dc.contributor.advisor | Laura L. Kiessling. | en_US |
dc.contributor.author | Ho, Jordan Sun. | en_US |
dc.contributor.other | Massachusetts Institute of Technology. Department of Chemistry. | en_US |
dc.date.accessioned | 2021-01-06T20:16:35Z | |
dc.date.available | 2021-01-06T20:16:35Z | |
dc.date.copyright | 2020 | en_US |
dc.date.issued | 2020 | en_US |
dc.identifier.uri | https://hdl.handle.net/1721.1/129288 | |
dc.description | Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, September, 2020 | en_US |
dc.description | Cataloged from student-submitted PDF of thesis. | en_US |
dc.description | Includes bibliographical references (pages 135-150). | en_US |
dc.description.abstract | Small molecule probes for biology have been instrumental in uncovering enzyme mechanisms and developing therapeutics. Covalent probes are valuable because they can irreversibly tag proteins of interest for analysis. Selective covalent proteins for lysine residues are especially valuable because they allow for fine control over biological systems. Many binding sites contain lysine residues, but current amine-reactive electrophiles in biology are largely unselective. Moreover, at almost 6% lysine is more prevalent in the proteome compared to other nucleophilic residues such as cysteine. The ability to selectively target specific lysines would open new avenues for analyzing biomolecular interactions. Current efforts have yielded compounds with high reactivity and low stability, severely limiting their utility. Squaric esters are small chemical compounds with multiple amine reactive sites that have been used extensively as a linker in organic synthesis. | en_US |
dc.description.abstract | Additionally, squaric esters are mild electrophiles when compared to other amine reactive electrophiles used in organic chemistry. This attenuated reactivity, coupled with their high selectivity for amines suggests that substituted squaric esters may serve as novel biological probes. To this end, we characterized the reactivity and the kinetics of squaric ester reactions. We also applied squaric esters in different biological contexts to evaluate their utilities as novel lysine-reactive electrophiles. We show that squaric esters react orders of magnitude slower than other amine-reactive electrophiles commonly used in biology. We then applied squaric esters practically in the design of novel galactofuranosyltransferase 2 inhibitors, an enzyme responsible for the biosynthesis of the galactan. The galactan is a polysaccharide chain of galactofuranose residues, and it is essential for the cell wall of many bacteria, including pathogens such as Mycobacterium tuberculosis. | en_US |
dc.description.abstract | We generated substituted squaric ester inhibitors that bind to galactofuranosyltransferase 2 with specificity that provided insight into a potential allosteric binding site of galactofuranosyltransferase 2. Finally using fragment-based ligand design, in efforts to expand the lysine target space of small molecular probes, we constructed a squaric ester fragment library to screen for novel ligandable lysines across entire proteomes. | en_US |
dc.description.statementofresponsibility | by Jordan Sun Ho. | en_US |
dc.format.extent | 150 pages | en_US |
dc.language.iso | eng | en_US |
dc.publisher | Massachusetts Institute of Technology | en_US |
dc.rights | MIT theses may be protected by copyright. Please reuse MIT thesis content according to the MIT Libraries Permissions Policy, which is available through the URL provided. | en_US |
dc.rights.uri | http://dspace.mit.edu/handle/1721.1/7582 | en_US |
dc.subject | Chemistry. | en_US |
dc.title | Squaric ester applications as novel lysine electrophiles in molecular probe design | en_US |
dc.type | Thesis | en_US |
dc.description.degree | Ph. D. | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Chemistry | en_US |
dc.identifier.oclc | 1227521820 | en_US |
dc.description.collection | Ph.D. Massachusetts Institute of Technology, Department of Chemistry | en_US |
dspace.imported | 2021-01-06T20:16:34Z | en_US |
mit.thesis.degree | Doctoral | en_US |
mit.thesis.department | Chem | en_US |