Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Jianfeng J. Cai, Ph.D.

Committee Member

Wayne Guida, Ph.D.

Committee Member

Cheng Feng, Ph.D.

Committee Member

Kirpal Bisht, Ph.D.

Keywords

Fusion inhibitor, Helical mimetics, Peptidomimetics library, Protein-protein interaction, γ-AApeptide

Abstract

In the past two decades, a lot of different peptidomimetics, such as β-peptides, oligoureas, azapeptides, peptoids, aromatic oligoamides, and others, have been developed. These peptidomimetics with distinctive scaffolds have shown potential in protein surface recognition and mimicry, PPI regulation, catalysis, etc. Moreover, these bioactive peptidomimetics demonstrate much better bioavailability and biostability than the bioactive peptides. To expand the application of peptidomimetics, our group have developed a new sequence-specific peptidomimetics- γ-AApeptide, which is derived from chiral γ-PNA. It shows excellent advantages including highly resistant to various proteolytical degradations and has the potential to increase chemodiversity. γ-AApeptide also exhibits remarkable biomedical applications, such as antibacterial, anti-cancer and anti-Alzheimer’s development. However, it has never been reported before to use γ-AApeptide scaffold to design inhibitors to prevent virus infection. Especially, COVID-19 is a pandemic that has a serious impact on global health right now. In this work, we were trying to apply the γ-AApeptide based foldamers to three different projects. Firstly, we have reported the design and synthesis of constrained α, γ-AApeptide, which served as the scaffold to design aldehydes and ketoamides to bind Mpro of the SARS-CoV-2. Secondly, Macrocyclic γ-AApeptides combinational library was used to screen against the HR1 domain of the S2 subunit of the SARS-CoV-2 virus. As such, we found a potential macrocyclic γ-AApeptides potently inhibited SARS-CoV-2 infection. Thirdly, we also applied a combinational library of macrocyclic γ-AApeptides to the target, GpsB, a specific target of Gram-positive bacteria, which allowed us to identify a possible antibiotic. All the findings in my dissertation revealed a new application of the γ-AApeptides, especially in the development to combat the viral pandemic and bacterial infection. These findings also emphasize the relationship between structure and function of γ-AApeptides and highlight γ-AApeptides as an alternative paradigm for future PPI modulation.

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