the implementation of the KAHA ligation on solid phase. However, the procedure was restricted to 5-residue beta3-peptides due to the instability of PL-PEGA resin. By optimizing the procedure, including changing resins, coupling a less hindered monomer in the first residue, and thermal hydrolysis of alpha-ketoesters, we have successfully synthesized a beta3-octapeptide with acid and base functionality on the side chains. This novel SPPS of beta3-peptides via KAHA ligation provides an alternative to the traditional SPPS of long beta3-peptides.

We also applied the KAHA ligation to DNA-templated polymerization of beta 3-peptides. Combining the advantage of iterative KAHA ligation and DTS which increases the effective reactant molarity, sequence-controlled synthesis of beta3-peptides can be constructed. We have successfully coupled the alpha-ketoacid and isoxazolidine to DNAs. However, no desired KAHA ligation product was observed in our early test due to the instability of isoxazolidine monomer on DNA. After modifying the DNA construct and making a more stable monomer, we successfully perform the first KAHA ligation on DNA. To avoid thermal destruction of monomer, we have to adopt isothermal strategies to implement the multistep synthesis of beta3-peptides on DNA. We believe that these two synthetic methods of beta3-peptide can help the development of beta3-peptides in biological study and therapeutic application.

Notes:

Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 2013.

Source: Dissertation Abstracts International, Volume: 74-10(E), Section: B.

Adviser: Jeffrey W. Bode.

Local Notes:

School code: 0175.

ISBN:

9781303145384

Access Restriction:

Restricted for use by site license.