WO2021262825A2 - Disrupting lipid synthesis: a novel target for broad-spectrum host-directed anti-virulence therapeutics - Google Patents

Abstract

The present invention comprises methods of identifying compounds suitable for treating viral disease including COVID-19 which functionally require ELO2, ELO3, ACB1 and ACC1. to synthesize the virus. The invention further comprises compounds for disrupting viral synthesis and methods of use thereof.

Description

[1] Disrupting Lipid Synthesis: A Novel Target for Broad-Spectrum Host-Directed Anti-Virulence Therapeutics

[2] Priority Claim and Incorporation by Reference.

[3] This application claims priority to United States provisional patent application 63/093,765 filed on October 19, 2020; United States provisional patent application 63/074,475 filed on September 4, 2020; United States provisional patent application 63/043,084 filed on June 23, 2020. All References cited herein are expressly incorporated by reference for all purposes.

[4] Background

[5] Illness and mortality from COVID 19 caused by the SARS-CoV-2 coronavirus is an unprecedented concern for healthcare at the time of filing. There are currently 179 million confirmed cases worldwide, with 33.5 million of those in the United States alone. Globally there are around 3,880,000 deaths attributed to COVID 19 with 602,000 of those deaths in the United States.

[6] In May of 2020, the FDA issued an Emergency Use Authorization for the drugs Hydroxychloroquine, chloroquine phosphate, and remdesivir. By June 2020, the EUA had been revoked for hydroxychloroquine and chloroquine phosphate, highlighting the lack of data regarding whether either of the treatments covered by the Emergency Use Authorization by the U.S. Food and Drug Administration are safe or effective. As of this writing there are 5,996 studies listed in clinicaltrials.gov for COVID, including 1,728 drug studies for 593 drugs/compounds. Most of the experimental products in the therapeutic category will take years to acquire data, seek approval and ramp up manufacturing.

[7] Even with vaccines for COVID- 19 infection now available, drug therapies that mitigate disease severity and duration are essential to lessen the humanitarian and economic damage of this virus. Indeed, to treat any subsequent waves of COVID- 19 and the emerging SARS-CoV-2 variants, as well as to prepare for future viral outbreaks, a robust armamentarium of anti-infective agents is sorely needed. Given the extended times required for both vaccine and novel drug development (estimated to be 5-15 years for drug development) the most straightforward approach to obtaining an effective anti- infective quickly is to identify approved drugs and to repurpose them for treatment of COVID- 19 infected individuals. [8] Summary of the Invention

[9] An essential part of drug repurposing is to understand the mechanism of action of each therapeutic. This is particularly relevant for repurposing because, while the traditional target of any given drug may have been shown for example by biochemical, crystallographic, or other biophysical assays, the functional mechanism of action is often less well understood. Furthermore, many re-purposing candidates were approved for their original indications before 1980, and as a consequence, mechanistic information is lacking.

[10] Genetic Networks’ proprietary FI-Tech™ is a comprehensive, industrialized version of HIPHOP (Science. 2014 Apr 11; 344(6180): 208-211) herein incorporated by reference for all purposes. The industrialization of HIPHOP involves the addition of quality control steps, improvement of the processing algorithms and switching to next generation sequencing with barseq, multiple runs for each dataset for statistical power, and the incorporation of a robotic platform specifically designed for H-Tech to improve throughput and reduce human introduced errors. Using H-Tech we performed genome wide screens to uncover such fundamental, functional targets and target pathways, and thereby provide important mechanistic insight. In these assays (Figure 1), a drug is applied to a comprehensive collection of deletion yeast mutants, and those strains that manifest sensitivity to the applied drug report those pathways and targets that are essential for the drug function. By collecting thousands of such chemical genomic datasets, one can predict and delineate the cellular response to drug treatment and identify modules that are required for drug function. These modules are highly conserved units of biological function between species, including humans, and the individual components need not be conserved and may participate in multiple modules. Modules are often not an annotated pathway or complex, and they integrate inputs and outputs in a systems dependent manner. An example of this is that the module involved in cell wall synthesis in yeast, is repurposed for angiogenesis in humans.

[11] Modules described in this patent are created by integrating the results of H-Tech experiments for a given drug, for example, remdesivir, with two types of functional biological networks that together capture large-scale drug responses across millions of chemogenomic interactions (drug-gene) and genetic interactions (gene-gene). The first network is built using the correlation between genes across Genetic Networks’ database of drug response matrices (fitness defect correlation network). The second network is built using the correlation of synthetic genetic interactions across millions of double knockouts in yeast (synthetic lethality network, Science 327, 425-431 (2010) herein incorporated by reference for all purposes. The module is created by scoring the genes that are connected in both networks to the gene knockouts that respond to the relevant drug in H-Tech (i.e., “hits”). Each gene’s score is calculated as the geometric mean of the scores from both networks. The fitness defect correlation network score for a given gene is the sum of the products of the effect size (log2 of the fold change between controL- and Treatment) of each H-Tech hit and its Pearson correlation with the gene. The synthetic lethality network scores for a given gene is the sum of the products of the effect size (as above) and the genetic correlation linking each H-Tech hit to the gene being scored. Genetic Networks has utilized this approach to build a database of modules that is constantly being refined with each additional H-Tech completed. For each module, a score threshold for including genes in addition to the hits is chosen to capture approximately as many non-hit genes as hits. The module is visualized as a network by drawing edges between genes with a Pearson correlation of 0.25 or greater in the fitness defect correlation network.

[12] In the Genetic Networks proprietary database is a module we have termed the Lipid Module (Figure 2) that we identified from screening of ACC inhibitors. The Lipid Module includes the yeast genes ACC1, ACB1, EL03, and EL02 as key functional targets. ACC1, acetyl-CoA carboxylase, is a biotin containing enzyme that catalyzes cytosolic acetyl-CoA to malonyl-CoA and regulates histone acetylation. In addition, ACC1 is the rate-limiting step for de novo biosynthesis of long-chain fatty acids. The human orthologs for cerevisiae ACC1 are ACC1 and ACC2. ACB1 is acyl-CoA- binding protein that transports newly synthesized acyl-CoA esters from fatty acid synthetase to the acyl-CoA-consuming processes. In humans the ACB1 ortholog is DBI/ACBP. EL02 and EL03 are elongases in cerevisiae that are involved in fatty acid and sphingolipid biosynthesis, with the human orthologs being ELOVL1, ELOVL3 and ELOV7. Collectively this module is functionally involved in the biosynthesis of very long-chain fatty acids.

[13] The first and only approved treatment against COVID-19 (approved in October 2020) is Remdesivir which showed positive results in shortening both disease duration and severity in a randomized controlled trial. Remdesivir is a nucleotide analog that has been shown to bind and disrupt RNA polymerase, and recent Remdesivir-RNA polymerase co-crystals validate this polymerase as the traditional target.

[14] Early in 2020, we found retrospective data indicating that the FDA approved calcium- channel blocker amlodipine may act as an anti-virulent against COVID-19. Specifically, there was a reduction in mortality for hospitalized patients with the positive-sense single-stranded RNA virus SARS-CoV-2.

[15] Our approach is to repurpose human approved and investigational drugs as anti- infective therapeutics that act as host-directed anti-virulence agents to mitigate drug resistance and destruction of the host commensal microbial community. Using methods described herein we identified a novel host module, the Lipid Module, and identified known drugs and investigational compounds that regulate this module and which until this time were unknown.

[16] Using proprietary screening processes and databases, we have identified 15 drugs derived from a functional module (Lipid Module) with a drug shown to reduce mortality in patients with COVID-19 and the only approved FDA drug against SARS-CoV-2. This module contains several genes involved in the biosynthesis of very-long chain fatty acids including ACC1, ACB1, EL02 AND EL03. We also observed that some of these drugs, which were identified based on their potential to reduce mortality, also have host-directed antiviral activity presumably due to inhibition of lipid synthesis that directly affects RNA replication and viral assembly. The blocking of viral replication has been confirmed for at least one of the candidate drugs.

[17] Description of the Figures.

[18] Figure 1 shows the basic experimental steps for the screening part of H-Tech.

[19] Figure 2 is a diagram of the Lipid Module including the key genes ACC1, ACB 1, EL02 and EL03 (highlighted in yellow). Module constructed as in [10]

[20] Figure 3 is a graph showing growth of 4800 homozygous knockout strains, ranked by their growth response to RDV. For clarity, only top hit genes are labeled.

