Fatty Acid Synthase inhibitor TVB-3166 prevents S-acylation of the Spike protein of human coronaviruses

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the causative agent of COVID19 that has infected >76M people and caused >1.68M deaths. The SARS-CoV2 Spike glycoprotein is responsible for the attachment and infection of target cells. The viral Spike protein serves the basis for many putative therapeutic countermeasures including vaccines, blocking and neutralizing antibodies, and decoy receptors. Here we investigated the cytosolic domain of Spike and its interaction with the protein palmitoyltransferase ZDHHC5. The Spike protein is palmitoylated on multiple juxtamembrane cysteine residues conserved among coronavirus. Increased abundance of ZDHHC5 resulted in hyper-palmitoylation, while silencing of ZDHHC5 reduced the ability of the human CoV 229E to form viral plaques in cell monolayers. Inhibition of fatty acid synthase using the pharmacological inhibitor TVB-3166 eliminated palmitoylation of SARS-CoV2 Spike. Additionally, TVB-3166 attenuated plaque formation and promoted the survival of mice from a lethal murine CoV infection. Thus, inhibition of the Spike protein palmitoylation has the potential to treat SARS-CoV-2 and other CoV infections.

A bioorthogonal chemical reporter for fatty acid synthase-dependent protein acylation

“…FASN activity is required for replication of several enveloped viruses, including Chikungunya, 10 HIV-1, 9 Influenza, 42 and SARS-CoV-2, 43 and many others. 6,7,13 FASN inhibitors, including Fasnall 9,35 and the TVB compounds 44,45 have therapeutic potential, and pharmacological inhibition of FASN has been shown to modulate fatty acylation of viral proteins, including Chikungunya virus nsP1 palmitoylation, 46 SARS-CoV-2 spike palmitoylation, 43 and HIV-1 Gag myristoylation (Figure 3). In other cases, modulation of FASN activity affects host proteins that regulate infection, including MYD88 palmitoylation, 47 and the results presented here that reveal that FASN activity is required for an effective IFNβ immune response against influenza virus, possibly by providing fatty acyl moieties for modification of IFITM3.…”

A bioorthogonal chemical reporter for fatty acid synthase–dependent protein acylation

“…FASN activity is required for replication of several enveloped viruses, including chikungunya ( 10 ), HIV-1 ( 9 ), influenza ( 43 ), severe acute respiratory syndrome coronavirus 2 ( 44 ), and many others ( 6 , 7 , 13 ). FASN inhibitors, including Fasnall ( 9 , 36 ) and the TVB compounds ( 45 , 46 ), have therapeutic potential, and pharmacological inhibition of FASN has been shown to modulate fatty acylation of viral proteins, including chikungunya virus nsP1 palmitoylation ( 11 ), severe acute respiratory syndrome coronavirus 2 spike palmitoylation ( 44 ), and HIV-1 Gag myristoylation ( Fig. 3 ).…”

Protein S -palmitoylation in immunity

“…Moreover, It should be noted that S-palmitoylation not only plays a role in the host immune system but the host S-palmitoylation machinery is also exploited by many viral or bacterial proteins for host infection [93,94]. For example, S-palmitoylation of the currently pandemic SARS-CoV-2 spike protein by DHHC5 is important for virus entry in ACE2 expressing cells [95].…”