PhD defence Y. (Yunlong) Li

Dissertation in short:

Hepatitis E remains a major public health challenge that provokes a tremendous burden of morbidity and mortality worldwide. Since the limited treatment options are available, there is a clinical need for further development of new antiviral therapies against HEV infection. Drug repurposing has emerged as an attractive strategy to discover new applications for existing drugs. Thus, there is a clear need for developing drug repurposing of existing medication for treating HEV infection and understanding the potential mechanism-of-action of potent anti-HEV candidates. In this thesis, I propose to systematically screen in a safe-in-human broad-spectrum antiviral agents (BSAAs) library and repurpose the existing drugs that can be readily used in the clinic. I identified several potent inhibits HEV agents and focus on the leading candidates of HEV inhibitors. In Chapter 5, I identified gemcitabine, a widely used anti-cancer drug, potently inhibits HEV infection. Unexpectedly, it functions through the activation of interferon-like response via STAT1 phosphorylation but is independent of Janus kinases. In Chapter 6, I found ivermectin, an FDA-approved anti-parasitic drug, effectively inhibits HEV infection and the mechanism-of-action of ivermectin is associated with the host nuclear transport protein importin α1. In Chapter 7, I showed that macrolide antibiotic azithromycin is a potent HEV inhibitor, and the anti-HEV activity of azithromycin is independent of its induction of interferon-like response. In Chapter 8, I studied niclosamide, a widely used anthelmintic drug, as a potent inhibitor of HEV replication by inhibiting NFκB signaling but independent of STAT3. These findings provide new strategies to develop new antiviral therapies for combating HEV infection.