DOI
https://doi.org/10.25772/5V7C-2406
Author ORCID Identifier
https://orcid.org/ 0000-0003-4821-0907
Defense Date
2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Chemical Biology
First Advisor
Nicholas Farrell
Second Advisor
Michael McVoy
Abstract
The majority of antiviral drug development has focused on virus-specific discovery targeting discrete steps in the individual life cycles. Although great strides have been made for a number of clinically relevant diseases such as human immunodeficiency virus, influenza virus, and hepatitis B, broad spectrum antivirals do not exist. Broad spectrum antivirals would offer (1) treatment for viruses without specifically-targeted antivirals, (2) treatment for viruses which have developed resistance to their available treatments, and (3) a rapidly deployable treatment option in viral epidemics. Many viruses including human cytomegalovirus (HCMV), HIV, and SARS-CoV-2. rely on heparan sulfate (HS), a highly sulfated glycosaminoglycan (GAG), to attach and infect cells. Inhibition of the HS-viral interaction therefore has the potential to be of broad-spectrum utility. Substitution-inert polynuclear platinum complexes (PPCs) are known to have both DNA and HS affinity; PPCs metalloshield, or mask, HS to impede a myriad of HS functions including cancer metastasis. In this work, we demonstrate that high-GAG affinity PPCs act as broad-spectrum antivirals by inhibiting virion attachment via HS. In extending this concept to charged coordination complexes (CCCs) in general, the Co-containing Werner’s complex (WC), maintains DNA and HS affinity and displays antiviral activity. The mechanism of action is not as well-defined as the PPC family and may reflect a hitherto unappreciated relationship between structure, DNA and HS affinity, and biological activity. In summary, this work outlines an extension of glycobiology and medicinal inorganic chemistry in developing broad-spectrum antivirals.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-4-2022