Date of Award

Spring 5-19-2018

Degree Type

Dissertation

Degree Name

PhD. Chemistry

Department

Chemistry and Biochemistry

Advisor

Monika Raj, Ph.D.

Committee Member

Cecilia Marzabadi, Ph.D.

Committee Member

David Sabatino, Ph.D.

Committee Member

Cosimo Antonacci, Ph.D.

Keywords

peptides, lasso peptides, peptidomimetics, cyclic peptides, sequencing, thioesters

Abstract

While peptides have impeccable potential due to their biological and therapeutic abilities, they are inherently limited in clinical practice due to their instability towards proteolysis and poor bioavailability. In the past few years peptidomimetics have emerged as a powerful class of compounds that overcomes the shortcomings associated with peptides. Peptidomimetics essentially mimic a natural peptide or protein in its chemical composition, structure and its ability to perform a biologically relevant role. In addition to increased stability and bioavailability, peptidomimetics can also have increased receptor binding affinity and selectivity, thereby making these mimics lead compounds in the field of drug design and discovery. Most recently, modifications to the peptide backbone have been introduced to increase the versatility of peptidomimetic applications. This thesis work is based on the unrestricted ability to modify amino acid side chain residues within biologically relevant peptides and form new classes of peptidomimetics for studying their structure-function properties.

Motivated by the idea of introducing a multipurpose moiety to increase the functionality of peptides, we sought to incorporate the cyclic urethane moiety otherwise known as 2-oxazolidinone and to explore the plethora of applications that accompany this incorporation. In the process of designing cyclic urethane containing peptides, we sought to peruse an approach where the cyclic urethane moiety would be derived from naturally occurring amino acids serine, threonine, glutamic acid, and/or cysteine.

Modification of serine’s hydroxymethyl side chain to a 2- oxazolidinone moiety activates the peptide backbone chain and increases its susceptibility towards cleavage. Due to the versatility of this moiety, 2-oxazolidinone has been used to explore various applications such as protease mimics, formation of peptide thioesters, and modified C-terminal peptides. When used as a protease mimic, formation of 2-oxazolidinone allows for site-selective cleavage of extremely unreactive peptide bonds using neutral aqueous conditions. This method exhibits broad substrate scope and selectively cleaves various bioactive peptides with post-translational modifications (e.g. N-acetylation and N-methylation) and mutations (D- and β-amino acids), which are unsuitable substrates for enzymes. Further application of this method has been demonstrated by the sequencing of cyclic peptides which is difficult to achieve by utilizing traditional methods such as Edman’s degradation and MS/MS. Identifying the sequence of macrocyclic peptides is vital in exploring potential therapeutic candidates found in nature and/or created through split and pool techniques. Building on the susceptibility of 2-oxazolidinone to cleavage, this moiety was also utilized for the formation of peptide thioesters, which is of significance in native chemical ligation for the synthesis of large proteins. This approach allows the synthesis of peptide thioesters by using Fmoc SPPS, which is usually an incompatible method due to the nucleophilic secondary amine required for Fmoc removal. Moreover, 2-oxazolidinone was used for the synthesis of various C-terminally modified peptides which are otherwise unattainable without the use of specialized resins, handles, or linkers. By exploring the various applications of the cyclic urethane moiety, this thesis work has demonstrated the effectiveness and wide-spread applicability of cyclic urethane derived peptidomimetics in the field of synthetic organic chemistry.

Included in

Biochemistry Commons

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