Small Molecule Ligand-Targeted Delivery of Therapeutic Agents for Treatment of Influenza Virus Infections

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.