Cannabinoids and Covid-resistance: A spike protein connection
October 12, 20223 min read
The SARS-CoV-2 virus has the vexing ability to produce variants that escape humoral immunity elicited by natural infection or vaccination. One way of countering this is to prevent the virus’s entry into human cells altogether, a process that begins with the attachment of the receptor-binding domain of the virus’s S1 spike protein. The idea is to find ligands with high affinity there, and mechanically prevent conjoinment with host cells. This approach has been used with other viruses, including HIV-1 and hepatitis C virus. Vaccination, in other words, may do with some help from small-molecule ancillary drugs.
New small-molecule drugs since 1981 have tended to derive from natural products, or at least to mimic them. One natural product with anti-SARS-CoV-2 activity already discovered is panduratin, from the medicinal plant Boesenbergia rotunda. In search of more of these, with the S1 spike protein in mind, a team of researchers at the Linus Pauling Institute in the Department of Pharmaceutical Sciences at Oregon State University and the Department of Molecular Microbiology & Immunology at the Oregon Health & Science University recently undertook an affinity selection–mass spectrometry investigation into candidate ligands, and have published their results this year (van Breemen RB, Muchiri RN, Bates TA, Weinstein JB, Leier HC, Farley S, Tafesse FG. Cannabinoids Block Cellular Entry of SARS-CoV-2 and the Emerging Variants. J Nat Prod. 2022 Jan 28;85(1):176-184).
They immobilized the S1 subunit on magnetic microbeads, incubated it with a surface recognition peptide, and subjected it to contact with a range of hemp extracts predicted, on the grounds of molecular shape, to bind to the subunit orthosterically or allosterically. They identified and ranked several cannabinoid ligands by their binding affinity. The two with the highest affinities were cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA).
To see whether CBDA or CBGA could actually prevent infection by blocking SARS-CoV-2 cell entry, incubation assays were carried out with live and pseudo-viruses. They found an absence of SARS-CoV-2 viral RNA in cells treated with either cannabinoid. They validated the virus-neutralizing capabilities of CBDA and CBGA with focus-forming assays using serial dilutions of CBDA or CBGA that were incubated with the virus. CBDA and CBGA did prevent SARS-CoV-2 entry into the cells. This was not variant-dependent, either. More focus assays showed that CBDA and CBGA both blocked variants B.1.1.7, containing the N501Y spike protein mutation, and B.1.351, containing the K417N, E484 K, and N501Y spike mutations.
Previous reporting has shown that another cannabinoid, decarboxylated cannabidiol (CBD), may activate innate immunity to SARS-CoV-2. The Oregon team’s live-virus data show that inhibition by CBDA and CBGA happens at the point of cell entry, a different mechanism from this altogether. It may be that a complex mixture of small-molecule plant extracts could act in synergy with each other and with vaccines to enhance virus-resistance.
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The foregoing is a report on trends and developments in the cannabinoid industry. No product described herein is intended to diagnose, treat, cure or prevent any disease or syndrome.
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