Author

Yi Liang

Graduation Year

2016

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Mark Mclaughlin, Ph.D.

Committee Member

David Morse, Ph.D.

Committee Member

Jianfeng Cai, Ph.D.

Committee Member

Juan Del Valle, Ph.D.

Keywords

anticancer, antivirus, multiple myeloma, peptide, Peptidomimetics

Abstract

The high demand of novel peptide and peptidomimetics based on the amount of

genomic and proteomic data need be matched by synthesis and screening. The design and

synthesis of peptide and peptidomimetics are so important because the peptide and

protein-protein interaction play a key role in molecule recognition and signaling. The

modified peptides have better stability and pharmacokinetic properties which may be guided

by rational design and molecular modeling. Now many organic and medicinal chemists have

chosen peptide and peptidomimetics as potential drug candidates for many targets.

In this dissertation, research efforts in design and synthesis of cyclic peptides with

stabilized secondary structure have been investigated. Cyclization of linear peptides may

restrict the number of available conformations which may improve the affinity attaching to

the target. In this study, different beta turn linkers have been designed and synthesized to

achieve more stable cyclic peptides with beta-sheet structures. Based on different beta turn

linkers, analogs of cyclic peptides have been synthesized and screened. The structure activity

relationships (SAR) of these cyclic peptide analogs have been studied.

In chapter three, analogs of peptidomimetic inhibitors have been designed and

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synthesized. These peptide analogs are targetingHuman Rhinovirus (HRV) and Coronavirus

(CoV) by inhibiting the cysteine protease. The docking and modeling studies have been

shown. The structures of this kind of inhibitors include five fragments. The warhead provides

the activity, which can covalently react with the thiol of cysteine protease and permanently

eliminate its proteolytic activity. The warhead is linked to a peptide backbone including the

other four parts that are designed to position the warhead where it can specially react with the

critical thiol of the cysteine protease active site. The side chain of each amino acid has been

optimized to achieve better solubility and permeability. We successfully synthesized some

compounds with good potency.

Included in

Chemistry Commons

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