CHEMOENZYMATIC MODULATION OF GLYCOPEPTIDE ANTIGENS AS TARGETS FOR HIV VACCINE DISCOVERY AND LIVER CANCER DIAGNOSIS

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dc.contributor.advisorWang, Lai-Xien_US
dc.contributor.authorZhang, Roushuen_US
dc.contributor.departmentBiochemistryen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2021-02-15T06:30:51Z
dc.date.available2021-02-15T06:30:51Z
dc.date.issued2020en_US
dc.description.abstractGlycosylation is a critical post-translational modification of proteins. Viral pathogens use the host glycosylation machinery to facilitate their entry and hide them from the host immune recognition. Moreover, changing the glycosylation pattern is often related to the development of diseases, such as the emergence of carcinomas. Therefore, carbohydrates are attractive targets for various infectious diseases and pathogenic disorders. Nonetheless, as the synthesis of glycans is not template-driven, glycoforms obtained from natural resources are heterogeneous. We address this issue by employing glycosidase inhibitors to modulate protein glycosylation during expression, and also by chemoenzymatic glycan remodeling of glycopeptide antigens. Three projects related to this topic are described herein.In the first project, a series of glycan-defined HIV-gp120-derived glycoprotein immunogens were expressed and engineered. We successfully demonstrated the glycan-dependency of a variety of HIV-targeting broadly neutralizing antibodies (bnAbs). Our immunogens bearing the high-mannose glycosylation have adequate antigenicity towards the bnAbs evaluated, rendering these immunogens promising vaccine candidates for HIV/AIDS. The second project focused on designing novel glycopeptide immunogens for raising glycan-specific antibodies to detect the early stage of liver cancer. Here we chose the fucosylated alpha-fetoprotein as our target since it is related to the development of liver cancer. There is no available antibody specifically recognizing this glycoform and therefore it is still challenging to utilize this parameter to evaluate the condition of patients. We chemoenzymatically synthesized alpha-fetoprotein-derived glycopeptides with core-fucosylation and subjected these immunogens to animal studies. The antisera displayed glycan-dependent IgG responses, laying a foundation to develop monoclonal antibodies that target the fucosylated alpha-fetoprotein. The discovery of such antibodies will be valuable to sensitively diagnose liver cancer in clinics. Lastly, developing enzyme tools is equally important to harness the field. In the final project of my dissertation, we revisited the substrate preference of the human α(1-6) fucosyltransferase. The enzyme exhibited a relaxed substrate preference when a proper glycoprotein, glycopeptide, or an Fmoc modification is attached to the acceptor substrates. This discovery provides new insights into studying glycosyltransferases and offers new approaches to chemoenzymatically synthesizing core-fucosylated glycoproteins and glycopeptides. Together, the studies present new avenues for studying glycan-related biological processes and diseases.en_US
dc.identifierhttps://doi.org/10.13016/t5rn-wgao
dc.identifier.urihttp://hdl.handle.net/1903/26849
dc.language.isoenen_US
dc.subject.pqcontrolledBiochemistryen_US
dc.subject.pquncontrolledchemoenzymaticen_US
dc.subject.pquncontrolledglycoconjugateen_US
dc.subject.pquncontrolledglycosylationen_US
dc.subject.pquncontrolledHIVen_US
dc.subject.pquncontrolledliver canceren_US
dc.subject.pquncontrolledvaccineen_US
dc.titleCHEMOENZYMATIC MODULATION OF GLYCOPEPTIDE ANTIGENS AS TARGETS FOR HIV VACCINE DISCOVERY AND LIVER CANCER DIAGNOSISen_US
dc.typeDissertationen_US

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