Graduation Year

2015

Document Type

Dissertation

Degree

Ph.D

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Chemistry

Degree Granting Department

Chemistry

Major Professor

Jianfeng Cai, Ph.D.

Committee Member

Chuanhai Cao, Ph.D.

Committee Member

Li-June Ming, Ph.D.

Committee Member

Mark McLaughlin, Ph.D.

Keywords

anticancer, antimicrobial, protein-protein interactions inhibitors

Abstract

Protein-Protein Interactions (PPIs) play a very important role in biological functions and therefore the inhibition of specific Protein-Protein Interactions has a huge therapeutic value. The most successful small molecular PPIs inhibitors do not fit with the prevalent `Rule of Five' drug profile. To overcome the disadvantages of small molecular PPIs inhibitors, peptide based PPIs inhibitors were developed. Herein we describe the development of a new class of peptidomimetics AA-peptides. The AApeptides were designed based on chiral PNA backbone. Substitution of nucleobases yields AApeptides that are resistant to proteolysis and capable of mimicking peptides. Two types of AApeptides were discussed in this dissertation "α-AApeptides" and "γ-AApeptides". The AApeptides were shown to disrupt p53/MDM2 protein-protein interaction and tomimic fMLF tripeptide to target G protein-coupled formyl peptide receptors (FPRs). Moreover, the lipidated α-AApeptides can mimic the structure and function of natural antimicrobial lipopeptides and show broad-spectrum activity against both Gram-positive and Gram-negative bacteria. Lastly I have designed and synthesized a serials of phosphopeptides to disrupt cancer related STAT3-STAT3 dimerization.

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