Identification and Characterization of New Small Molecule Inhibitors of Picornavirus Replication

The Picornaviridae family consists of positive-strand RNA viruses that are the causative agents of a variety of diseases in humans and animals. Few drugs targeting picornaviruses are available, making the discovery of new antivirals a high priority. Here, we identified and characterized three compounds from a library of kinase inhibitors that block replication of poliovirus, coxsackievirus B3, and encephalomyocarditis virus. The antiviral effect of these compounds is not likely related to their known cellular targets because other inhibitors targeting the same pathways did not inhibit viral replication. Using an in vitro translation-replication system, we showed that these drugs inhibit different stages of the poliovirus life cycle. A4(1) inhibited the formation of a functional replication complex, while E5(1) and E7(2) affected replication after the replication complex had formed. A4(1) demonstrated partial protection from paralysis in a murine model of poliomyelitis. Poliovirus resistant to E7(2) had a single mutation in the 3A protein. This mutation was previously found to confer resistance to enviroxime-like compounds, which target either PI4KIIIβ (major enviroxime-like compounds) or OSBP (minor enviroxime-like compounds), cellular factors involved in lipid metabolism and shown to be important for replication of diverse positive-strand RNA viruses. We classified E7(2) as a minor enviroxime-like compound, because the localization of OSBP changed in the presence of this inhibitor. Interestingly, both E7(2) and major enviroxime-like compound GW5074 interfered with the viral polyprotein processing. Multiple attempts to isolate resistant mutants in the presence of A4(1) or E5(1) were unsuccessful, showing that effective broad-spectrum antivirals could be developed on the basis of these compounds. Studies with these compounds shed light on pathways shared by diverse picornaviruses that could be potential targets for the development of broad-spectrum antiviral drugs.

Reconciling History and International Law: Territorial and Maritime Claims in the South China Sea and East China Sea

High-ranking Chinese military officials are often quoted in international media as stating that China cannot afford to lose even an inch of Chinese territory, as this territory has been passed down from Chinese ancestors. Such statements are not new in Chinese politics, but recently this narrative has made an important transition. While previously limited to disputes over land borders, such rhetoric is now routinely applied to disputes involving islands and maritime borders. China is increasingly oriented toward its maritime borders and seems unwilling to compromise on delimitation disputes, a transition mirrored by many states across the globe. In a similar vein, scholarship has found that territorial disputes are particularly intractable and volatile when compared with other types of disputes, and a large body of research has grappled with producing systematic knowledge of territorial conflict. Yet in this wide body of literature, an important question has remained largely unanswered - how do states determine which geographical areas will be included in their territorial and maritime claims? In other words, if nations are willing to fight and die for an inch of national territory, how do governments draw the boundaries of the nation? This dissertation uses in-depth case studies of some of the most prominent territorial and maritime disputes in East Asia to argue that domestic political processes play a dominant and previously under-explored role in both shaping claims and determining the nature of territorial and maritime disputes. China and Taiwan are particularly well suited for this type of investigation, as they are separate claimants in multiple disputes, yet they both draw upon the same historical record when establishing and justifying their claims. Leveraging fieldwork in Taiwan, China, and the US, this dissertation includes in-depth case studies of China’s and Taiwan’s respective claims in both the South China Sea and East China Sea disputes. Evidence from this dissertation indicates that officials in both China and Taiwan have struggled with how to reconcile history and international law when establishing their claims, and that this struggle has introduced ambiguity into China's and Taiwan's claims. Amid this process, domestic political dynamics have played a dominant role in shaping the options available and the potential for claims to change in the future. In Taiwan’s democratic system, where national identity is highly contested through party politics, opinions vary along a broad spectrum as to the proper borders of the nation, and there is considerable evidence that Taiwan’s claims may change in the near future. In contrast, within China’s single-party authoritarian political system, where nationalism is source of regime legitimacy, views on the proper interpretation of China’s boundaries do vary, but along a much more narrow range. In the dissertation’s final chapter, additional cases, such as South Korea’s position on Dokdo and Indonesia’s approach to the defense of Natuna are used as points of comparison to further clarify theoretical findings.