As summarized in Table 1 and 2, Metadichol had a direct antiviral effect against SARS-CoV-2 in Caco-2 cells at an EC90 of 0.15 µg/mL (0.00026 µM). Thus, this demonstrated that Metadichol was 2000-fold more effective as an antiviral agent than Remdesivir (EC50 0.77 µM) and 3000-fold more potent than hydroxychloroquine phosphate (EC50 1.13 µM) .
A previously published work  of antiviral data against other viruses is presented in Tables 3 and 4. The raw data depict the cytotoxicity of Metadichol in the absence of a virus in Vero cells measured using a neutral red assay. No viral CPE value was reported when the “cytotoxicity” was >75%. These results may suggest that Metadichol is cytotoxic to cells at concentrations above 5 μg/ml. However, Metadichol is not toxic, as the LD50 value is 5000 mg/kg in a rats [20–22]. It is likely that Metadichol mimics characteristics of soaps and disrupts the lipid membrane of virus at higher concentrations, whereas it neutralizes the virus by a different mechanism at lower concentrations. Additionally, Meadichol selectively targets cancer cells in Caco-2 cells.  and cancer cell lines Mia-Paca, Colo 205, and Panc1 where Metadichol was cytotoxic to all these cell lines above 1 µg/ml. It is selectively cytotoxic at 10 µg/mL in leukemia cells .
Metadichol also inhibited TMPRSS2 (Table 6 and Figures 1 and 2) and was 270-fold more potent than CM . Nevertheless, for all practical purposes, it does not inhibit ACE2 (Table 7 and Figures 3 and 4). and inhibits TMPRSS2 which is needed for the virus to bind to ACE 2. Thus, the reported results provide a gateway to effective and safe therapies for COVID-19 patients. On the other hand, Metadichol did inhibit ACE (Table 8 and Figures 5 and 6). Inhibition of ACE, a blood pressure regulator, is crucial to mitigate COVID-19 infections, as Guan et al  validated that the single highest risk factor in infections is hypertension in 15% of the 1099 COVID-19 patients that participated in the study.
Vitamin D and the SARS-CoV-2 infection
An uncontrolled inflammatory response to SARS-CoV-2 is the major cause of disease severity and death in COVID-19 patients . This response is associated with high levels of circulating cytokines, tumor necrosis factors (TNF), monocyte chemoattractant protein 1
(CCL2), C-reactive protein (CRP), and ferritin. Notably, Metadichol  inhibits CCL2 (also known as MCP-1), TNF, NF-κB, and CRP, which is a surrogate marker of cytokine storms  and all these cytokines are increased in patients with vitamin D deficiency.
Vitamin D3 is produced in the skin upon exposure to ultraviolet B radiation via the generation of 7-dehydrocholesterol followed by a thermal reaction. It is converted to 25(OH)D in the liver and subsequently to 1,25(OH)2D (calcitriol) in the kidneys, where calcitriol binds to the nuclear vitamin D receptor (VDR). This receptor is a DNA-binding protein that interacts with regulatory sequences near target genes and recruit’s chromatin active complexes that genetically and epigenetically regulate the gene transcripts . Vitamin D reduces the risk of infections by mechanisms that induce Cathelicidin and defensins , resulting in lowered replication rates of viruses and reduced concentrations of pro-inflammatory cytokines . For instance, supplementation with 4000 IU/d of vitamin D decreased the dengue virus infection . Inflammatory cytokine levels increase in viral and bacterial infections, as is observed in COVID-19 patients. However, vitamin D can reduce the production of pro-inflammatory cytokines, such as TNF and interferon (IFN), secreted by T helper type 1 (Th1) cells , and thus is a modulator of adaptive immunity . For example, it primarily suppresses Th1-mediated immune responses by repressing the production of the inflammatory cytokines interleukin (IL)-2 and IFN-gamma . Additionally, 1,25(OH)2D3 promotes cytokine production by T helper type 2 (Th2) cells and enhances the indirect suppression of Th1 cells by promoting the actions of a multitude of cell types . It also induces the expression of T regulatory cells, thereby inhibiting inflammatory processes . Remarkably, Metadichol is an inverse agonist (protean agonist)  of VDR, i.e., it binds to VDR at the same site as calcitriol but has different properties. It is the only known inverse agonist of VDR in medical literature.
