Cannabis as antivirals.

Cannabis is a plant notorious for its psychoactive effect, but when used correctly, it provides a plethora of medicinal benefits. With more than 400 active compounds that have therapeutic properties, cannabis has been accepted widely as a medical treatment and for recreational purposes in several countries. The compounds exhibit various clinical benefits, which include, but are not limited to, anticancer, antimicrobial, and antioxidant properties. Among the vast range of compounds, multiple research papers have shown that cannabinoids, such as cannabidiol and delta-9-tetrahydrocannabinol, have antiviral effects. Recently, scientists found that both compounds can reduce severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral infection by downregulating ACE2 transcript levels and by exerting anti-inflammatory properties. These compounds also act as the SARS-CoV-2 main protease inhibitors that block viral replication. Apart from cannabinoids, terpenes in cannabis plants have also been widely explored for their antiviral properties. With particular emphasis on four different viruses, SARS-CoV-2, human immunodeficiency virus, hepatitis C virus, and herpes simplex virus-1, this review discussed the role of cannabis compounds in combating viral infections and the potential of both cannabinoids and terpenes as novel antiviral therapeutics.

Polyoxygenated Terpenoids and Polyketides from the Roots of Flueggea virosa and Their Inhibitory Effect against SARS-CoV-2-Induced Inflammation.

Six new polyoxygenated terpenoids, podovirosanes A-F (1-6), and two known polyketides (7 and 8) were isolated from the roots of F. virosa. Their structures, along with absolute configurations, were deduced using spectroscopic analysis as well as computational calculations, including TDDFT calculation of ECD spectra and GIAO NMR calculations combined with DP4+ probability analysis. Compounds 2, 3, 5, and 8 were found to reduce the phosphorylation levels of NF-κB p65 in SARS-CoV-2 pseudovirus-stimulated PMA-differentiated THP-1 cells.

Marine Alga Ulva fasciata-Derived Molecules for the Potential Treatment of SARS-CoV-2: An In Silico Approach.

SARS-CoV-2 is the causative agent of the COVID-19 pandemic. This in silico study aimed to elucidate therapeutic efficacies against SARS-CoV-2 of phyco-compounds from the seaweed, Ulva fasciata. Twelve phyco-compounds were isolated and toxicity was analyzed by VEGA QSAR. Five compounds were found to be nonmutagenic, noncarcinogenic and nontoxic. Moreover, antiviral activity was evaluated by PASS. Binding affinities of five of these therapeutic compounds were predicted to possess probable biological activity. Fifteen SARS-CoV-2 target proteins were analyzed by the AutoDock Vina program for molecular docking binding energy analysis and the 6Y84 protein was determined to possess optimal binding affinities. The Desmond program from Schrödinger's suite was used to study high performance molecular dynamic simulation properties for 3,7,11,15-Tetramethyl-2-hexadecen-1-ol-6Y84 for better drug evaluation. The ligand with 6Y84 had stronger binding affinities (-5.9 kcal/mol) over two standard drugs, Chloroquine (-5.6 kcal/mol) and Interferon α-2b (-3.8 kcal/mol). Swiss ADME calculated physicochemical/lipophilicity/water solubility/pharmacokinetic properties for 3,7,11,15-Tetramethyl-2-hexadecen-1-ol, showing that this therapeutic agent may be effective against SARS-CoV-2.

Interference of Chaga mushroom terpenoids with the attachment of SARS-CoV-2; in silico perspective.

Finding a potent inhibitor to the pandemic SARS-CoV-2 is indispensable nowadays. Currently, in-silico methods work as expeditious investigators to screen drugs for possible repurposing or design new ones. Targeting one of the possible SARS-CoV-2 attachment and entry receptors, Glucose-regulated protein 78 (GRP78), is an approach of major interest. Recently, GRP78 was reported as a recognized representative in recognition of the latest variants of SARS-CoV-2. In this work, molecular docking and molecular dynamics simulations were performed on the host cell receptor GRP78. With its many terpenoid compounds, Chaga mushroom was tested as a potential therapeutic against the SARS-CoV-2 receptor, GRP78. Results revealed low binding energies (high affinities) toward the GRP78 substrate-binding domain ß (SBDß) of Chaga mushroom terpenoids. Even the highly specific cyclic peptide Pep42, which selectively targeted GRP78 over cancer cells in vivo, showed lower binding affinity against GRP78 SBDß compared to the binding affinities of terpenoids. These are auspicious results that need to be tested experimentally. Intriguingly, terpenoids work as a double sword as they can be used to interfere with VUI 202,012/01, 501.V2, and B.1.1.248 variants of SARS-CoV-2 spike recognition.

