Graduation Year

2023

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

Wayne Guida, Ph.D.

Committee Member

Cheng Feng, Ph.D.

Committee Member

Kirpal Bisht, Ph.D.

Keywords

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

Abstract

Protein-protein interactions (PPIs) are essential for biological processes and are associated with a number of diseases, including cancer, infectious diseases, and neurodegenerative diseases. As a result, modulation of PPIs has been recognized as one of the most promising strategies to develop the novel drugs. Peptide modulators always exhibit higher specificity and affinities with targets than small compounds or monoclonal antibodies, but their broad medicinal effectiveness is constrained by their poor bioavailability and biostability. Peptidomimetics, which have been developed to mimic the structure as well as function of bioactive peptides and proteins, have shown excellent potential in protein surface mimicry and recognition, modulation of PPIs, catalysis, and other fields. In comparison to conventional α-helixes, these peptidomimetics with unique and unnatural monomers showed enhanced bioavailability and chemodiversity as well as higher resistance to proteolytic degradation. Inspired by this concept, our group had developed a new peptidomimetics-γ-AApeptide, which could fold into well-defined protein-like secondary and tertiary structures, and they display remarkable biological potential for the recognition of protein and nucleic acids. As a result, γ-AApeptides could be developed into useful tools and drug candidates that probe or modulate medicinally relevant cellular processes.In this study, we describe the development of bioactive antiviral peptidomimetics based on γ-AApeptides. First, we identified a new pan-coronavirus fusion inhibitor to SARS-CoV-2 using the one-bead-two-compound macrocyclic γ-AApeptides combinatorial library. According to this study, combinatorial libraries provide an excellent platform for the development of antiviral inhibitors and other protein-protein interactions’ inhibitors. Second, using the rational design strategy, we developed a series of helical mimetic sulfonyl-γ-AApeptides to prevent the fusion process of diverse viruses. These two investigations suggested that it is an extremely promising strategy to the development of new drugs by using of L-sulfonyl-AApeptides or D-sulfonyl-AApeptides to modulate a range of protein-protein interactions. A number of applications of γ-AApeptides in the biological field were further supported by all of these investigations.

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