[21] Figure 4 is a portion of the chemical -genetic network of EL03 determined by analysis of remdesivir, highlighting the genes that comprise this module. Genes in light gray are hits from H-Tech analysis of remdesivir. Genes in dark gray are included by module analysis described in paragraph [10] above. The primary module is the single, large connected network of genes. [22] Figure 5 is a graph showing a comparison of growth in the presence or absence of EL03 in the presence or absence of RDV.

[23] Figure 6 is a graph showing a single strain dose-response curve of the EL03 knockout strain in the presence of RDV.

[24] Figure b7 is a group of graphs showing representative dose response curves and matrix.

[25] Figures 8A-D shows representative synergy.

[26] Figure 9 is a matrix showing synergy of lomerizine and remdesivir in an EL03 deletion matrix.

[27] Figure 10 is a graph showing viral inhibition of 3 compounds versus a DMSO control.

[28] Detailed Description of the Invention.

[29] At the onset of the 2019 pandemic, unfortunately there were no medications available to prevent or treat infections of the novel SARS-CoV-2 coronavirus. To find safe existing drugs that could be repurposed to reduce the severity of the disease, Genetic Networks used their proprietary GeneScape™ platform to identify potential treatments from an existing database of several thousand screened drugs and/or compounds. The first step in this process was to complete an extensive literature search for drugs that had previously been shown to either inhibit viral RNA replication or reduce mortality in patients infected with RNA viruses. The first drug reported to have activity against the novel SARS-CoV-2 virus was Gilead’s Remdesivir, a drug originally intended for Ebola that had previously been shown to have activity against coronaviruses. Remdesivir, a selective RNA polymerase inhibitor, would later be granted approval for treatment of hospitalized COVID-19 patients, however the drug failed to show any significant reduction in mortality. In addition to Remdesivir, we also identified two retrospective studies for a class of drugs known as calcium channel blockers (CCBs). Amlodipine and Nifedipine, CCBs, which were reported to reduce mortality in patients infected with SARS-CoV-2 (Solaimanzadeh I (May 12, 2020) Nifedipine and Amlodipine Are Associated With Improved Mortality and Decreased Risk for Intubation and Mechanical Ventilation in Elderly Patients Hospitalized for COVID-19. Cureus 12(5): e8069. DOI 10.7759/cureus.8069; Zhang, L., Calcium channel blocker amlodipine besylate is associated 1 with reduced case 2 fatality rate of COVID-19 patients with hypertension, https://www.medrxiv.Org/content/10.l 101/2020.04.08.20047134vl.full.pdf, 2020) herein incorporated by reference for all purposes. In the same report, CCBs were also shown to have significant antiviral activity in vitro. Nifedipine has also been shown to reduce mortality in severe fever with thrombocytopenia syndrome caused by the negative- stranded RNA Dabie bandavirus (Lei-Ke Zhang, et. ah, Calcium channel blockers reduce severe fever with thromboc topenia syndrome virus (SFTSV) related fatality, Cell Research, 29:739-753, 2019) herein incorporated by reference for all purposes.

[30] These data prompted us to screen remdesivir and to explore our database for functional modules for CCBs to determine the potential modes of action that could support these encouraging in vivo and in vitro studies and provide a starting point for us to discover alternative treatments. Our GeneScape platform uses the genetically manipulatable and tractable model organism yeast, to interrogate drug action and determine the functional profile (modules) for each drug. In each screen, we measure the functional response of 6000 genetic mutants, each mutant deleted for a single gene, to gain a full genome-wide functional profile for each drug. Due to the strong evolutionary conservation between yeast and humans, Genetic Networks can extrapolate the information from drugs known to have activity in humans to a measured functional profile in yeast. This measurement can be correlated to other drug profiles within Genetic Networks proprietary database that contains more than 3000 drugs/compounds. This can help to predict a drug’s functional mode of action that is linked to the desired therapeutic activity and help to identify additional drugs within our database that share similar functional profiles. In this way, Genetic Networks can rapidly identify potential treatments for emerging biothreats and other diseases.

[1] For COVID-19, we first examined the functional profiles for CCBs (reduction of mortality and antiviral activity) and Remdesivir (antiviral only). Our database includes the following CCBs: Lomerizine, Felodipine, and Amlodipine. All these drugs showed very active profiles in yeast, and several specific deletion strains showed strong sensitivity to this class of drug. Our analysis showed that several of the strains that were sensitive to the CCB class of drugs corresponded to genes known to be critical for lipid metabolism, including EL02 and EL03, which were the most sensitive. Interestingly Remdesivir, a drug designed to have very little activity towards the host was also found to have increased sensitivity towards the EL03 strain, suggesting a possible off-target effect on lipid metabolism that might contribute to its antiviral activity. In fact, a recent report showed Remdesivir can alter lipid profiles in animal models consistent with our findings. Using this information, we identified the Lipid Module (Figure 2) from our database as a potential target for COVID-19 and screened our complete library of over 3000 drugs for other drugs that share a similar functional profile targeting the Lipid Module. We identified 15 therapeutic candidates for COVID- 19, with 8 being FDA approved drugs and 6 of these now in clinical trials for COVID- 19.

[31] Example 1:

The SARS-CoV-2 coronavirus is responsible for a worldwide pandemic that has killed millions and disrupted the lives of billions. To date the only therapeutic agent that has been shown effective in randomized controlled trials is the antiviral nucleotide analog remdesivir (RDV). This medication was originally designed for treating Ebola virus infections but has been successfully repurposed for COVID-19 and was granted FDA Emergency Approval on May 1, 2020, and FDA approval October 22, 2020. The intended target of RDV is the RNA-dependent RNA-polymerase (RdRv) and a recent co-crystal supports this. Our approach to finding a therapeutic was unconventional and assumed that host-directed agents can be effective at not only blocking viral replication and assembly, due to the fact the viral life cycle is dependent on the host, but more importantly we sought to find anti-virulence agents that would decrease mortality of patients infected with COVID-19. We addressed this question by first reviewing all published data on drugs that were shown to reduce mortality in hospitalized patients after infection with RNA viruses, including but not limited to coronaviruses, like SARS-CoV-2. Early in 2020, we found retrospective data demonstrating that the calcium channel blocker (CCB) Amlodipine reduced mortality after infection with the positive-sense single-stranded RNA virus SARS-CoV-2. Also, in the same report, several related CCBs were shown to not only reduce mortality, but to have antiviral activity against SARS-CoV-2 in vitro. Using our proprietary GeneScape platform we searched our module database for CCBs, which included data for Felodipine and Amlodipine, to show that these drugs targeted lipid metabolism through the Lipid Module (Figure 2). Two of the key genes in the Lipid Module include EL02 and EL03, that encode lipid elongases. Interestingly we found that Remdesivir, a standard of care antiviral for COVID-19, also targets EL03 upon H-Tech evaluation (Figure 3). Using the Lipid Module profile as a starting place, we then screened through several thousand drugs in our database and within just a few days we identified thirteen additional drugs (fifteen in total with amlodipine and felodipine) that we proposed would have anti virulence activity against SARS-CoV-2 (Table 1). Eight of the fifteen drugs are FDA approved, with six of these currently undergoing clinical evaluation for COVID-19 (including ivermectin, amiodarone, and fenofibrate). In addition to FDA approved compounds, we also identified additional preclinical and late-stage clinical drugs that target the Lipid Module, which include the key signature genes ACC1, ACB1, EL02, and EL03. These are currently being evaluated for preclinical activity against SARS- CoV-2 in animal studies.

[32] Table 1: Drugs/Compounds Identified As Potential Anti-Virulents

methoxyphenyljethyl)- 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-l,4-dihydrothieno[2,3- d]pyrimidin-3(2H)-yl)-2-methylpropanoic acid, CAS 1434641-55-0, also known as GS-834356.

