S-acylation controls SARS-Cov-2 membrane lipid organization and enhances infectivity

Mesquita, Francisco; Abrami, Laurence; Sergeeva, Oksana A.; Turelli, Priscilla; Kunz, Béatrice; Raclot, Charlène; Montoya, Jonathan Paz; Abriata, Luciano A.; Peraro, Matteo Dal; Trono, Didier; D’Angelo, Giovanni; Goot, F. Gisou van der

doi:10.1101/2021.03.14.435299

Cited by 23 publications

(34 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This modification is involved in the processes of membrane fusion and virion assembly. A monomer of SARS CoV 2 S protein contains a cluster of 10 S acylated cysteine residues (30 residues in the homotrimer) in the 39 aa intraviral segment [21] (Fig. 3a).…”

Section: Structural Studies Of Sars Cov 2 S Proteinmentioning

confidence: 99%

“…Fatty acid residues stabilize S protein and drive the formation of localized ordered lipid nanodomains enriched with sphingomyelins and cholesterol (typical composition of lipid rafts) already in the ERGIC, where maturation of the progeny virions takes place. In unin fected cell, ERGIC does not contain high cholesterol concentrations [21]. The substitution of cysteine residues in the CT domain with alanines results in dramatic changes in the S protein properties and decreases virus overall infectivity [21].…”

Section: Structural Studies Of Sars Cov 2 S Proteinmentioning

confidence: 99%

“…In unin fected cell, ERGIC does not contain high cholesterol concentrations [21]. The substitution of cysteine residues in the CT domain with alanines results in dramatic changes in the S protein properties and decreases virus overall infectivity [21]. Two cysteine residues closest to the lipid membrane were found to be most functionally significant.…”

Section: Structural Studies Of Sars Cov 2 S Proteinmentioning

confidence: 99%

“…Two cysteine residues closest to the lipid membrane were found to be most functionally significant. It was suggested that their modification facil itates the binding of fatty acids to the C terminal cysteine residues located farther away from the membrane, because this reaction is catalyzed by the integral mem brane enzyme belonged to the family of ZDHHC acyl transferases [21]. This lipid modification is also typical for other coronaviruses, in which the number of S acylation sites can vary from 6 to 10.…”

Section: Structural Studies Of Sars Cov 2 S Proteinmentioning

confidence: 99%

“…This lipid modification is also typical for other coronaviruses, in which the number of S acylation sites can vary from 6 to 10. It was found that modification with fatty acids is essential for the formation of function al virions [21,45,46].…”

Section: Structural Studies Of Sars Cov 2 S Proteinmentioning

confidence: 99%

See 4 more Smart Citations

COVID-19: Myths and Reality

Kordyukova

Shanko

2021

Biochemistry Moscow

View full text Add to dashboard Cite

COVID‑19, a new human respiratory disease that has killed nearly 3 million people in a year since the start of the pandemic, is a global public health challenge. Its infectious agent, SARS‑CoV‑2, differs from other coronaviruses in a number of structural features that make this virus more pathogenic and transmissible. In this review, we discuss some important characteristics of the main SARS‑CoV‑2 surface antigen, the spike (S) protein, such as (i) ability of the receptor-binding domain (RBD) to switch between the “standing-up” position (open pre-fusion conformation) for receptor binding and the “lying-down” position (closed pre-fusion conformation) for immune system evasion; (ii) advantage of a high binding affinity of the RBD open conformation to the human angiotensin-converting enzyme 2 (ACE2) receptor for efficient cell entry; and (iii) S protein preliminary activation by the intracellular furin-like proteases for facilitation of the virus spreading across different cell types. We describe interactions between the S protein and cellular receptors, co-receptors, and antagonists, as well as a hypothetical mechanism of the homotrimeric spike structure destabilization that triggers the fusion of the viral envelope with the cell membrane at physiological pH and mediates the viral nucleocapsid entry into the cytoplasm. The transition of the S protein pre-fusion conformation to the post-fusion one on the surface of virions after their treatment with some reagents, such as β-propiolactone, is essential, especially in relation to the vaccine production. We also compare the COVID‑19 pathogenesis with that of severe outbreaks of “avian” influenza caused by the A/H5 and A/H7 highly pathogenic viruses and discuss the structural similarities between the SARS‑CoV‑2 S protein and hemagglutinins of those highly pathogenic strains. Finally, we touch on the prospective and currently used COVID‑19 antiviral and anti-pathogenetic therapeutics, as well as recently approved conventional and innovative COVID‑19 vaccines and their molecular and immunological features.

