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

Available for download on Thursday, May 04, 2023

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