† ND-646 IUPAC (R)-2-(l-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)- 5-methyl-6-(oxazol-2-yl)-2,4-dioxo-l,4-dihydrothieno[2,3-d]pyrimidin- 3(2H)-yl)-2-methylpropanamide, CAS 1434639-57-2

J PF-05175157 IUPAC l,4-Dihydro-l'-[(2-methyl-lH-benzimidazol-6-yl)carbonyl]-l- (l-methylethyl)-spiro[5H-indazole-5,4'-piperidin]-7(6H)-one, CAS 1301214-47-0

[33] We found that Remdesivir (RDV), the current SOC for COVID-19 treatment, also targeted EL03. As shown in Figure 3, RDV induced significant sensitivity (p-value = 10e-12) of strains deleted for EL03, a fatty acid elongase. Other RDV-sensitive deletion mutants form a coherent “biological module” and include genes involved in long-chain fatty acid synthesis (EL02), membrane biosynthesis (CSG2, YPK1, SAC1), and membrane trafficking (COG1, YPT31, SWA2). All gene names are from the SGD - www.veastgenome.org and refer to the cerevisiae genes. From our proprietary database, we know that EL03 is a principal component of the Lipid Module that also contains ACC1, ACB1 and EL02 as key signature genes.

[34] Referring to Figure 3, which shows Growth of Homozygous Knockout Strains in the presence of RDV, a pool of >4,800 individually barcoded single-gene deletion strains were grown in triplicate in both control media and in the presence of 2mM RDV for 5 cell divisions. Barcode sequencing was used to quantify the abundance of each of the 4800 strains in the total population. Strains with increased sensitivity to RDV show a log2 (fraction of population in control / fraction of population in drug) greater than 1. The EL03 knockout strain shows the greatest sensitivity to RDV. P-values for the results were calculated using the negative binomial distribution (similarly to the method of DESeq2 Wang L, Wang. X (2020). DEGseq: Identify Differentially Expressed Genes from RNA-seq data. R package version 1.42.0.) herein incorporated by reference for all purposes.

[35] The overall reaction for fatty acid elongation involves four enzymes that utilize malonyl CoA, NADPH, and fatty acyl CoA as substrates. The first step of the reaction, the condensation reaction, involves a family of seven fatty acid elongase subtypes in humans (ELOVLl-7). These enzymes have substrate specificity distinct from other elongases and together they comprise important regulators of cellular lipid functions. Elongases are conserved across evolution, for example, yeast EL02/EL03 double mutants are functionally complemented by human ELOVL1, ELOVL3 or ELOV7.

[36] Acetyl CoA Carboxylase “ACC” inhibitors have been shown to block viral replication in animals. Compounds such as 6-chloro-5-[4-(l-hydroxycyclobutyl)phenyl]-lH- indole-3 -carboxylic acid (PF-06409577; AMPK activator) and compounds PF- 06427878 (CAS 1809064-23-0) and PF-06865571 (Ervogastat, CAS 2186700-33-2) are believed to aid in preventing viral replication. Additional suitable compounds can be found in granted patent EP2836490B1 herein incorporated by reference for all purposes. From our database we identified four specific ACC inhibitors for further testing firsocostat (CAS 1434635-54-7), ND-654 (CAS 1434641-55-0), ND-646 (CAS 1434639-57-2) and PF-05175157 (CAS 1301214-47-0).

[37] A loss of Acyl-CoA-Binding Protein (ACBP in human, ACB1 in yeast), one of the key signature genes in the Lipid Module, reduces positive-strand RNA viral replication >90% in yeast.

[38] To gain a better perspective on the effects of the targeted CCBs on host cell biology, we compared the identified genome-wide fingerprint across -3,250 compounds, comprising millions of gene-drug interactions. The same functional module engaged by the specific CCBs (the Lipid Module) was observed in other treatments that disrupted fatty acid synthesis and cellular membrane production, including 8 FDA- approved therapies as shown in Table 1. Because these drugs target the Lipid Module (Figure 2) in a manner orthogonal to RDV profile (Figure 4), we anticipate that at least some of these agents will be synergistic with RDV and will enhance the efficacy of its primary Mechanism of Action (MO A), a hypothesis that we are actively testing.

[39] Figure 2 sets forth the relationship of genes within the Lipid Module impacted in viral replication, specifically SARS-COV-2 replication. This represents approximately 3000 Drug Response Matrices from our FI-Tech platform representing 30 million chemo- genomic interactions and 5000 Gene Response Matrices representing 900K genetic interactions. Chemo-genomic interactions are the individual measurements between each screened compound/drug and a specific gene. Gene Response Matrix is the gene- gene functional interactions for a specific gene perturbation such as is generated from our Y-Tech™ platform.

[40] The module is based on the co-fitness of the genotype. And the Lipid Module prioritizes genes based on their functional impact within the cell and highlights the system dynamics underlying complex diseases. From this we can identify functional targets with the highest likelihood of success.

[41] Further inspection of the core genes in this module, along with ancillary, related genes, highlights the link between the enzyme ACB1, two conserved fatty acid elongases, EL03 and EL02, and ACC1. Notably, deletion of ACB1 (homolog of human ACBP/DBI), substantially reduces RNA replication in a yeast model of viral replication (Zhang, J., Diaz, A., Mao, L., Ahlquist, P., & Wang, X. (2012) Host Acyl Coenzyme A Binding Protein Regulates Replication Complex Assembly and Activity of a Positive-Strand RNA Virus. Journal of Virology , 86(9), 5110-5121) herein incorporated by reference for all purposes. The role of lipids in Covid-19 infection and maintenance is also suggested by its increased morbidity in diabetic and obese patients.

[42] Supporting our identification of Remdesivir’s lipid component, it is noteworthy that very recently RDV was shown to attenuate high fat diet (HFD)-induced NAFLD (Nonalcoholic Fatty Liver Disease) by regulating hepatocyte dyslipidemia and inflammation via the suppression of STING (Stimulator of Interferon Genes) (Biochemical and Biophysical Research Communications, 526(2), 381-388) herein incorporated by reference. STING has an important role in innate immunity and induces the production of interferon when cells are infected by intracellular pathogens, and modulates Fads2 (fatty acid desaturase 2) activity. RDV has been shown to have dramatic effects on lipid metabolism in mouse models of viral infection. Moreover, our analysis of GS-441524 (CAS 1191237-69-0), the monophosphorylated form of the active metabolite, reveals no similar impact as RDV on lipid metabolism. Thus, it is likely that RDV, or one of the intermediate metabolites created during conversion to the active form, is responsible for its effects on lipid metabolism.

[43] Figure 5 shows a single strain analysis of EL03 knockout in the presence of RDV. The parental strain of yeast grows well in control media (dark gray) with a small shift in growth in the presence of RDV (medium gray). The EL03 knockout strain grows moderately well in control media (light gray), but its growth is severely inhibited in the presence of RDV (black). Cell growth is expressed as relative OD600, a measure of light absorption by cells and an established proxy for population density.

[44] Figure 6 shows a dose-response curve of EL03 knockout strain in the presence of RDV. The EL03 knockout strains show a strong dose response to RDV. Growth in the control (light gray), 250 uM (light gray), 500 uM (black), and 1000 uM (dark gray). [45] Genetic Networks’ Database of HOP profiles was screened for compounds that functionally inhibit the EL03 deletion strain (Table 2). Its rank illustrates how strongly the drug inhibits the EL03 deletion strain relative to all other strains screened with the drug. The tested concentration of the drug is reported. The “EL03 FD” score is the “fitness defect” of the EL03 strain in the drug. Fitness defect is a score that measures the relative abundance of each deletion strains and its sensitivity to drugs relative to control media. It is similar to the log2(ratio) of Figure 3 but calculated slightly differently due to differences in the experimental technology used to measure growth (barcode sequencing in Figure 1 and barcode microarray hybridization in Table 2.

[46] Table 2: Drugs that functionally inhibit the EL03 deletion strain

Rank Drug Cone. EL03 Drug description uM FD

[47] Other compounds useful for treating SARS-CoV-2 or other positive strand RNA viruses can be identified by screening for activity against the Lipid Module (Table 1). [48] Felodipine’s chemical name is 5-O-eihyl 3-O-meihyl 4-(2,3-dichlorophenyl)-2,6- dimethyl-L4-dihydropyridine-3,5-dicarboxylate. This drug is FDA approved and marketed as Plendil for treatment of hypertension. The Package Insert for Plendil is expressly incorporated by reference for all purposes. Felodipine can be safely dosed from 2.5mg-20 mg per day until the viral load is diminished. Felodipine is readily available at any pharmacy or chemical supply house.

