Palmitoylation of SARS‐CoV‐2 Spike Protein is prevented by Fatty Acid Synthase Inhibitors
Bibliographic record
Abstract
The COVID‐19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV2), has resulted in a significant loss of human life due in part to the paucity of therapeutic options for treatment of the disease. The Spike glycoprotein is responsible for the attachment and infection of host cell and as such it is the target of many countermeasures including vaccines. Most of these therapeutics focus only on the ectodomain of the protein leaving the cytosolic domain of the Spike protein largely unexplored. Our study focuses on the cytosolic domain of the Spike protein as it conserved amongst coronaviruses. This domain contains numerous highly conserved cysteine (cys) residues that are potential sites of S ‐palmitoylation; a post‐translational modification mediated by the host enzymes (palmitoyltransferases) that add palmitate to the target protein. In other coronaviruses, palmitoylation of the cytosolic domain of the Spike protein is required for its partitioning into de novo synthesized viral progeny. Here we investigated the cytosolic domain of Spike and its interaction with the protein palmitoyltransferase ZDHHC5. We have found that the Spike protein is palmitoylated on multiple juxtamembrane cysteine residues. Additionally, increased abundance of ZDHHC5 resulted in hyper‐palmitoylation of Spike while silencing of ZDHHC5 reduced palmitoylation as well as the ability of the human coronavirus 229E to form viral plaques in cell monolayers. We used a fatty acid synthase inhibitor TVB‐3166 to reduce palmitoyl‐CoA levels which in turn eliminated palmitoylation of SARS‐CoV2 Spike. Treating cells with TVB‐3166 attenuates the ability of human coronavirus 229E to form plaques and promoted the survival of mice from a lethal murine coronavirus infection. Thus, inhibition of the Spike protein palmitoylation has the potential to treat SARS‐CoV‐2 and other coronavirus infections.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".