Date of Award

Spring 5-20-2019

Degree Type

Dissertation

Degree Name

PhD. Chemistry

Department

Chemistry and Biochemistry

Advisor

Gregory R. Wiedman, Ph.D.

Committee Member

Monika Raj, Ph.D.

Committee Member

David Sabatino, Ph.D.

Committee Member

Stephen Kelty, Ph.D.

Keywords

Organocatalyst, Aldol Reaction, Amino Acid, Antibody-Drug-Conjugates, Aldehyde, Asparagine Glutamine

Abstract

Bioconjugation is an important tool for studying complex biological systems, with site-specificity being the major challenge. Reactions based on amino acid derived organocatalysts have been widely used in organic synthesis, particularly for the asymmetric synthesis of small molecules but this concept has not been vastly explored on biomolecules. To combat these limitations, two chemical strategies are developed to effectively attach synthetic molecules site specifically to proteins. First, a protein modification technique based on conjugation at a non-native functional handle, an aldehyde or ketone, is developed. This functional handle is chemically introduced onto the biomolecules before undergoing the organocatalyzed aldol reaction, resulting in a stable bioconjugate. This method uses amino acids, such as proline and threonine, as organocatalysts. Next, the focus is on the development of a bioconjugation technique based on a native functionality found on proteins. The site of interest for this technique is the a-amine of theN-terminus, which stands out as a unique reactive site for site-specific modification strategies. This involves a reaction between an aldehyde containing molecule and one with either asparagine or glutamine at the N-terminal, resulting in formation of a bioconjugate product. Both methods demonstrate similar advantages, such as selectivity, specificity, and broad applicability, including their potential use for the synthesis of homogeneous antibody-drug-conjugates.

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