[49] Lomerizine, l-[Bis(4-fluorophenyl)methyl]-4-[(2,3,4-trimethoxyphenyl)methyl] piperazine dihydrochloride (also known as KB-2796), is a diphenylpiperazine class L- type and T-type calcium channel blocker. This drug is currently used clinically for the treatment of migraines, while also being used experimentally for the treatment of glaucoma and optic nerve injury. Doses from l-20mg one or more times a day may be safely given orally or intravenously. Imai, Noboru; Konishi, Takashi; Serizawa, Masahiro; Okabe, Takashi (2007). "Do the Effects of Long-term Lomerizine Administration Differ with Age?". Internal Medicine. 46 (10): 683-684 herein incorporated by reference. Lomerizine is not approved in the US but can be purchased from chemical supply houses such as Sigma Aldrich and from Kanebo Ltd., 5-90, Tomobuchi-cho 1-chome, Miyakojima-ku, Osaka 534, Japan.

[50] Diclazuril, 2-(4-chlorophenyl)-2-[2,6-dichloro-4-(3,5-dioxo-2,3,4,5-tetrahydro-l,2,4- triazin-2-yl)phenyl]acetonitrile, is currently approved for use in animals but not humans. It has been tested in humans at 50-800mg per day. This drug is readily available from Merck and from chemical supply houses such as Sigma Aldrich.

[51] Amiodarone, 2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride, is FDA approved to treat arrhythmia and is sold under the Cordarone and Pacerone brands. It is routinely dosed between 100 and 600mg/ day. The package inserts for Cordarone and Pacerone are expressly incorporated by reference.

[52] Abamectin, ( 1 'R,2R,3S,4'S,6S,VR, 10Έ, 12'S, 13 A, 1 Έ, 16'£,207?,217?,24\S)-2-butan-2- yl-21 ',24'-dihydroxy- 12'-[(2A4,V,5ri,6A)-5-[(2k,4ri,5k,6A)-5-hydroxy-4-methoxy-6- methyloxan-2-yl]oxy-4-methoxy-6-methyloxan-2-yl]oxy-3,ir,13',22'- tetramethylspiro[2,3-dihydropyran-6,6'-3,7,19-trioxatetracyclo[15.6.1.14,8.020,24] pentacosa-10,14,16,22-tetraene]-2'-one, is widely used as an insecticide and anthelmintic. It can be purchased from chemical supply houses such as Sigma Aldrich. Abamectin has been dosed 5 mg/kg. i.p. for treatment of alcoholism. Khoja S, Huynh N, Wamecke AMP, Asatryan L, Jakowec MW, Davies DL. Preclinical evaluation of avermectins as novel therapeutic agents for alcohol use disorders. Psychopharmacology (Berl). 2018;235(6): 1697-1709. doi:10.1007/s00213-018-4869-9 herein incorporated by reference.

[53] Ivermectin, (lR,4S,5'S,6R,6'R,8R,10E,12S,13S,14E,16E,20R,21R,24S)-6'-[(2S)- butan-2-yl]-21,24-dihydroxy-12-[(2R,4S,5S,6S)-5-[(2S,4S,5S,6S)-5-hydroxy-4- methoxy-6-methyloxan-2-yl]oxy-4-methoxy-6-methyloxan-2-yl]oxy-5', 11,13,22- tetramethylspiro[3,7,19-trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22- tetraene-6,2'-oxane]-2-one, is believed that it will have significant activity against COVID-19. Ivermectin is typically dosed from 0.15-0.2 mg/kg with doses as high as 6 mg given when treating some diseases. See, stromectol package insert. Recently two retrospective studies have been published confirming our data on ivermectin.

[54] Table 3 below summarizes the retrospective study published as Saiful Islam Khan, Sakirul Islam Khan,” Chitto Ranjan Debnath^c, Progga Nanda Nath³, Mamun A1 Mahtab^d, Hiroaki Nabeka^b, Seiji Matsuda^b, Sheikh Mohammad Fazle Akbar⁶ Ivermectin Treatment May Improve the Prognosis of Patients With COVID-19, Archivos de Bronconeumologia https ://www. archbronconeumol or / es-estadi sticas- S030028962030288X herein incorporated by reference.

[55] TABLE 3: Ivermectin

[56] Table 4 below summarizes the data published in Rajter, Juliana Cepelowicz and Sherman, Michael S. and Fatteh, Naaz and Vogel, Fabio and Sacks, Jaime and Rajter, Jean-Jacques, ICON (Ivermectin in COvid Nineteen) Study: Use of Ivermectin Is Associated with Lower Mortality in Hospitalized Patients with COVID-19 (6/16/2020). Available at

SSRN: https://ssrn.com/abstract=3631261 or http://dx.doi.org/10.2139/ssrn.3631261 https://www.archbronconeumol.org/es-estadisticas-S03002896203Q288X herein incorporated by reference. [57] TABLE 4: Ivermectin

[58] Idebenone, (CAS58186-27-9) has been used for treatment of Alzheimer’s disease at doses of 10-900 mg per day given as single and divided doses. It is available from Takeda Pharmaceuticals and from chemical supply houses such as Sigma Aldrich.

[59] Salinomycin (2R)-2-[(5S,6R)-6-[(lS,2S,3S,5R)-5-[(2S,5R,7S,9S,10S,12R,15R)-2- [(2R,5R,6S)-5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl]-15-hydroxy-2,10,12- trimethyl-l,6,8-trioxadispiro[4.1.5^A{7}.3^A{5}]pentadec-13-en-9-yl]-2-hydroxy-l,3- dimethyl-4-oxoheptyl]-5-methyl-2-tetrahydropyranyl]butanoic acid Salinomycin can be dosed intravenous administrations of 0.5 to 5 mg/kg per day in single or divided doses. Doses of 250 /g kg^-1 delivered daily, every other day, every three days, every four days, every five days, every six days or once a week may be effective. This drug is in preclinical development for cancer by Hillstream biopharma as HSB-1216. The bulk drug can be purchased from APEXBIO as Catalog No. A3785 at apexbt.com. Apex bio has offices at 7505 Fannin Street, Suite 410, Houston, TX 77054.

[60] Benidipine, 05-methyl 03-[(3f?)-l-(phenylmethyl)piperidin-3-yl] 2,6-dimethyl-4-(3- nitrophenyl)-l,4-dihydropyridine-3,5-dicarboxylate. It inhibits L-, N- and T-type Ca²⁺ channels. Dosing. It is approved for dosing at 2mg-8mg a day in Japan and elsewhere in Asia. Hiromichi Suzuki and Takao Saruta, Benidipine, Cardiovascular Drug Reviews Vol. 7, No. 1, pp. 25-38 0 1989 Raven Press, Ltd., New York

[61] It is believed that the class of drugs known as calcium channel blockers will be effective in treating SARS-CoV 2. Suitable calcium channel blockers can be selected from the dihydropyridine calcium channel blockers such as amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine; the non-hydropyridine calcium channel blockers such as phenylalkylamine: fendiline, gallopamil, verapamil; the benzothiazepine calcium channel blockers such as diltiazem; the non-selective calcium channel blockers such as mibefradil, bepridil, flunarizine, fluspirilene, and fendiline; the gabapentinoids such as gabapentin and pregabaline; and the N-type calcium channel blockers such as ziconotide; and diphenylpiperazine class L-type and T-type calcium channel blockers such as lomerizine. These drugs are all marketed and can be safely used at dosages provided for in their official package inserts, the contents of which are expressly incorporated by reference herein.

[62] Heparin may also be useful alone or in combination with the compounds disclosed herein for treatment of SARS-CoV-2. Heparin is dosed in accordance with published prescribing information such as provided in the package insert in heparin sodium injection sold by Pfizer Laboratories Division of Pfizer Inc

[63] The class of drugs known as Acetyl-CoA carboxylase 1 (ACC1) inhibitors are also believed to be inhibitors of SARS-COV-2 replication. ACC1 inhibitors are disclosed in US patents 7981904B2 and 6,979,741 B2 herein incorporated by reference for all purposes. In particular, the ACC inhibitors known as firsocostat (ND-630, GS-0976, CAS 1434635-54-7) 1 ,4-dihydro- l-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H- pyran-4-yl)oxy]ethyl] -a,a,5-trimethyl-6-(2-oxazolyl)-2,4-dioxo-thieno[2,3- d]pyrimidine-3(2H)-acetic acid; 2-[l-[2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5- methyl-6-(l,3-oxazol-2-yl)-2,4-dioxo-lH,2H,3H,4H-thieno[2,3-d]pyrimidin-3-yl]-2- methylpropanoic acid; ND-646 2-[l-[(2i?)-2-(2-methoxyphenyl)-2-(oxan-4- yloxy)ethyl]-5-methyl-6-(I,3-oxazol-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-3-yl]-2- methylpropanamide (CAS 1434639-57-2) and ND-654 (CAS 1434641-55-0) a derivative of firsocostat. Firsocostat and derivatives of firsocostat are disclosed in published PCT applications W02013071169A1 W02017075056A1,

W02017091602A1, W02017091600A1, W02017091617A1 each one herein incorporated by reference. Enantiomers of these compounds, particularly the S enantiomer may have improved activity. Firsocostat can be dosed from 20-200mg. Stiede K, Miao W, Blanchette HS, et al. Acetyl -coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double-blind, crossover study . Hepatology. 2017;66(2):324-334. doi: 10.1002/hep.29246 herein incorporated by reference.

