A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry

Tong, Liangqin; Wang, Lin; Liao, Shumin; Xiao, Xiaoping; Qu, Jing; Wu, Chunli; Zhu, Yibin; Tai, Wanbo; Huang, Yanhong; Wang, Penghua; Li, Liang; Zhang, Renli; Xiang, Ye; Cheng, Gong

doi:10.1128/mbio.01485-22

Cited by 20 publications

(15 citation statements)

References 53 publications

(56 reference statements)

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“…Of the retinoids, all-trans retinoic acid (ATRA) and vitamin A were shown to have antiviral activity against SARS-CoV-2. A recent cryo-EM structure reveals that ATRA indeed binds to the hydrophobic pocket of SARS-CoV-2 spike protein (Tong et al, 2022). Similar to LA binding, ATRA binds with its hydrophobic tail to one RBD and interacts with Arg408 and Gln409 of the adjacent RBD.…”

Section: The Hydrophobic Pocket In Spike Is Druggablementioning

confidence: 98%

“…Similar to LA binding, ATRA binds with its hydrophobic tail to one RBD and interacts with Arg408 and Gln409 of the adjacent RBD. Thereby, ATRA stabilizes a closed/locked spike conformation which only inefficiently interacts with the ACE2 receptor (Tong et al, 2022). However, the affinity of ATRA and vitamin A for spike is in the micromolar range (3 mM for ATRA; Tong et al, 2022), which is significantly lower than the affinity of LA for one RBD alone (K d = $41 nM).…”

Section: The Hydrophobic Pocket In Spike Is Druggablementioning

confidence: 98%

“…Thereby, ATRA stabilizes a closed/locked spike conformation which only inefficiently interacts with the ACE2 receptor (Tong et al, 2022). However, the affinity of ATRA and vitamin A for spike is in the micromolar range (3 mM for ATRA; Tong et al, 2022), which is significantly lower than the affinity of LA for one RBD alone (K d = $41 nM). Importantly, ATRA inhibits the entry of SARS-CoV and MERS-CoV pseudoviruses into human cells, confirming the conservation of the hydrophobic pocket (Tong et al, 2022).…”

Section: The Hydrophobic Pocket In Spike Is Druggablementioning

confidence: 98%

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Cryo-EM reveals binding of linoleic acid to SARS-CoV-2 spike glycoprotein, suggesting an antiviral treatment strategy

Toelzer¹,

Gupta²,

Berger³

et al. 2023

Acta Cryst Sect D Struct Biol

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The COVID-19 pandemic and concomitant lockdowns presented a global health challenge and triggered unprecedented research efforts to elucidate the molecular mechanisms and pathogenicity of SARS-CoV-2. The spike glycoprotein decorating the surface of SARS-CoV-2 virions is a prime target for vaccine development, antibody therapy and serology as it binds the host cell receptor and is central for viral cell entry. The electron cryo-microscopy structure of the spike protein revealed a hydrophobic pocket in the receptor-binding domain that is occupied by an essential fatty acid, linoleic acid (LA). The LA-bound spike protein adopts a non-infectious locked conformation which is more stable than the infectious form and shields important immunogenic epitopes. Here, the impact of LA binding on viral infectivity and replication, and the evolutionary conservation of the pocket in other highly pathogenic coronaviruses, including SARS-CoV-2 variants of concern (VOCs), are reviewed. The importance of LA metabolic products, the eicosanoids, in regulating the human immune response and inflammation is highlighted. Lipid and fatty-acid binding to a hydrophobic pocket in proteins on the virion surface appears to be a broader strategy employed by viruses, including picornaviruses and Zika virus. Ligand binding stabilizes their protein structure and assembly, and downregulates infectivity. In the case of rhinoviruses, this has been exploited to develop small-molecule antiviral drugs that bind to the hydrophobic pocket. The results suggest a COVID-19 antiviral treatment based on the LA-binding pocket.

