Browsing by Author "Ding, Yuxuan"

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    Copper-Mediated Approaches to Selective Modification of Peptides and Proteins
    (2024-12-05) Ding, Yuxuan; Ball, Zachary
    Peptides and proteins have long played crucial roles in diverse applications, including drug development, biomaterials, and diagnostic imaging. However, recent advances in biosynthetic engineering, synthetic methodology, combinatorial screening approaches, and analytical methods have allowed more routine access to diverse peptidic structures that diverge markedly from natural structures, incorporating unnatural amino acids or significantly altering the canonical polypeptide structure. Indeed, the very definition of “peptide” is less clear today, with blurred lines separating peptides from peptoids, peptidomimetics, stapled structures, foldamers, hybrid conjugates, and other structures. Peptides and proteins play increasing roles in drug development, and non-canonical modification is often employed as a tool to improve drug properties, including cellular uptake, in vivo stability, and selective localization. This thesis focuses on the development of selective modification of natural peptides and proteins by transition-metal catalysis. The first chapter provides a summary of important approaches to side chain modification methods developed in the past two decades, focusing on fundamentally enabling mechanistic, selectivity, or reactivity ideas. The second chapter reviews the synthesis and transformations of sulfines, a class of S-oxides of thiocarbonyl compounds which are widely studied in synthetic chemistry but rarely used in peptide stapling or protein bioconjugation. Development of selective peptide and protein modification methodologies is discussed in chapters 3-5. Chapter 3 describes a straightforward means of late-stage one-step oxidation of methionine residues within polypeptides to afford NH-sulfoximines. The use of an ex situ gaseous chlorosulfine reagent for peptide macrocyclization and protein bioconjugation is shown in chapter 4. Furthermore, chapter 5 highlights a copper-catalyzed cross-coupling selective for pyroglutamate post-translational modifications (PTMs) that is directed by peptide backbone amides, which serves as a complementary strategy for the histidine-directed pyroglutamate arylation chemistry reported previously. Based on the rhodium(II)-metallocarbene catalysis developed in the Ball group, the application of rhodium proximity labelling in cell lysates for identifying new drug-protein interactions was described in chapter 6. Taken together, these contributions expand the toolbox for peptide and protein modification, and could provide new opportunities in several areas of chemical biology, such as inhibitor design, cellular imaging, and PTM profiling, etc.
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    Direct formation and site-selective elaboration of methionine sulfoximine in polypeptides
    (Royal Society of Chemistry, 2022) Ding, Yuxuan; Pedersen, Simon S.; Lin, Alex; Qian, Ruoyu; Ball, Zachary T.
    Sulfoximines are emerging moieties for medicinal and biological chemistry, due in part to their efficacy in selective inhibition of amide-forming enzymes such as γ-glutamylcysteine synthetase. While small-molecule sulfoximines such as methionine sulfoximine (MSO) and its derivatives are well studied, structures with methionine sulfoximine residues within complex polypeptides have been generally inaccessible. This paper describes a straightforward means of late-stage one-step oxidation of methionine residues within polypeptides to afford NH-sulfoximines. We also present chemoselective subsequent elaboration, most notably by copper(II)-mediated N–H cross-coupling at methionine sulfoximine residues with arylboronic acid reagents. This development serves as a strategy to incorporate diverse sulfoximine structures within natural polypeptides, and also identifies the methionine sulfoximine residue as a new site for bioorthogonal, chemoselective bioconjugation.