[64] The known ACC inhibitors Olumacostat glasaretil (CAS 1261491-89-7); TOFA (CAS 54857-86-2); ND-646 (CAS 1434639-57-2); RS 79948 hydrochloride (CAS 186002- 54-0); andPF-05175157 (CAS 1301214-47-0) are likely to have activity against SARS- CoV-2.

[65] ACC inhibitors, such as PF-05175157, have been shown to reduce platelet synthesis in humans by blocking de novo lipid synthesis, which could be beneficial in COVID-19 cases by preventing the formation of microclots.

[66] It is believed that antibodies can be generated to inhibit ACC1 using conventional techniques well known in the art.

[67] Fenofibrate, propan-2-yl 2-[4-(4-ehlorobenzoyi)phenoxy]-2-methylpropanoate, is a drug known to increase lipid oxidation and reduce triglycerides. Recently, fenofibrate has been correlated to reductions in mortality in a small cohort of COVID-19 patients. Fenofibrate was also reported to inhibit SARS-CoV-2 viral replication in primary lung cells. Currently fenofibrate is in clinical trials for COVID-19.

[68] The above drugs can be administered alone, in combination with each other or in combination with one or more antiviral drugs. Known antivirals include but are not limited to: abacavir used for HIV, acyclovir (Aciclovir) is used for herpes e.g. chicken pox, adefovir used for chronic hepatitis b, amantadine used for influenza, ampligen, amprenavir (Agenerase) used for inhibition of HIV, arbidol, atazanavir used for HIV, atripla (fixed dose drug) used for HIV, balavir, baloxavir marboxil (xofluza) used for treating influenza, biktarvy used for HIV, boceprevir (Victrelis) used for hepatitis c, cidofovir, cobicistat (Tybost), Combivir (zidovudine + lamivudine fixed dose drug) used for hiv, daclatasvir (Daklinza), darunavir, delavirdine, descovy used for hepatitis b, didanosine used for hiv, docosanol, dolutegravir, doravirine (Pifeltro), ecoliever, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine (intelence), famciclovir, fixed dose combination (antiretroviral), fomivirsen, fosamprenavir, foscarnet, fosfonet, fusion inhibitor, ganciclovir (Cytovene), ibacitabine, ibalizumab (Trogarzo), idoxuridine, imiquimod, imunovir, indinavir, inosine, integrase inhibitor, interferon type i, interferon type ii, interferon type iii, interferon, lamivudine, letermovir (Prevymis), lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfmavir, nevirapine, nexavir, nitazoxanide, norvir, nucleoside analogues, oseltamivir (Tamiflu), peginterferon alfa-2a, peginterferon alfa- 2b, penciclovir, peramivir (Rapivab), pleconaril, podophyllotoxin, protease inhibitor (pharmacology), pyramidine, raltegravir, remdesivir, reverse transcriptase inhibitor, ribavirin, rilpivirine (edurant), rimantadine, ritonavir, saquinavir, simeprevir (Olysio), sofosbuvir, stavudine, synergistic enhancer (antiretroviral), telaprevir, telbivudine (Tyzeka), tenofovir alafenamide, tenofovir disoproxil, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir (Valtrex), valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir (Relenza), zidovudine, sotrovimab, baricitinib, tocilizumab, casirivimab and imdevimab (REGEN-COV), bamlanivimab and etesevimab, PF-00835231, rupintrivir, 3CLpro-l, carmofur, ebselen, GC376, PF- 07304814, and PF-07321332. These compounds can be administered in combination with drugs of the present invention as per their package inserts or dosing as described in the medical or scientific literature.

[69] The EL03 response modifiers disclosed herein can also be co-administered with dexamethasone 9-fluoro-lip, 17, 21 -trihydroxy- 16a-methylpregna-l, 4-diene, 3, 20- dione at dosages from 0.75 to 30 mg per day as per the dexamethasone package insert herein incorporated by reference.

[70] The EL03 response modifiers disclosed herein can be co-administered with chloroquine drugs. Dosing is believed to be 200mg-600mg per day for hydroxychloroquine and 250-600mg per day for chloroquine.

[71] Favipiravir can be dosed from 400-1200 mg.

[72] One of skill in the art will appreciate that the compounds disclosed herein can be delivered through any known route suitable for the particular composition. Oral and intravenous are preferred routes. Dosing can be given as a bolus or divided into 2, 3, 4 or more doses per day. Dosing can be daily, every other day, every three days, every 4 days, every 5 days, every 6 days or once a week. Treatment can be given for 1, 2,3, 4 or more weeks or until the patient is symptom free.

[73] Doses of the compounds disclosed herein can be given as therapeutics or as preventative s. Prevention doses are often lower than the therapeutic dose and may be 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70% 80% or 90% of the therapeutic dose.

[74] Dosing may be administered initially as a bolus with subsequent smaller doses to maintain therapeutic levels.

[75] Combination therapies may require lesser dosing than a monotherapy with the individual drugs of the combination.

[76] The treatments disclosed herein are believed to be useful in treating any positive strand RNA virus. It is believed to be most effective in the enveloped capsid viruses selected from the Flaviviridae, Togaviridae, Arteriviridae and Coronaviridae families. The present invention is also believed to be useful in treating non-enveloped capsid viruses selected from the Picomaviridae, Caliciviridae and Hepeviridae families.

[77] In particular, the present invention is believed to be effective against the Coronavirus family including but not limited to: Genus Alphacoronavirus which includes Alphacoronavirus 1, Human coronavirus 229E, Human coronavirus NL63, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Porcine epidemic diarrhea virus, Rhinolophus bat coronavirus HKU2 and Scotophilus bat coronavirus 512 species; the genus Betacoronavirus including Murine coronavirus (MHV): Betacoronavirus 1 (Bovine Coronavirus, Human coronavirus OC43), Hedgehog coronavirus 1, Human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus, Murine coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome-related coronavirus (SARS-CoV, SARS-CoV-2) and Tylonycteris bat coronavirus HKU4 species; the Gammacoronavirus genus which includes; Avian coronavirus and Beluga whale coronavirus SW1 species and the Deltacoronavirus genus which includes Bulbul coronavirus HKU11 and porcine coronavirus HKU15 species.

[78] One of skill in the art will understand that the classes of compounds disclosed herein, and the named viruses, are not complete and that analogs and derivatives of the compositions disclosed herein may also be used against the disclosed viral families.

[79] Example 2: Synergistic Combinations for Treatment of Coronavirus

[80] It has been surprisingly discovered that the compounds disclosed in Example 1 act synergistically with remdesivir to clear SARS-CoV-2.

[81] Remdesivir can be administered as shown in the package insert for Veklury ® herein incorporated by reference. For adults and pediatric patients >12 years old and weighing >40 kg: 200 mg on Day 1, followed by once-daily maintenance doses of 100 mg from Day 2 administered only via intravenous infusion over 30 to 120 minutes.

[82] Drug synergy can be defined in many different ways, and while there is no true consensus, a leading model for determining synergy is the so-called Bliss multiplicative model. If one wants to test for synergy using the Bliss model, you need to first determine the effect of each individual agent. Synergy is then tested by assembling a matrix where a dilution series of drug A is prepared on one axis and a dilution series of the second drug (B) is prepared on the second axis to build a synergy matrix. Next one scores the growth across the matrix and looks for combinations that are greater than the multiplication of the effect of drug Y and drug X (Figures 7 and 8A-D).

