“Background/Objectives: COVID-19 was responsible for millions of deaths worldwide. This study aimed to identify substances with in vitro and in vivo effects against the SARS-CoV-2 virus. 

Methods: Compounds PQM-243 and PQM-249, two terpene-N-acyl-aryl-hydrazone analogues, were evaluated in vitro against SARS-CoV-2 to a antiviral activity and inhibitory effect against angiotensin converting enzyme 2 (ACE2). A possible inhibitory effect affecting the interaction between the receptor-binding domain (RBD) protein and/or ACE2 was evaluated using LUMMIT kit. A SARS-CoV-2-induced pulmonary pneumonia model was developed to evaluate the effects of the compounds after 3 days of treatment. 

Results: Compounds PQM-243 and PQM-249 exhibited IC₅₀ values of 0.0648 ± 0.041 µM and 0.2860 ± 0.057 µM against SARS-CoV-2 with a selective index of >1543.21 and 349.65, respectively, and IC₅₀ values of 12.1 nM and 13.3 nM, respectively, against ACE2. All concentrations used significantly reduced interactions between ACE2 and RBD. Computational studies suggest that these new compounds are potent direct anti-SARS-CoV-2 agents, capable of reducing both virus viability and its invasive ability in the host cells by reducing the interaction between RBD and ACE2. It was also demonstrated that even when administered by the oral route, both compounds reduced SARS-CoV-2-induced lung inflammation. Our data suggests that both compounds can act as potent direct anti-SARS-CoV-2 agents, reducing both viral viability and host cell entry. In addition, they exhibited a significant multi-target-directed pharmacological profile, also reducing SARS-CoV-2-induced lung inflammation when administered orally. 

Conclusions: Overall, these findings support further investigation of PQM-243 and PQM-249 as promising antiviral and anti-inflammatory multi-target prototypes for the development of innovative drug candidates targeting SARS-CoV-2 and other virus-related respiratory diseases.”

https://pubmed.ncbi.nlm.nih.gov/41155678/

“Taken together, our data suggests that PQM-243 and PQM-249—two newly synthesized, easily accessible, and structurally simplified CBD-based compounds—can act as potent direct anti-SARS-CoV-2 agents, capable of reducing both viral viability and host cell entry by inhibiting the interaction between the viral receptor-binding domain (RBD) and the ACE2 receptor. Notably, both compounds exhibited a significant multi-target-directed pharmacological profile, demonstrating not only virucidal activity but also the ability to reduce SARS-CoV-2-induced lung inflammation when administered orally.”

https://www.mdpi.com/1424-8247/18/10/1565

“The global pandemic coronavirus disease 2019 (COVID-19) attributable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The current study aimed at combination therapies with natural polyphenolic compounds, such as cannabidiol (CBD), green tea polyphenols (Tea-poly), epigallocatechin gallate (EGCG) and theaflavin (TF), to investigate in vitro their inhibitory effects on virus invasion and viral spike (S) protein expression.

Among the compounds tested, CBD and Tea-poly exhibited the most significant inhibitory effects on virus entry, comparable to the positive control chloroquine (CQ). EGCG showed the strongest suppression of the expression of the S protein, while CBD remarkably decreased ACE2 expression. CoIP-MS revealed eleven S-protein-interacting proteins that were significantly affected by EGCG.

Transcriptome analysis demonstrated similar trends of CBD and EGCG in the modulation of many SARS-CoV-2-associated genes, with CBD showing greater impact on the gene profile than EGCG. GO and KEGG functional enrichment analyses revealed overlapping pathways of EGCG and CBD, including DNA repair, cell-cycle, and ER-, spliceosome- and ribosome-related processes.

The combined use of CBD and EGCG can complement each other’s advantages in inhibiting the invasion and reinvasion process of the virus at multiple levels, while minimizing the adverse effects of ACE2 expression level changes.

Findings in this work offer new information for developing multi-level therapeutic strategies to control SARS-CoV-2 infection and, specifically, provide a novel antiviral agent combination of CBD and EGCG for the control of COVID-19.”

https://pubmed.ncbi.nlm.nih.gov/40460494/

“Cannabidiol (CBD), one of the well-known pharmacologically active ingredients from the extracts of cannabis (Cannabis sativa L.), exerts a wide range of anti-inflammatory and immunomodulatory properties, leading to the presumption that CBD might be a potent agent also against COVID-19. Indeed, CBD may alleviate systemic symptoms of COVID-19 and reduce respiratory distress as well as cytokine storm reactions. Additionally, CBD may prime components of the innate immune system, enhancing innate anti-viral response to viral genes.”

“Green tea polyphenols, along with their most abundant bioactive constituent epigallocatechin gallate (EGCG), have been recognized as multi-functional compounds with broad-spectrum antiviral effects in addition to anti-inflammatory, antioxidative, antibacterial and antiproliferative properties.”

“To summarize, natural compounds, such as CBD and EGCG, have the benefits of being widely available, inexpensive, and low in toxicity for supplementing conventional therapies. Our findings in this study indicate great potentials of CBD and EGCG for novel therapeutics against SARS-CoV-2 infection as a multi-level antiviral strategy.”

https://www.sciencedirect.com/science/article/abs/pii/S0042682225001928?via%3Dihub

“Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease pathway is heavily influenced by different inflammatory cytokines. There is ample evidence of cannabidiol (CBD) immunomodulation effects.

Objectives: To investigate the effect of CBD on patients with SARS-CoV-2 and to measure the impact on inflammatory cytokines.