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Section: The Hydrophobic Pocket In Spike Is Druggablementioning

confidence: 98%

Section: The Hydrophobic Pocket In Spike Is Druggablementioning

confidence: 98%

Section: The Hydrophobic Pocket In Spike Is Druggablementioning

confidence: 98%

See 1 more Smart Citation

Cryo-EM reveals binding of linoleic acid to SARS-CoV-2 spike glycoprotein, suggesting an antiviral treatment strategy

Toelzer¹,

Gupta²,

Berger³

et al. 2023

Acta Cryst Sect D Struct Biol

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“…The increased flexibility of the aliphatic chain is likely associated with the increased entropy cost and reduces the binding affinity. Notably, several compounds (SPC-14, SPC-15, and SPC-16) obtained better binding affinity in the SPR assay than the reference compounds reported in previous studies (LA, 34.2 μM; OA, 28.5 μM; ATRA, 15.7 μM). − To investigate the contribution of the carboxylic acid group for binding, we also tested the binding affinity of the ester analog of SPC-15 (Ester-SPC-15, K D = 6.9 μM), which showed comparable binding affinity to SPC-15 ( K D = 8.2 μM).…”

Section: Resultsmentioning

confidence: 99%

In Silico Discovery of Small Molecule Modulators Targeting the Achilles’ Heel of SARS-CoV-2 Spike Protein

et al. 2023

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The spike protein of SARS-CoV-2 has been a promising target for developing vaccines and therapeutics due to its crucial role in the viral entry process. Previously reported cryogenic electron microscopy (cryo-EM) structures have revealed that free fatty acids (FFA) bind with SARS-CoV-2 spike protein, stabilizing its closed conformation and reducing its interaction with the host cell target in vitro. Inspired by these, we utilized a structure-based virtual screening approach against the conserved FFA-binding pocket to identify small molecule modulators of SARS-CoV-2 spike protein, which helped us identify six hits with micromolar binding affinities. Further evaluation of their commercially available and synthesized analogs enabled us to discover a series of compounds with better binding affinities and solubilities. Notably, our identified compounds exhibited similar binding affinities against the spike proteins of the prototypic SARS-CoV-2 and a currently circulating Omicron BA.4 variant. Furthermore, the cryo-EM structure of the compound SPC-14 bound spike revealed that SPC-14 could shift the conformational equilibrium of the spike protein toward the closed conformation, which is human ACE2 (hACE2) inaccessible. Our identified small molecule modulators targeting the conserved FFA-binding pocket could serve as the starting point for the future development of broad-spectrum COVID-19 intervention treatments.

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“…For example, tretinoin ( Figure 6C , right panel, line 2), also known as all-trans retinoic acid, is a natural metabolite of vitamin A. It was reported to inhibit SARS-CoV-2 infection by interrupting spike protein-mediated cellular entry [37]. In this case, alitretinoin, isotretinoin, and tretinoin were listed in lines 2, 6, and 9 ( Figure 6C ).…”

Section: Resultsmentioning

confidence: 99%

Utilizing Pre-trained Network Medicine Models for Generating Biomarkers, Targets, Re-purposing Drugs, and Personalized Therapeutic Regimes: COVID-19 Applications

Xiong¹

2023

Preprint

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In this paper, we present a novel pre-trained network medicine model called Selective Remodeling of Protein Networks by Chemicals (SEMO). We divide the global human protein-protein interaction (PPI) network into smaller sub-networks, and quantify the potential effects of chemicals by statistically comparing their target and non-target gene sets. By combining 9607 PPI gene sets with 2658 chemicals, we created a pre-trained pool of SEMOs, which we then used to identify SEMOs related to Covid-19 severity using DNA methylation profiling data from two clinical cohorts. The nutraceutical-derived SEMO features provided an effective model for predicting Covid-19 severity, with an AUC score of 81% in the training data and 80% in the independent validation data. Our findings suggest that Vitamin D3, Lipoic Acid, Citrulline, and Niacin, along with their associated protein networks,particularly STAT1, MMP2, CD8A, and CXCL8 as hub nodes,could be used to effectively predict Covid-19 severity. Furthermore, the severity-associated SEMOs were found to be significantly correlated with CD4+ and monocyte cell proportions. These insights can be used to generate personalized nutraceutical regimes by ranking the relative severity risk associated with each SEMO. Thus, our pre-trained SEMO model can serve as a fundamental knowledge map when coupled with DNA methylation measurements, allowing us to simultaneously generate biomarkers, targets, re-purposing drugs, and nutraceutical interventions.

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A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry

Cited by 20 publications

References 53 publications

Cryo-EM reveals binding of linoleic acid to SARS-CoV-2 spike glycoprotein, suggesting an antiviral treatment strategy

Cryo-EM reveals binding of linoleic acid to SARS-CoV-2 spike glycoprotein, suggesting an antiviral treatment strategy

In Silico Discovery of Small Molecule Modulators Targeting the Achilles’ Heel of SARS-CoV-2 Spike Protein

Utilizing Pre-trained Network Medicine Models for Generating Biomarkers, Targets, Re-purposing Drugs, and Personalized Therapeutic Regimes: COVID-19 Applications

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