Veterinary and Biomedical Sciences, Department of
School of Veterinary and Biomedical Sciences: Dissertations, Theses, and Student Research
First Advisor
Fernando A. Osorio
Date of this Version
7-2021
Document Type
Dissertation
Citation
A dissertation presented to the faculty of the Graduate College at the University of Nebraska in partial fulfillment of requirements for the degree of Doctor of Philosophy
Major: Integrative Biomedical Sciences
Under the supervision of Professor Fernando A. Osorio
Lincoln, Nebraska, August 2021
Abstract
The re-emergence of Zika virus (ZIKV), an arbovirus, poses a major global human health concern because of its ability to cause congenital abnormalities and neurological diseases. While many candidate vaccines and antiviral drugs are in the developmental pipeline, none have been approved for use against ZIKV infection. This dissertation describes the characterization of one vaccine and two antiviral drug candidates against ZIKV infection. A bacterial ferritin-based nanoparticle vaccine, termed zDIII-F, is designed to display multiple copies of ZIKV E protein domain III on its surface. These stable nanoparticles are shown to induce robust antibody-mediated protection against lethal ZIKV infection in mice. Additionally, passive transfer of sera from zDIII-F immunized mice also conferred protection in animals following ZIKV challenge. By employing a homology-based modelling approach, we predicted the structure of ZIKV RNA-dependent RNA polymerase (RdRp) and used it to screen for small molecule compounds that bind the viral RdRp. Among the top 10 compounds with high docking scores, we observed that the molecule with the highest score, TPB, strongly suppressed ZIKV replication in vitro and in vivo. With the ability to target the conserved regions of flavivirus RdRp, a high selective index of 206 combined with a low molecular weight of ~500 daltons, TPB promises to be an excellent candidate for development as an anti-ZIKV as well as an anti-flavivirus drug. Analysis of ZIKV genome sequences suggested the presence of conserved guanine (G)-rich motifs that can fold under physiological conditions to form secondary structures called G-quadruplexes. Such structures, when stabilized, can inhibit transcription, translation, and replication. We have demonstrated that stabilization of ZIKV genome G-quadruplexes by G-quadruplex-binding ligands, BRACO-19 and TMPyP4, significantly suppressed ZIKV protein synthesis and replication. Therefore, we propose further development and potential use of G-quadruplex-binding ligands as a strategy for treatment of ZIKV infection. Overall, the studies described in this dissertation significantly contribute to development of anti-ZIKV therapeutics.
Advisor: Fernando A. Osorio
Included in
Community Health and Preventive Medicine Commons, Immunology of Infectious Disease Commons, Immunopathology Commons, Immunoprophylaxis and Therapy Commons, Infectious Disease Commons, Medical Immunology Commons, Medical Pharmacology Commons, Medicinal and Pharmaceutical Chemistry Commons, Medicinal Chemistry and Pharmaceutics Commons, Pathogenic Microbiology Commons, Pharmaceutics and Drug Design Commons, Therapeutics Commons, Translational Medical Research Commons, Virology Commons, Virus Diseases Commons, Viruses Commons
Comments
Copyright 2021, Aryamav Pattnaik. Used by permission