Typescript / 184 leaves : 1 reprint, ill. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physical and Inorganic Chemistry, 1966

Thesis (Ph.D.) -- University of Adelaide, Dept. of Physical and Inorganic Chemistry, 1966. / Typescript.

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Typescript. / Thesis (Ph. D.)--University of Hawaii, 1964. / Bibliography: leaves 153-156. / xv, 156 leaves mounted ill., tables

Typescript. / Thesis (Ph. D.)--University of Hawaii, 1966. / Bibliography: leaves 135-139. / vi, 139 l illus

Thesis--Wisconsin. / Vita. Includes bibliographical references (leaf 157).

Doctor of Philosophy / Department of Diagnostic Medicine/Pathobiology / Ying Fang / Viral papain-like proteases (PLPs)-related proteins have been shown to be actively involved in host innate immunity manipulation and virus replication. In this dissertation, the research were focused on the elucidation of biological roles of nidoviral PLPs-related proteins in innate immunity suppression and viral RNA transcription regulation. Porcine Respiratory and Reproductive Syndrome Virus (PRRSV) is the most prominent swine diseases worldwide. Understanding PRRSV pathogenesis and development efficient vaccines are highly required in swine industry. PRRSV nsp2-related proteins including nsp2 and two ribosomal frameshifting products-nsp2TF and nsp2N share the same N-terminal PLP2 domain. In chapter 2, nsp2TF and nsp2N were demonstrated to be critical for host innate immunity suppression at least through the PLP2 domain-mediated deubiquitination and deISGylation effects. The infection of nsp2TF/nsp2N knockout mutants significantly upregulated antiviral innate immune responses in vitro. Furthermore, manipulating the expression of nsp2TF/nsp2N could enhance innate and adaptive immunity in pigs, providing potential basis for modified live vaccine development. In addition to the PLP2 domain of PRRSV nsp2-related proteins, the biological roles and biochemical nature of the poorly investigated long mysterious PLP2 downstream region was also characterized in Chapter 3. This long unknown region is also shared by nsp2-related proteins. At first, the hyper-phosphorylation nature of nsp2-related proteins was demonstrated. Physical features of this uncharacterized region was then delineated, including two intrinsically disordered hypervariable regions spaced by a structured inter-species conserved domain. One critical phosphorylated residues in the conserved domain were later proved to be of great importance in recombinant virus rescue and subgenomic RNAs accumulation. Collectively, our investigations underline the pleiotropic effects exerted by nsp2-related proteins in virus life cycle and potential contributions with pathogenesis. In Chapter 4, potential functions of PLP encoded by other nidovirus was also investigated. We discovered a unique cross-order recombination event, in which the chimeric picornavirus-enterovirus G expresses the PLP gene, homologous to torovirus (ToV) PLPs. Like other nidoviral PLPs, the recombinant ToV-PLP was proved to be a highly active deubiquinase/deISGylase and potent innate immune antagonist. After PLP knockout, viral fitness is significantly decreased and the suppression on host ubiquitination/ISGylation is largely reduced. Furthermore, host antiviral innate immune responses have been greatly upregulated post PLP knockout mutant infection. Our study underscores potential contributions of PLP domain in viral pathogenicity, and further provides an ideal example for how recombination shapes virus evolution. In summary, studies in this dissertation highlight the critical roles of nidoviral PLPs-related proteins in host immunity manipulation and virus replication, and more importantly, potential links with viral pathogenicity and application in vaccine development.

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Ferrocene-peptide conjugates represent a hybrid area between organometallic chemistry and biochemistry. In these bioconjugates, the ferrocene (Fc) moiety can serve as molecular scaffold, chromophore, sensitive probe, biological marker, redox active site, etc. Disubstituted Fc systems, in which both cyclopentadienyl rings are substituted, provide influence over the supramolecular structure of the assemblies, and serve as starting materials for the design of electronic biomaterials. Recently, 1'-amino-ferrocene-1-carboxylic acid (Fca) and 1,1'-diaminoferrocene Fc[NH2]2 were recognized as useful tools in bioorganometallic chemistry. This work sketches some novel preparative and structural aspects of Fc-peptide conjugates and explores their applications as biosensors and as polymeric materials. <p>First, I demonstrated that Fca invariably induces a turn-like structure, which is stable in solution and the solid state. The obtained results showed different behaviour for Fca peptides depending on the chirality and position of the attached amino acid. The axial chirality of the Fca is completely dependent on the chirality of the first amino acid attached to the amino terminal of the Fca group.<p>Second, I was able to develop a surface based sensor for the electrochemical detection of papain based on Fc-peptide conjugates. The idea was to place a surface-bound redox probe in close proximity to the electrode surface. In addition, the redox-active Fca label will be part of the recognition site but will not interfere with the recognition process. My sensor provides an attractive alternative for the electrochemical detection of non-labelled non-redox active proteins, which under current detection schemes remains a significant challenge.<p>This work represents a truly important proof of concept for establishing this novel bioorganometallic approach for the electrochemical detection of important biological targets.<p>Last, I was successful in developing a very convenient method to synthesize 1,1'-bis(tert-butoxycarbonylamino)ferrocene as a stable derivative of Fc[NH2]2. This new synthetic approach has circumvented the problems encountered with the explosive diazide usually used as a precursor in the conventional synthons of Fc[NH2]2. Building on this achievement, a series of novel peptide-like oligomeric and polymeric ferrocenyl-amides were synthesized and fully characterized. The electrochemical investigations on these polymers suggested unresolved or no electronic interaction between the ferrocene groups in all systems. These results may reveal the influence of the amide groups on suppressing the electronic interaction between the iron centers in my polymers. <p>Thus, my systematic work on Fc-peptide conjugates lays solid foundations in the fields of structural control, biosensors, and material science.