Telomerase and viral infections
Viral infection places substantial strain on the body. Notably, CD8+ T cells mediate adaptive immunity  to protect the body from microbial invaders. However, they can easily reach their Hayflick limit due to progressive telomere shortening ; this is more likely if the telomeres are already short. Thus, infections can enormously strain the immune cells to replicate. Naive T and B cells[40,41] are particularly important for protection against new pathogens, such as SARS-CoV-2. Thus, the quantity of these cells is crucial to initiate an effective immune response. In this regard, 1 pico gram/ml of Metadichol has been found to increase h-TERT (telomerase) expression by 16-fold .
Aryl hydrocarbon receptor and viral infections
One of the major complications observed in infected COVID-19 patients is respiratory failure. A possible underlying mechanism is the activation of the aryl hydrocarbon receptor (AHR) during COVID-19 that can impact antiviral immunity and the function of repair-associated lung cells . Thus, the AHR signaling pathway can dampen the immune response against SARS-CoV-2 . Remarkably, studies have reported that while AHR signaling is required for SARS-CoV-2 replication, upregulation of this pathway may be deleterious to the virus. This is because AHR limits activation and interferes with multiple antiviral immune mechanisms, including IFN-I production and intrinsic immunity.  which suggests that AHR signaling constrains IFN type I-mediated innate antiviral defense and the need to block constitutive AHR activity. Of note, only an inverse agonist can hinder this activity. Previously, we have shown that Metadichol® binds to AHR as an inverse/protean agonist  and thus reduces complications attributed to uncontrolled inflammation and cytokine storms.
Vitamin C and viral infections
There is a need to boost the innate and adaptive immunity of a person in response to infectious diseases. Micronutrients that have been identified to robustly promote immunity are vitamins C and D. Vitamin C is essential for a healthy and functional host defense, and its pharmacological application has been demonstrated to enhance immune function . It exhibits antiviral properties that inhibit the replication of HSV-1, poliovirus type 1, influenza virus type A and B , and rabies virus in vitro .
Vitamin C deficiency reduces cellular [50–54] and humoral immune responses. Treatment of healthy subjects promotes and enhances natural killer (NK) cell activities , underlining the immunological importance of vitamin C [56,57]. This validates its crucial role in various aspects of immune cell functions, such as immune cell proliferation and differentiation, in addition to its anti-inflammatory properties. Vitamin C is also required as a cofactor for the optimal activity of newly characterized hydroxylase enzymes, which regulate the activity, gene transcription, and signaling of hypoxia-inducible factors in immune cells [58–60]. Of note, studies have demonstrated that Metadichol administration increases the endogenous vitamin C levels by recycling it to levels that are not achieved by oral intake, and these levels bring about changes in improving diverse biomarkers [61–63].
Gene cluster network analysis in COVID-19 infections
The present drug discovery paradigm is based on the idea of one gene, one target, and one disease. Nevertheless, it has become clear that it is difficult to achieve single target specificity. Thus, it is more likely that targeting multiple genes rather than single genes can help block multiple paths of disease progression [64,65]. Gene network analysis provides a minimum set of target genes that form the basis of a disease. This cluster of genes modulates gene pathways and biological networks involved in the disease. The database www.ctdbase.org  was used to curate genes that were relevant to COVID-19 (Table 9). Table 10 lists the curated genes and the diseases that they are involved in.