[83] You can quantify growth in many ways. For the majority of our assays, we convert growth inhibition as a value between 0 (no inhibition) and 1 total inhibition (no growth).

[84] The synergy assay was described in a 2013 publication: Torres NP, Lee AY, Giaever

G, Nislow C, Brown GW. A high-throughput yeast assay identifies synergistic drug combinations. Assay Drug Dev Technol. 2013 ; 11(5):299-307. doi:10.1089/adt.2012.503 herein incorporated by reference.

[85] The platform was developed to assess synergy and antagonism of drug combinations using growth inhibition of yeast as our metric. Dose response experiments were first performed for each to determine the concentrations that produce inhibitory concentrations of 5%, 10%, 20% 30% and 40% (IC5, IC10, IC20, IC30, and IC40). These concentrations provide a wide dynamic range of growth inhibition for observing synergy and antagonism, and were within the solubility limit for each drug. These concentrations of each drug are then tested in all possible pairwise combinations in arrays of 36 doses. In this format, the 2% DMSO control is at the top-left well and single-drug treatments are in the topmost row and leftmost column. Two such arrays can be analyzed on one 96-well plate. Saturated cultures of yeast cells were diluted and added to all wells of the plate. We measured growth via optical density (OD) readings collected every 15 minutes for 24h, or the equivalent of 5 generations of growth, using a temperature controlled shaking spectrophotometer.

[86] The growth data were processed and plotted as heat maps of inhibition and deviation from the null expectation. The null expectation is based on the multiplicative (Bliss) mode which states that a non- synergistic combination of drugs inhibits growth as much as the product of the inhibition caused by each drug alone. The Bliss model, while an approximation, is an established model and has been used extensively to study synergy. A script in R was written to process the growth curves in several steps: 1) growth curves were normalized to background ODs and OD readings past the saturation time point were set to a single saturation OD value, 2) For each array of 36 treatments, the area under the curve (AUC) was calculated for all wells and normalized to the area of the DMSO control, 3) The inhibition (deviation from the null expectation) values were calculated from the AUC values and displayed as a heat map (Figure 8D). [87] Of the compounds identified in Example 1, 2 compounds showed clear synergistic effects with RDV, lomerizine and ivermectin. The matrix data for lomerizine and remdesivir is shown in Figure 9. Given the safety profile of lomerizine, a CCB used for migraine, a clinical trial of this combination is warranted.

[88] The compounds disclosed herein can be used in combination with any standard of care therapeutic. The standard of care changes based on clinical data and evidence of standard of care and the recommended therapeutics can be found in medical society at the CDC (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance- management-patients.html), the Infectious Disease Society of America (https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and- management/), the National Institutes of Health

(https://www.covidl9treatmentguidelines.nih.gov/about-the-guidelines/whats-new/); the Mayo Clinic (https://www.mayoclinic.org/diseases- conditions/coronavirus/diagnosis-treatment/drc-20479976), the American Medical Association (https://www.ama-assn.org/delivering-care/public-health/covid-19-2019- novel-coronavirus-resource-center-physicians) among others. One of skill in the art will know how to locate the current standard of care in a given country or state.

[89] The compounds disclosed in Example 1 can be administered in combination with a Standard of Care therapeutic. In particular, these compounds can be administered with antiviral antibodies such as sotrovimab, baricitinib, tocilizumab, casirivimab and imdevimab (REGEN-COV), bamlanivimab and etesevimab.

[90] ND-646 can be given alone or in combination with the EL03 and ACC1 inhibitors disclosed herein. In particular, ND-646 is expected to be synergistic with remdesivir, salinomycin and ivermectin. It is expected that ND-646 will be synergtistic with any standard of care therapeutic.

[91] The inventors have observed synergy between salinomycin and remdesivir, Salinomycin and EIDD-1931, firsocostat and remdesivir, and firsocostat and EIDD- 1931 in initial testing. This synergy is being furthered tested using methods disclosed herein. [92] EXAMPLE 3: Anti- Viral Testing

[93] Based on the predictions herein, 3 compounds, remdesivir, firsocostat and GS-834356 were submitted to a contract research organization for testing in pre-plated 96-well plates to result in final serial dilutions of 10 - 0.0015 mM.

[94] A549-hACE2 cells were seeded in separate 96-well plates and incubated overnight. The next day, live SARS-CoV-2 virus and compounds diluted in media as described above were added to the cultures and incubated. After 48h, Nanoluc™ luciferase from Promega was added to the wells and the photo counts per second were measured.

[95] The EC50 (amount of drug required to reduce viral load 50%) and the CC50 (the cytotoxic concentration required to reduce cell viability by 50%) were measured. CC50 was also tested in MT4 cells. SI (Selectivity Index) is a ratio that measures the window between cytotoxicity and antiviral activity by dividing the EC 50 value into the CC50 value.

[96] The results are set forth in Table 5 below:

[97] TABLE 5: Antiviral activity.

[98] The results are graphed in Figure 10. The data shows that GS-834356 (ND-654) and firsocostat have greater antiviral efficacy than remdesivir as evidenced by the lower doses required to reach the EC50. Similarly, they are less cytotoxic as evidenced by the CC50. This gives them a surprisingly greater SI which means they should be safer than remdesivir.

[99] Because the results of the initial screen showed so much promise for treatment of COVD-19, the additional compounds of Table 6 were submitted for analysis. Remdesivir and Firsocostat were included a second time. The results are shown in Table 6 below. [100] Table 6: Antiviral Activity

[101] ND-646 (CAS 1434639-57-2) was tested in a female Balb/c mouse model for SARS- CoV-2. Mice were infected with SARS-CoV-2 MA10 at 10⁴ PFU intranasally. Treatment with ND-646 was started one day prior to infection and continued two days post infection (BID, oral). Virus lung titers at two days post infection showed a reduction in median viral RNA loads by 0.69 logio. There was minimal weight loss observed in the treatment group as compared to the control group. These results support our findings that ND-646 can function as an antiviral in addition to our prediction of ND-646 being an anti-virulent.

[102] These data show firsocostat, ND-646, salinomycin and Pfizer compound PF-05175157 are likely to be safe and effective against SARS-COV-2. All compounds listed show an effect against SARS, and merit follow-up (as indicated in the ivermectin retrospective data). Using the methods herein one of skill in the art can predict the likelihood of efficacy of an antiviral drug against SARS-COV-2 using the A549- hACE2 cell assay used herein. One aspect of the invention provides a method of treating a positive-strand RNA virus infection in a patient in need thereof comprising the administration of a compound which inhibits fatty acid synthesis through the Lipid Module containing EL03, ACB1, EL02 and ACC1. In another aspect of the invention more than one EL03 effector is administered. In another aspect the virus is selected from enveloped and non-enveloped capsid positive strand RNA viruses. The non- enveloped capsid virus can be selected from Picomaviridae, Caliciviridae and Hepeviridae. The enveloped capsid viruses are selected from Flaviviridae, Togaviridae, Arteriviridae and Coronaviridae. In another aspect of the invention the coronavirus is selected from Genus Alphacoronavirus which includes Alphacoronavirus 1, Human coronavirus 229E, Human coronavirus NL63, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Porcine epidemic diarrhea virus, Rhinolophus bat coronavirus HKU2 and Scotophilus bat coronavirus 512 species; the genus Betacoronavirus including Murine coronavirus (MHV): Betacoronavirus 1 (Bovine Coronavirus, Human coronavirus OC43), Hedgehog coronavirus 1, Human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus, Murine coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome-related coronavirus (SARS-CoV, SARS-CoV-2) and Tylonycteris bat coronavirus HKU4 species; the Gammacoronavirus genus which includes; Avian coronavirus and Beluga whale coronavirus SW1 species and the Deltacoronavirus genus which includes Bulbul coronavirus HKU11 and Porcine coronavirus HKU15 species. In another aspect of the invention the treating of a positive-strand RNA virus infection in a patient in need thereof the composition is selected from two or more of the following compounds felodipine, lomerizine, diclazuril, amiodarone, abamectin, idebenone, firsocostat, ivermectin, PF-05175157, amlodipine, benidipine, ND-646, ND-654, nifedipine, fenofibrate or salinomycin.