Cannabidiol and Terpene Formulation Reducing SARS-CoV-2 Infectivity Tackling a Therapeutic Strategy.

In late 2019, COVID-19 emerged in Wuhan, China. Currently, it is an ongoing global health threat stressing the need for therapeutic compounds. Linking the virus life cycle and its interaction with cell receptors and internal cellular machinery is key to developing therapies based on the control of infectivity and inflammation. In this framework, we evaluate the combination of cannabidiol (CBD), as an anti-inflammatory molecule, and terpenes, by their anti-microbiological properties, in reducing SARS-CoV-2 infectivity. Our group settled six formulations combining CBD and terpenes purified from Cannabis sativa L, Origanum vulgare, and Thymus mastichina. The formulations were analyzed by HPLC and GC-MS and evaluated for virucide and antiviral potential by in vitro studies in alveolar basal epithelial, colon, kidney, and keratinocyte human cell lines. Conclusions and Impact: We demonstrate the virucide effectiveness of CBD and terpene-based formulations. F2TC reduces the infectivity by 17%, 24%, and 99% for CaCo-2, HaCat, and A549, respectively, and F1TC by 43%, 37%, and 29% for Hek293T, HaCaT, and Caco-2, respectively. To the best of our knowledge, this is the first approach that tackles the combination of CBD with a specific group of terpenes against SARS-CoV-2 in different cell lines. The differential effectiveness of formulations according to the cell line can be relevant to understanding the pattern of virus infectivity and the host inflammation response, and lead to new therapeutic strategies.

The Potential of Dietary Bioactive Compounds against SARS-CoV-2 and COVID-19-Induced Endothelial Dysfunction.

COVID-19 is an endothelial disease. All the major comorbidities that increase the risk for severe SARS-CoV-2 infection and severe COVID-19 including old age, obesity, diabetes, hypertension, respiratory disease, compromised immune system, coronary artery disease or heart failure are associated with dysfunctional endothelium. Genetics and environmental factors (epigenetics) are major risk factors for endothelial dysfunction. Individuals with metabolic syndrome are at increased risk for severe SARS-CoV-2 infection and poor COVID-19 outcomes and higher risk of mortality. Old age is a non-modifiable risk factor. All other risk factors are modifiable. This review also identifies dietary risk factors for endothelial dysfunction. Potential dietary preventions that address endothelial dysfunction and its sequelae may have an important role in preventing SARS-CoV-2 infection severity and are key factors for future research to address. This review presents some dietary bioactives with demonstrated efficacy against dysfunctional endothelial cells. This review also covers dietary bioactives with efficacy against SARS-CoV-2 infection. Dietary bioactive compounds that prevent endothelial dysfunction and its sequelae, especially in the gastrointestinal tract, will result in more effective prevention of SARS-CoV-2 variant infection severity and are key factors for future food research to address.

Target-Based Virtual Screening and LC/MS-Guided Isolation Procedure for Identifying Phloroglucinol-Terpenoid Inhibitors of SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 5 million deaths worldwide to date. Due to the limited therapeutic options so far available, target-based virtual screening with LC/MS support was applied to identify the novel and high-content compounds 1-4 with inhibitory effects on SARS-CoV-2 in Vero E6 cells from the plant Dryopteris wallichiana. These compounds were also evaluated against SARS-CoV-2 in Calu-3 cells and showed unambiguous inhibitory activity. The inhibition assay of targets showed that compounds 3 and 4 mainly inhibited SARS-CoV-2 3CLpro, with effective Kd values. Through docking and molecular dynamics modeling, the binding site is described, providing a comprehensive understanding of 3CLpro and interactions for 3, including hydrogen bonds, hydrophobic bonds, and the spatial occupation of the B ring. Compounds 3 and 4 represent new, potential lead compounds for the development of anti-SARS-CoV-2 drugs. This study has led to the development of a target-based virtual screening method for exploring the potency of natural products and for identifying natural bioactive compounds for possible COVID-19 treatment.

Role of ACE2-Ang (1-7)-Mas axis in post-COVID-19 complications and its dietary modulation.

Severe acute respiratory syndrome-coronavirus-2 (COVID-19) virus uses Angiotensin-Converting Enzyme 2 (ACE2) as a gateway for their entry into the human body. The ACE2 with cleaved products have emerged as major contributing factors to multiple physiological functions and pathogenic complications leading to the clinical consequences of the COVID-19 infection Decreased ACE2 expression restricts the viral entry into the human cells and reduces the viral load. COVID-19 infection reduces the ACE2 expression and induces post-COVID-19 complications like pneumonia and lung injury. The modulation of the ACE2-Ang (1-7)-Mas (AAM) axis is also being explored as a modality to treat post-COVID-19 complications. Evidence indicates that specific food components may modulate the AAM axis. The variations in the susceptibility to COVID-19 infection and the post-COVID its complications are being correlated with varied dietary habits. Some of the food substances have emerged to have supportive roles in treating post-COVID-19 complications and are being considered as adjuvants to the COVID-19 therapy. It is possible that some of their active ingredients may emerge as the direct treatment for the COVID-19.