The 13 identified genes were screened and categorized in set of five genes: TNF, CCL2, ACE2, TMPRSS2, and AGT, which belongs to the renin-angiotensin system network (Figure 7). Metadichol modulated all these genes by binding to VDR. A similar analysis of these genes demonstrated that they were clustered closely in diseases and had a highly significant p-value < 10-6. Furthermore, a network of these five closely related genes was generated using www.innatedb.org  (Figure 8). This analysis integrates known gene interactions and pathways curated from major public databases. The highlighted ones in yellow are SIRT1, androgen receptor (AR), and FOS.
Glinsky  suggested that vitamin D is a potential mitigation agent that prevents SARS-CoV-2 entry. Notably Metadichol binds to VDR which controls the expression of FOS . Moreover, VDR regulates SIRT1  in viral infections . Subsequently, SIRT1 regulates the expression of AR  that in turn regulates the expression of TMPRSS2. Figure 9, generated using PACO , presents the gene network and corresponding regulatory relationships. The analysis revealed that VDR also regulated FOS expression, whereas FOS regulated AGT expression and , AGT mediated the expression levels of AGTR1 and ACE.
Wambier and Goren  suggested that the SARS-CoV-2 infection is likely to be androgen-mediated as AR controls expression of TMPRSS2.The first step that occurs in the COVID-19 infection is the priming of the SARS-CoV-2 spike proteins by TMPRSS2; these proteins cleave ACE2 to augment viral entry into the host cells. However, Metadichol can completely inhibit this key priming step.
Proteases such as Furin  and Adam-17 have been reported to activate the spike protein in vitro, enabling viral spread and pathogenesis in infected hosts. Notably, VDR controls Furin expression via its interaction with SRC (Proto-oncogene tyrosine-protein kinase Src)
. On the other hand, Adam-17 is regulated via CEPBP (CCAAT Enhancer Binding Protein Beta) [77,78], which is involved in the regulation of genes involved in immune and inflammatory responses. Recently, Ulrich and Pillat  proposed that CD147, like ACE2, is another host receptor used by the virus to enter host cells. CD147 is a known receptor  of Plasmodium falciparum, the parasite that causes malaria in humans. Remarkably, a previous study has demonstrated that Metadichol (US patent 9,006,292) inhibits malarial parasites.
Controlling cytokine storms
A cytokine storm develops when an initial immune response induces the production of cytokines. It is initiated in the host body in response to SARS-CoV-2 and leads to inflammation and increases the secretion of the pro-inflammatory cytokines
Figure 10 depicts the cytokine relationship network generated in this study using PACO. Cytokines can activate T cells and cause tissue damage and infection in the lungs. Remarkably, Metadichol is an in vivo inhibitor  (US patent 8,722,093) of TNF alpha. The endocytosis of ACE2 with SARS-CoV-2 results in a reduction in ACE2 on cell surfaces, thus increasing serum angiotensin II levels . Angiotensin II is a vasoconstrictor and pro-inflammatory cytokine (Figure 11) that acts via AT1R . The angiotensin II-AT1R axis leads to a pro-inflammatory state  in the host, causing infections by activating NF-κB and increasing IL-6 levels in multiple inflammatory and autoimmune diseases .
Thus, the dysregulation of angiotensin II downstream of ACE2 leads to cytokine release in COVID-19 patients. This increases TNF levels that in-turn elevate IL-6, CCl2, and CRP levels. Therefore, cytokine storms  result in ARDS. However, Metadichol is an ACE inhibitor that blocks the angiotensin I and II pathways, promoting an anti-inflammatory state.
A pilot study conducted by a third party, Kasturaba Hospital in Mumbai, India, on 30 COVID-19 patients with minor symptoms revealed that Metadichol treatment (20 mg/day) eliminated by Rt-PCR test the virus in 75% of patients after four days of treatment (Supplements). To validate this finding, a larger study consisting of a Metadichol treatment group and control groups with only standard care provided to the participants were initiated. We hope to communicate these results in the future.