Although
seasonal influenza epidemics represent a significant threat to public health,
their treatment options remain limited. With deaths from the 1918 influenza
pandemic estimated at >50,000,000 worldwide and future pandemics predicted,
the need for a potent broad-spectrum influenza therapy is critical. In this
thesis, I describe the use of a structurally modified zanamivir, an influenza
neuraminidase inhibitor that blocks the release of nascent virus, to deliver
attached therapeutic agents specifically to the surfaces of viruses and virus-infected
cells, leading to simultaneous inhibition of virus release and immune-mediated
destruction of both free virus and virus-infected cells. Chapter 1 describes
the major characteristics of the influenza virus, the morbidity and mortality
associated with annual infections by current strains of the virus, and the
treatments available to reduce the disease burden associated with these
infections. Chapter 2 describes the design, synthesis, and evaluation of a
zanamivir-related targeting ligand and its conjugation to two orthogonal
imaging agents which are then used to characterize the binding specificity and
biodistribution of the targeting ligand in influenza virus-infected cells and
in infected mice. Chapter 3 describes the development of an influenza virus-targeted
immunotherapy, where a zanamivir-targeted hapten is exploited to redirect the
immune system to destroy influenza virus and virus-infected cells. When tested
in vivo, this immunotherapy is shown to be significantly superior to zanamivir
in protecting mice from lethal influenza virus infections. Finally, both a
zanamivir-targeted chemotherapy and a CAR-T cell therapy with different
mechanisms of cytotoxicity against neuraminidase expressing cells are
introduced in Chapter 4.
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/12195588 |
| Date | 12 October 2021 |
| Creators | Xin Liu (8765016) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/Small_Molecule_Ligand-Targeted_Delivery_of_Therapeutic_Agents_for_Treatment_of_Influenza_Virus_Infections/12195588 |
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