Graduation Year
2022
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Medical Sciences
Major Professor
Robert Deschenes, Ph.D.
Committee Member
Vladimir Uversky, Ph.D., D.Sc.
Committee Member
Laura Blair, Ph.D.
Committee Member
Javier Cuevas, Ph.D.
Keywords
Post-translational Modifications, Palmitoyl-transferase, SARS-CoV-2, Bis-piperazine, Antiviral
Abstract
The spike proteins of enveloped viruses are transmembrane glycoproteins that typically undergo post-translational attachment of palmitate on cysteine residues on the cytoplasmic facing tail of the protein. The role of spike protein palmitoylation in virus biogenesis and infectivity is being actively studied as a potential target of novel antivirals. Here, we report that palmitoylation of the first five cysteine residues of the C-terminal cysteine-rich domain of the SARS-CoV-2 S protein are indispensable for infection, and palmitoylation-deficient spike mutants are defective in membrane fusion. The DHHC9 palmitoyltransferase interacts with and palmitoylates the spike protein in the ER and Golgi, and knockdown of DHHC9 results in reduced fusion and infection of SARS-CoV-2. Two bis-piperazine backbone-based DHHC9 inhibitors inhibit SARS-CoV-2 S protein palmitoylation, and the resulting progeny virion particles released are defective in fusion and infection. This establishes these palmitoyltransferase inhibitors as potential new intervention strategies against SARS-CoV-2.
Scholar Commons Citation
Ramadan, Ahmed A., "The Role of Protein Palmitoylation in Two Disorders; X-Linked Intellectual Disability and COVID-19" (2022). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/10344