show abstract

Section: Structural Studies Of Sars Cov 2 S Proteinmentioning

confidence: 99%

Section: Structural Studies Of Sars Cov 2 S Proteinmentioning

confidence: 99%

Section: Structural Studies Of Sars Cov 2 S Proteinmentioning

confidence: 99%

Section: Structural Studies Of Sars Cov 2 S Proteinmentioning

confidence: 99%

Section: Structural Studies Of Sars Cov 2 S Proteinmentioning

confidence: 99%

See 3 more Smart Citations

COVID-19: Myths and Reality

Kordyukova

Shanko

2021

Biochemistry Moscow

View full text Add to dashboard Cite

show abstract

Antiviral efficacy of selective estrogen receptor modulators against SARS‐CoV‐2 infection in vitro and in vivo reveals bazedoxifene acetate as an entry inhibitor

Gen¹,

Peng²,

Tang³

et al. 2022

Journal of Medical Virology

View full text Add to dashboard Cite

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the seventh member of the coronavirus family that can infect humans. Recently, more contagious and pathogenic variants of SARS‐CoV‐2 have been continuously emerging. Clinical candidates with high efficacy and ready availability are still in urgent need. To identify potent anti‐SARS‐CoV‐2 repurposing drugs, we evaluated the antiviral efficacy of 18 selective estrogen receptor modulators (SERMs) against SARS‐CoV‐2 infection. Six SERMs exhibited excellent anti‐SARS‐CoV‐2 effects in Vero E6 cells and three human cell lines. Clomifene citrate, tamoxifen, toremifene citrate, and bazedoxifene acetate reduced the weight loss of hamsters challenged with SARS‐CoV‐2, and reduced hamster pulmonary viral load and interleukin‐6 expression when assayed at 4 days postinfection. In particular, bazedoxifene acetate was identified to act on the penetration stage of the postattachment step via altering cholesterol distribution and endosome acidification. And, bazedoxifene acetate inhibited pseudoviruses infection of original SARS‐CoV‐2, Delta variant, Omicron variant, and SARS‐CoV. These results offer critical information supporting bazedoxifene acetate as a promising agent against coronaviruses.

show abstract

COVID‐19 metabolism: Mechanisms and therapeutic targets

Wang

Cao

Zhang³

et al. 2022

MedComm

View full text Add to dashboard Cite

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) dysregulates antiviral signaling, immune response, and cell metabolism in human body. Viral genome and proteins hijack host metabolic network to support viral biogenesis and propagation. However, the regulatory mechanism of SARS‐CoV‐2‐induced metabolic dysfunction has not been elucidated until recently. Multiomic studies of coronavirus disease 2019 (COVID‐19) revealed an intensive interaction between host metabolic regulators and viral proteins. SARS‐CoV‐2 deregulated cellular metabolism in blood, intestine, liver, pancreas, fat, and immune cells. Host metabolism supported almost every stage of viral lifecycle. Strikingly, viral proteins were found to interact with metabolic enzymes in different cellular compartments. Biochemical and genetic assays also identified key regulatory nodes and metabolic dependencies of viral replication. Of note, cholesterol metabolism, lipid metabolism, and glucose metabolism are broadly involved in viral lifecycle. Here, we summarized the current understanding of the hallmarks of COVID‐19 metabolism. SARS‐CoV‐2 infection remodels host cell metabolism, which in turn modulates viral biogenesis and replication. Remodeling of host metabolism creates metabolic vulnerability of SARS‐CoV‐2 replication, which could be explored to uncover new therapeutic targets. The efficacy of metabolic inhibitors against COVID‐19 is under investigation in several clinical trials. Ultimately, the knowledge of SARS‐CoV‐2‐induced metabolic reprogramming would accelerate drug repurposing or screening to combat the COVID‐19 pandemic.

show abstract

S-acylation controls SARS-Cov-2 membrane lipid organization and enhances infectivity

Cited by 23 publications

References 66 publications

COVID-19: Myths and Reality

COVID-19: Myths and Reality

Antiviral efficacy of selective estrogen receptor modulators against SARS‐CoV‐2 infection in vitro and in vivo reveals bazedoxifene acetate as an entry inhibitor

COVID‐19 metabolism: Mechanisms and therapeutic targets

Contact Info

Product

Resources

About