Methods: A double blind, placebo-controlled study to compare the clinical outcomes and selected serum cytokine levels in patients with SARS-CoV-2 that received sublingual CBD extraction. Seven patients were randomized to the treatment arm and three to the placebo group.

Results: Clinical outcomes were better in the patient group that received sublingual CBD vs. patients receiving placebo treatment. Serum cytokine mean concentration levels showed differences between the two groups but of mixed trends.

Conclusions: Patients presenting with SARS-CoV-2 and receiving CBD sublingually had better outcomes than those receiving a placebo, although these results did not reflect in selected serum cytokines. Further study is needed.”

https://pubmed.ncbi.nlm.nih.gov/40170643/

“Recently, cannabinoids have gained scientific interest as a promising anti-infective natural product class, as reported in several studies. However, the existing knowledge is mainly limited to common cannabinoids like THC and CBD.

Therefore, this study aims to fill the knowledge gap by investigating the anti-infective potential of nine selected cannabinoids (both common and rare cannabinoids): THC, CBD, CBC, CBE, CBF, CBG, CBL, CBN, and CBT against Clostridium perfringens and Influenza A (H5N1) neuraminidases and SARS-CoV-2 main protease and spike protein-human ACE2 interaction using a standard in vitro biochemical enzyme-binding assay.

As a result, to the authors’ knowledge, this study is the first to demonstrate the most promising effect of CBG over others in its class against C. perfringens and influenza A (H5N1) neuraminidases and SARS-CoV-2 main protease and spike protein-human ACE2 interaction. In comparison to CBG, CBD and THC were the second and third most promising candidates. Meanwhile, the other derivatives, such as CBC, CBE, CBF, CBL, CBN, and CBT, showed at least one anti-infective effect.

Our findings during the early drug discovery process indicate a promising anti-infective potential of cannabinoids, which can be considered for further investigation in a biological setup.”

https://pubmed.ncbi.nlm.nih.gov/40136439/

“In this study, the authors reported the anti-infective potential of nine selected cannabinoids against three common pathogenic mechanisms of C. perfringens, influenza A, and SARS-CoV-2 viruses for the first time. The results show that cannabinoids are a promising natural product class against C. perfringens and influenza A neuraminidases, and SARS-CoV-2 main protease and spike protein–human ACE2 interaction. Therefore, this study provides a solid scientific background for research on the pharmaceutical application of cannabinoids.”

https://www.mdpi.com/1467-3045/47/3/185

“This study deals with the comprehensive phytochemical composition and antiviral activity against SARS-CoV-2 of acidic (non-decarboxylated) and neutral (decarboxylated) ethanolic extracts from seven high-cannabidiol (CBD) and two high-Δ⁹-tetrahydrocannabinol (Δ⁹-THC) Cannabis sativa L. genotypes.

Their secondary metabolite profiles, phytocannabinoid, terpenoid, and phenolic, were determined by LC-UV, GC-MS, and LC-MS/MS analyses, respectively. All three secondary metabolite profiles, cannabinoid, terpenoid, and phenolic, varied significantly among cannabinoid extracts of different genotypes.

The dose-response analyses of their antiviral activity against SARS-CoV-2 showed that only the single predominant phytocannabinoids (CBD or THC) of the neutral extracts exhibited antiviral activity (all IC₅₀ < 10.0 μM). The correlation matrix between phytoconstituent levels and antiviral activity revealed that the phenolic acids, salicylic acid and its glucoside, chlorogenic acid, and ferulic acid, and two flavonoids, abietin, and luteolin, in different cannabinoid extracts from high-CBD genotypes are implicated in the genotype-distinct antagonistic effects on the predominant phytocannabinoid.

On the other hand, these analyses also suggested that the other phytocannabinoids and the flavonoid orientin can enrich the extract’s pharmacological profiles. Thus, further preclinical studies on cannabinoid extract formulations with adjusted non-phytocannabinoid compositions are warranted to develop supplementary antiviral treatments.”

https://pubmed.ncbi.nlm.nih.gov/39543317/

“Our studies showed that neutral extracts of different C. sativa genotypes have antiviral properties against SARS-CoV-2 though further preclinical studies on formulations of these extracts are needed to enhance their antiviral potential. One direction of these studies might be to obtain the extract formulations with modified non-phytocannabinoid compositions and asses their antiviral potential.”

https://onlinelibrary.wiley.com/doi/10.1002/ardp.202400607

“The aim of this study was to determine the antiviral activity of cannabidiol (CBD) against SARS-CoV-2 infection. CBD is the second most studied cannabinoid obtained from Cannabis plants.

We investigated the potential use of CBD, which has so far proven to have a positive effect on different diseases, in the SARS-CoV-2 infection.

To test this, in vivo studies were carried out using K18-hACE2 transgenic mice. To reveal the potential therapeutic effect of the CBD at the histopathological and molecular level challenge experiments were performed. The study was designed with two groups (n = 10) and in the treatment group animals were infected with SARS-CoV-2 virus strain B.1.1.7 alpha before the administration of CBD.

While the disease progressed and resulted in death in the control group that was infected by the virus alone, it was observed that the infection slowed down and the survival rate increased in the mice treated with CBD along with the virus.

In this study, K18-hACE2 transgenic mice infected with the wild SARS-CoV-2 virus were used to investigate and prove the antiviral activity of CBD.”

https://pubmed.ncbi.nlm.nih.gov/39267200/

“The antiviral action of CBD, which had been stated in previous studies, was evaluated and proved on mice using the wild SARS-CoV-2 virus in this study.”

https://onlinelibrary.wiley.com/doi/10.1111/jcmm.70030