[103] In another aspect of the invention a patient with a viral infection is given a therapeutically effective amount of at least one compound selected from calcium channel blockers, felodipine, lomerizine, diclazuril, amiodarone, abamectin, idebenone, firsocostat, PF-05175157, amlodipine, benidipine, ND-646, ND-654, nifedipine, fenofibrate or salinomycin. In another aspect of the invention the calcium channel blockers are selected from the dihydropyridine calcium channel blockers, the non hydropyridine calcium channel blockers, the benzothiazepine calcium channel blockers, the non-selective calcium channel blockers, the gabapentinoids, and the N- type calcium channel blockers. In another aspect of the invention the dihydropyridine calcium channel blockers are selected from amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine. In another aspect of the invention the non hydropyridine calcium channel blockers are selected from the phenylalkylamine calcium channel blockers. In another aspect of the invention the phenyalkylamine calcium channel blockers are selected from fendiline, gallopamil, and verapamil. In another aspect of the invention the benzothiazepine calcium channel blockers are selected from diltiazem. In another aspect of the invention the non-selective calcium channel blockers are selected from mibefradil, bepridil, flunarizine, fluspirilene, and fendiline. In another aspect of the invention the gabapentinoids are selected from gabapentin and pregabaline. In another aspect of the invention the N-type calcium channel blockers are selected from ziconotide.

[104] Another aspect of the invention provides a method of inhibiting viral replication in a patient in need thereof comprising the administration of a therapeutically effective amount of an Acetyl-CoA carboxylase inhibitor. In another aspect of the invention the Acetyl-CoA carboxylase inhibitor is selected from firsocostat or derivatives thereof, Olumacostat glasaretil (CAS 1261491-89-7); TOFA(CAS 54857-86-2); ND-646 (CAS 1434639-57-2); firsocostat (ND-630) (CAS 1434635-54-7) andND-630 S enantiomer); RS 79948 hydrochloride (CAS 186002-54-0); PF-05175157 (CAS 1301214-47-0); ND-654 (GS-834356); or antibodies to Acetyl-CoA carboxylase.

[105] Another aspect of the invention involves treating a coronavirus infection comprising administration of remdesivir together with a calcium channel blocker, salinomycin, or an avermectin. Another aspect of the invention involves treating a coronavirus infection comprising administration of a calcium channel blocker as described herein. In another aspect of the invention the avermectin is ivermectin.

[106] In another aspect of the invention a method of treating a coronavirus infection involves administration of ND-646 together with a calcium channel blocker, salinomycin or an avermectin. In another aspect of the invention the calcium channel blocker is selected from the calcium channel blockers described herein. In another aspect of the invention the avermectin is ivermectin. In another aspect of the invention with the methods of treatment described above the compositions and compounds can be administered with one or more antiviral compounds selected from: abacavir, acyclovir, adefovir, amantadine, ampligen, amprenavir, arbidol, atazanavir, atripla, balavir, baloxavir marboxil, biktarvy, boceprevir, cidofovir, cobicistat, combivir, daclatasvir, darunavir, delavirdine, descovy , didanosine, docosanol, dolutegravir, doravirine, ecoliever, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, fusion inhibitors, ganciclovir, ibacitabine, ibalizumab, idoxuridine, imiquimod, imunovir, indinavir, inosine, integrase inhibitors, interferon type i, interferon type ii, interferon type iii, interferon, lamivudine, letermovir, lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfmavir, nevirapine, nexavir, nitazoxanide, norvir, nucleoside analogues, oseltamivir, peginterferon alfa-2a, peginterferon alfa-2b, penciclovir, peramivir, pleconaril, podophyllotoxin, pyramidine, raltegravir, remdesivir, reverse transcriptase inhibitors, ribavirin, rilpivirine, rimantadine, ritonavir, saquinavir, simeprevir, sofosbuvir, stavudine, synergistic enhancers, telaprevir, telbivudine, tenofovir alafenamide, tenofovir disoproxil, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir and zidovudine.

[107] The invention also provides a method for identifying drugs for treating viral infections in a mammal comprising screening compounds for activity against EL03 or genes in its associated functional module, such as ACC1, ACC2, ACB1, and EL02. In another aspect of the invention the virus is a coronavirus. In another aspect of the invention the coronavirus is SARS CoV 2.

[108] The invention also provides a method of preventing infection or reducing the severity of a positive strand RNA virus infection in a patient in need thereof comprising the administration of a compound which inhibits fatty acid synthesis identified through the functional module described above containing EL03. In another aspect of the invention the RNA virus is selected from enveloped and non-enveloped capsid positive strand RNA viruses. In another aspect of the invention the non-enveloped capsid viruses are selected from Picomaviridae, Caliciviridae and Hepeviridae. In another aspect of the invention the enveloped capsid viruses are selected from Flaviviridae, Togaviridae, Arteriviridae and Coronaviridae. In another aspect of the invention the coronaviruses are selected from the coronaviruses described in paragraph 77. The compositions used in preventing infection or reducing the severity of a positive strand RNA virus infection in a patient is selected from one or more of the following compounds felodipine, lomerizine, diclazuril, amiodarone, abamectin, idebenone, salinomycin, or Lorenzo’s Oil.

[109] The invention also provides a method of preventing or reducing the severity of an RNA virus infection by inhibiting viral replication in a patient in need thereof comprising the administration of a therapeutically effective amount of at least one calcium channel blockers. In another aspect of the invention the calcium channel blockers are described herein.

[110] The invention also provides a method of preventing or reducing the severity of an RNA virus comprising inhibiting viral replication in a patient in need thereof by administering a therapeutically effective amount of an Acetyl-CoA carboxylase inhibitor. In another aspect of the invention the Acetyl-CoA carboxylase inhibitor is selected from firsocostat or derivatives thereof, Olumacostat glasaretil (CAS 1261491- 89-7); TOFA (CAS 54857-86-2); ND-646 (CAS 1434639-57-2); ND-630 (CAS 1434635-54-7) and ND-630 S enantiomer); RS 79948 hydrochloride (CAS 186002-54- 0); PF-05175157 (CAS 1301214-47-0) or antibodies to Acetyl-CoA carboxylase.

[111] The invention also provides a method of preventing or reducing the severity of an RNA virus infection comprising administration of an effective amount of remdesivir together with a calcium channel blocker, salinomycin or an avermectin. The invention also provides a method selected from the calcium channel blockers described herein. The method of the invention provides the dosage wherein the lomerizine is dosed at l-20mg one or more times per day and the remdesivir is dosed 100-200mg once per day. In another aspect of the invention the avermectin is ivermectin.

[112] The methods of treatment, prevention and propholaxsis describes can include the use of one or more antiviral compounds selected from: abacavir, acyclovir, adefovir, amantadine, ampligen, amprenavir, arbidol, atazanavir, atripla, balavir, baloxavir marboxil, biktarvy, boceprevir, cidofovir, cobicistat, combivir, daclatasvir, darunavir, delavirdine, descovy didanosine docosanol, dolutegravir, doravirine, ecoliever, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscamet, fosfonet, fusion inhibitors ganciclovir, ibacitabine, ibalizumab, idoxuridine, imiquimod, imunovir, indinavir, inosine, integrase inhibitor, interferon type i, interferon type ii, interferon type iii, interferon, lamivudine, letermovir, lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfmavir, nevirapine, nexavir, nitazoxanide, norvir, nucleoside analogues, oseltamivir, peginterferon alfa-2a, peginterferon alfa-2b, penciclovir, peramivir, pleconaril, podophyllotoxin, pyramidine, raltegravir, remdesivir, reverse transcriptase inhibitor, ribavirin, rilpivirine, rimantadine, ritonavir, saquinavir, simeprevir, sofosbuvir, stavudine, synergistic enhancer, telaprevir, telbivudine, tenofovir alafenamide, tenofovir disoproxil, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir and zidovudine.

[113] The invention also includes a method of identifying drugs for treating viral infections in a mammal comprising screening compounds for activity against EL03 or genes in its associated functional module, such as ACC1, ACC2, ACB1, and EL02. In another aspect of the invention the virus is a coronavirus. In another aspect of the invention the corona virus is SARS-CoV-2.

[114] The invention also provides for drugs for treating SARS-COV-2 infections identified by screening compounds for activity against EL03 or genes in its associated functional module, such as ACC1, ACC2, ACB1, and EL02.

