Cannabinoids Block Cellular Entry of SARS-CoV-2 and the Emerging Variants

Research Focus: The study investigated the potential of cannabinoids from hemp (Cannabis sativa) as therapeutic agents against SARS-CoV-2, including its emerging variants.

Key Findings:

  1. Cannabinoids as Ligands for SARS-CoV-2 Spike Protein: Using affinity selection-mass spectrometry (AS-MS), the study identified cannabinoid acids from hemp as both allosteric and orthosteric ligands for the SARS-CoV-2 spike protein. Specifically, cannabigerolic acid (CBGA) and cannabidiolic acid (CBDA) demonstrated the ability to prevent the infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 spike protein and the entry of live SARS-CoV-2 into cells​​.
  2. Variants of Concern (VOC) and Cannabinoid Efficacy: The study addressed the effectiveness of CBDA and CBGA against notable SARS-CoV-2 variants of concern, such as the alpha (B.1.1.7) and beta (B.1.351) variants. The cannabinoids were found to block the infection of these variants effectively, indicating their potential utility against different strains of the virus​​.
  3. Dissociation Constants and Binding Efficacy: The dissociation constants for CBGA and CBDA binding to the spike protein were determined, with CBGA showing a Kd value of 19.8 ± 2.7 μM and CBDA 5.6 ± 2.2 μM. This indicates a significant affinity of these cannabinoids for the spike protein​​.
  4. Mechanism of Action: Computational modeling suggested that CBGA binds allosterically to the S1 subunit of the spike protein, whereas CBDA and tetrahydrocannabinolic acid (THCA-A) tend to bind at the orthosteric site. This implies different modes of interaction with the spike protein between these cannabinoids​​.
  5. Potential Clinical Application: The study suggests that concentrations needed to achieve 50% inhibition of viral entry might be clinically achievable. CBDA, in particular, has shown promising bioavailability and tolerability in humans and animals. The study also notes that CBDA and CBGA might work more effectively when used in combination with other cannabinoids from hemp extracts​​.
  6. Implications for Future Variants: The study’s findings are significant in the context of ongoing concerns about the emergence of SARS-CoV-2 variants. Since CBGA primarily binds to an allosteric site on the spike protein, it may exert less evolutionary pressure on the virus to mutate its binding sites compared to orthosteric sites targeted by neutralizing antibodies​​.

Conclusion: This study presents evidence that cannabinoids like CBDA and CBGA can effectively block the cellular entry of SARS-CoV-2 and its emerging variants. These findings open up possibilities for new therapeutic strategies against COVID-19, particularly in managing infections by different variants of the virus.

Read More: https://pubs.acs.org/doi/10.1021/acs.jnatprod.1c00946

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