Asparagine and Glutamine Bioconjugation Open Access

Abstract

Bioconjugation is a method that joins together bioactive and small molecules and has applications for activity-based protein profiling, chemoproteomics, and probing proteins. While there are bioconjugation methods for the selective modification of nucleophilic amino acids, there are no methods for the bioconjugation of weak nucleophiles- glutamine and asparagine. This study focuses on the development of a bioconjugation method for the chemoselectivity of asparagine and glutamine. Specifically, this study highlights the synthesis of dihydroxyl amine hydrocarbon and polyethylene glycol linkers to staple asparagine and glutamine residues on peptides. The impact of the results is a method to selectively label asparagine and glutamine, which can be applied to chemoproteomics labeling, stability of peptide drugs, and the discovery of new proteins containing asparagine and glutamine at the active site through flurosequencing. The impact of stapling asparagine and glutamine residues on a peptide will increase peptide rigidity, which improves biophysical properties to increase binding ability. 

Table of Contents

Introduction-1

Results- 8                                                                                 

Conclusions- 14

Supplemental Information-14

References-27

 

Figures:    

Figure 1 Stapled Peptides -2

Figure 2 deGruyter Biconjugation Chart-3

Figure 3 Popp and Ball Asn and Gln Side Chain Modification Method-4

Figure 4 Previous reports of primary amides to nitriles-5

Figure 5 RN-BioCoRe Conditions-5

Figure 6 Envisioned Asn/Gln Nitrile Trapping-7

Figure 7 Proposed Linker Structures-8

Figure 8 First Reaction Step for Dihydroxyl Amine Hydrocarbon Linker-9

Figure 9 Proposed Triethylamine Impurity-10

Figure 10 Second Reaction Step for Dihydroxyl Amine Hydrocarbon Linker-11

Figure 11 DBU Reaction Step for Dihydroxyl Amine Hydrocarbon Linker-11

Figure 12 First Reaction Step of Water-Soluble Dihydroxyl Amine Linkers-12

Figure 13 Second Reaction Step of Water-Soluble Dihydroxyl Amine Linkers-13    

Figure 14 Second Step of Water-Soluble Dihydroxyl Amine Linker Impurity-13

 

Tables:      

Table 1 Palladium Catalyst Optimization-6

Table 2 Buffer Trials-6                                                      

Schematics:

Scheme 1 Proposed Synthesis of Dihydroxyl Amine Hydrocarbon Linkers-8

Scheme 2 Proposed Synthesis of Water-Soluble Dihydroxyl Amine-12                                          

 

 

About this Honors Thesis

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Biochemistry Chemistry, Organic
Keyword	Bioconjugation
Committee Chair / Thesis Advisor	Weinschenk, Matthew , Emory University Raj, Monika, Emory University
Committee Members	Soria, Jose, Emory University

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