Graduation Year

2021

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Jianfeng Cai, Ph.D.

Committee Member

James Leahy, Ph.D.

Committee Member

Wayne Guida, Ph.D.

Committee Member

Cheng Feng, Ph.D.

Keywords

Helix Mimetic, HIF-1 Alpha Inhibitor, LPS Inhibitor, Macrocyclic Peptide Library, Protein-Protein interaction inhibitor, VEGF Inhibitor

Abstract

Proteins are complex macromolecules that are responsible for almost all biochemical processes and play vital roles in signaling pathways, metabolic pathways, and all other cellular functions. Proteins accomplish this by interacting with other proteins and macromolecules like DNA and RNA, for instance, as transcription factors. As such, we can find protein interactions behind every cellular action or inaction, and it is easy to see how protein interactions are crucial in understanding disease processes. Advance in proteomics has particularly provided a wealth of insights into molecular mechanisms of disease processes of cancers and other rare diseases, which has helped identify key therapeutic protein targets for intervention. In this work, we describe the design, synthesis, and testing of peptidomimetic protein-protein interaction inhibitors. We employed our Sulfonyl--AA-peptide based helical mimetics to develop rationally designed inhibitors of VEGF and HIF-1[U+F061], two cancer targets responsible for angiogenesis and hypoxia respectively, hallmarks of cancer cells. Our mimics demonstrated effective inhibition of the targeted protein-protein interactions. We also describe the synthesis of a -AA-peptide based macrocyclic peptidomimetic library to identify hits against VEGF and LPS. We also describe hits optimizations to develop promising lead compounds effective against drug resistant Gram-negative bacteria.

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