Computational and Synthetic Biology Approaches for the Biosynthesis of Antiviral and Anticancer Terpenoids from Bacillus subtilis.

Recent advancements in medicinal research have identified several antiviral and anticancer terpenoids that are usually deployed as a source of flavor, fragrances and pharmaceuticals. Under the current COVID-19 pandemic conditions, natural therapeutics with the least side effects are the need of the hour to save the patients, especially, which are pre-affected with other medical complications. Although plants are the major sources of terpenoids; however, for the environmental concerns, the global interest has shifted to the biocatalytic production of molecules from microbial sources. The gram-positive bacterium Bacillus subtilis is a suitable host in this regard due to its GRAS (generally regarded as safe) status, ease in genetic manipulations and wide industrial acceptability. The B. subtilis synthesizes its terpenoid molecules from 1-deoxy-d-xylulose-5-phosphate (DXP) pathway, a common route in almost all microbial strains. Here, we summarize the computational and synthetic biology approaches to improve the production of terpenoid-based therapeutics from B. subtilis by utilizing DXP pathway. We focus on the in-silico approaches for screening the functionally improved enzyme-variants of the two crucial enzymes namely, the DXP synthase (DXS) and Farnesyl Pyrophosphate Synthase (FPPS). The approaches for engineering the active sites are subsequently explained. It will be helpful to construct the functionally improved enzymes for the high-yield production of terpenoid-based anticancer and antiviral metabolites, which would help to reduce the cost and improve the availability of such therapeutics for the humankind.

Chaga Medicinal Mushroom Inonotus obliquus (Agaricomycetes) Terpenoids May Interfere with SARS-CoV-2 Spike Protein Recognition of the Host Cell: A Molecular Docking Study.

The most challenging threat facing the global community today is the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite global efforts to develop suitable treatments, very few specific antiviral agents have been suggested and the virus remains a serious global health risk. In vivo animal experiments have demonstrated that bioactive mycochemical constituents of Inonotus obliquus have immunomodulatory, antimicrobial, and antiviral properties. The present study investigates the antiviral potential of I. obliquus terpenoids against COVID-19 using a molecular docking study. The in silico study elucidates the ability of most of the terpenoid components to interact with the receptor-binding domain of SARS-CoV-2 spike glycoprotein with excellent affinity. Additionally, we found that both betulinic acid and inonotusane C could bind and stably interact with the spike protein near the host cell recognition site of angiotensin-converting enzyme 2.

COVID-19 Prophylaxis Efforts Based on Natural Antiviral Plant Extracts and Their Compounds.

During the time of the novel coronavirus disease 2019 (COVID-19) pandemic, it has been crucial to search for novel antiviral drugs from plants and well as other natural sources as alternatives for prophylaxis. This work reviews the antiviral potential of plant extracts, and the results of previous research for the treatment and prophylaxis of coronavirus disease and previous kinds of representative coronaviruses group. Detailed descriptions of medicinal herbs and crops based on their origin native area, plant parts used, and their antiviral potentials have been conducted. The possible role of plant-derived natural antiviral compounds for the development of plant-based drugs against coronavirus has been described. To identify useful scientific trends, VOSviewer visualization of presented scientific data analysis was used.

Bioactive Terpenes and Their Derivatives as Potential SARS-CoV-2 Proteases Inhibitors from Molecular Modeling Studies.

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel coronavirus; the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Millions of cases and deaths to date have resulted in a global challenge for healthcare systems. COVID-19 has a high mortality rate, especially in elderly individuals with pre-existing chronic comorbidities. There are currently no effective therapeutic approaches for the prevention and treatment of COVID-19. Therefore, the identification of effective therapeutics is a necessity. Terpenes are the largest class of natural products that could serve as a source of new drugs or as prototypes for the development of effective pharmacotherapeutic agents. In the present study, we discuss the antiviral activity of these natural products and we perform simulations against the Mpro and PLpro enzymes of SARS-CoV-2. Our results strongly suggest the potential of these compounds against human coronaviruses, including SARS-CoV-2.

Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment.

Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes. The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson's disease, Tourette's syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors. The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood-brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.