[115] The invention also provides a method of treating a coronavirus infection comprising the administration of ND-646 to a patient in need thereof. The invention also includes the administration of at least one compound selected from Salinomycin, Amlodipine, Ivermectine, Lomerizine, Amiodaron, PF-05175157, Firsocostat, Fenofibrate, Nifedipine and EIDD-1931 (P-D-N4-hydroxycytidin) with ND-646 to a patient in need thereof. In another aspect of the invention Salinomycin is administered with ND-646, Amlodipine is administered with ND-646, Lomerizine is administered with ND-646, Amiodaron is administered with ND-646, PF-05175157 is administered with ND-646 Firsocostat, is administered with ND-646. Fenofibrate is administered with ND-646, Nifedipine is administered with ND-646, and EIDD-1931 is administered with ND- 646. In another aspect of the invention ND-646 or ND-646 and at least one compound selected from Salinomycin, Amlodipine, Ivermectin, Lomerizine, Amiodarone, PF- 05175157, Firsocostat, Fenofibrate, Nifedipine and EIDD-1931 is administered with at least one compound selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, ampligen, amprenavir, arbidol, atazanavir, atripla, balavir, baloxavir marboxil, biktarvy, boceprevir, cidofovir, cobicistat, combivir, daclatasvir, darunavir, delavirdine, descovy didanosine docosanol, dolutegravir, doravirine, ecoliever, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscamet, fosfonet, fusion inhibitors ganciclovir, ibacitabine, ibalizumab, idoxuridine, imiquimod, imunovir, indinavir, inosine, integrase inhibitor, interferon type i, interferon type ii, interferon type iii, interferon, lamivudine, letermovir, lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfmavir, nevirapine, nexavir, nitazoxanide, norvir, nucleoside analogues, oseltamivir, peginterferon alfa-2a, peginterferon alfa-2b, penciclovir, peramivir, pleconaril, podophyllotoxin, pyramidine, raltegravir, remdesivir, reverse transcriptase inhibitor, ribavirin, rilpivirine, rimantadine, ritonavir, saquinavir, simeprevir, sofosbuvir, stavudine, synergistic enhancer, telaprevir, telbivudine, tenofovir alafenamide, tenofovir disoproxil, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir and zidovudine.

[116] Definitions

[117] Dihydropyridine calcium channel blockers are defined as derivatives of 1,4- dihydropyridine that are used as L-type calcium channel blockers with the majority of their activity being as arterial-specific vasodilators of peripheral resistance that cause generalized vasodilation.

[118] The non-hydropyridine calcium channel blockers are defined as two classes of calcium channel blockers, phenylalkylamine and benzothiazepine.

[119] The phenylalkylamine calcium channel blockers are defined as those

Phenyla!ky!amines which block the L-type calcium current in an use-dependent manner from the intracellular side of the membrane.

[120] The benzothiazepine calcium channel blockers, are defined as those calcium channel blockers having a benzothiazipine ring.

[121] The non-selective calcium channel blockers are defined as those calcium channel blockers which are not primarily limited to cardiovascular effects.

[122] The gabapentinoids are a a class of drugs that are derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) (i.e., GABA analogues) which block o^d subunit-containing voltage-dependent calcium channels.

[123] The N-type calcium channel blockers are defined as Ca(v)2.2 voltage-gated calcium channel (V GCC) inhibitors

[124] The diphenylpiperazine class L-type and T-type calcium channel blockers are defined as calcium channel blockers which are derivative of diphenlypiperizine.

[125] A Chemical Abstracts number is a unique identifier given to a chemical compound. One of ordinary skill in the art would understand that this number can be used with the printed volumes of Chemical Abstracts or Scifmder, an online service of Chemical Abstracts and the American Chemical Society, to identify the name and structure of the compound so identified. Acifmder and Chemical Abstracts will also cite the scientific articles and patents where the compound can be found. In this application the CAS number is usually designated as (CAS followed by the number).

Claims

We claim:

1. A method of treating a positive-strand RNA virus infection in a patient in need thereof comprising the administration of a compound which inhibits fatty acid synthesis through the Lipid Module containing EL03, ACB1, EL02 and ACC1.

2. The method of claim 1, wherein the RNA virus is selected from enveloped and non- enveloped capsid positive-strand RNA viruses.

3. The method of claim 2, wherein the non-enveloped capsid viruses are selected from Picornaviridae, Caliciviridae and Hepeviridae

4. The method of claim 2, wherein the enveloped capsid viruses are selected from Flaviviridae, Togaviridae, Arteriviridae and Coronaviridae.

5. The method of claim 4, wherein the coronavirus is selected from Genus Alphacoronavirus which includes Alphacoronavirus 1, Human coronavirus 229E, Human coronavirus NL63, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Porcine epidemic diarrhea virus, Rhinolophus bat coronavirus HKU2 and Scotophilus bat coronavirus 512 species; the genus Betacoronavirus including Murine coronavirus (MHV): Betacoronavirus 1 (Bovine Coronavirus, Human coronavirus OC43), Hedgehog coronavirus 1, Human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus, Murine coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome-related coronavirus (SARS-CoV, SARS-CoV-2) and Tylonycteris bat coronavirus HKU4 species; the Gammacoronavirus genus which includes ; Avian coronavirus and Beluga whale coronavirus SW 1 species and the Deltacoronavirus genus which includes Bulbul coronavirus HKL111 and Porcine coronavirus HKU 15 species.

6. The method of claim 1, wherein the composition is selected from two or more of the following felodipine, lomerizine, diclazuril, amiodarone, abamectin, idebenone, firsocostat, ivermectin, PF-05175157, amlodipine, benidipine, ND-646, ND-654, nifedipine, fenofibrate or salinomycin.

7. A method of inhibiting viral replication in a patient in need thereof comprising the administration of a therapeutically effective amount of at least one compound selected from calcium channel blockers, felodipine, lomerizine, diclazuril, amiodarone, abamectin, idebenone, firsocostat, PF-05175157, amlodipine, benidipine, ND-646, ND-654, nifedipine, fenofibrate or salinomycin.

8. The method of claim 7, where in the calcium channel blockers are selected from the dihydropyridine calcium channel blockers, the non-hydropyridine calcium channel blockers, the benzothiazepine calcium channel blockers, the non-selective calcium channel blockers, the gabapentinoids, the N-type calcium channel blockers and the diphenylpiperazine L- and T-type calcium channel blockers.

9. The method of claim 8, wherein the dihydropyridine calcium channel blockers are selected from amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilni dipine, cl evi dipine, efoni dipine, felodipine, isradipine, laci dipine, lercani dipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine.

10. The method of claim 8, wherein the non-hydropyridine calcium channel blockers are selected from phenylalkylamine calcium channel blockers.

11. The method of claim 10 wherein the pheny alkyl amine calcium channel blockers are selected from fendiline, gallopamil, and verapamil.

12. The method of claim 8, wherein the benzothiazepine calcium channel is diltiazem.

13. The method of claim 8, wherein the non-selective calcium channel blockers are selected from mibefradil, bepridil, flunarizine, fluspirilene, and fendiline.

14. The method of claim 8, wherein the gabapentinoids are selected from gabapentin and pregab aline.

15. The method of claim 8, wherein the N-type calcium channel blockers are selected from ziconotide and the L- and TT-type calcium channel blockers are selected from lomerizine.

16. A method of inhibiting viral replication in a patient in need thereof comprising the administration of a therapeutically effective amount of an Acetyl-CoA carboxylase inhibitor.

17. The method of claim 16 wherein the Acetyl-CoA carboxylase inhibitor is selected from firsocostat or derivatives thereof, Olumacostat glasaretil (CAS 1261491-89-7); TOFA (CAS 54857-86-2); ND-646 (CAS 1434639-57-2); ND-630 (CAS 1434635-54-7) and ND-630 S enantiomer); RS 79948 hydrochloride (CAS 186002-54-0); PF-05175157 (CAS 1301214-47-0); ND-654 (GS-834356); or antibodies to Acetyl-CoA carboxylase.

18. A method of treating a coronavirus comprising administration of remdesivir together with a calcium channel blocker or an avermectin.

19. The method of claim 18, wherein the calcium channel blocker is selected from dihydropyridine calcium channel blockers, the non-hydropyridine calcium channel blockers, the benzothiazepine calcium channel blockers, the non-selective calcium channel blockers, the gabapentinoids, the N-type calcium channel blockers and diphenylpiperazine class L-type and T-type calcium channel blockers.

20. The method of claim 19, wherein the dihydropyridine calcium channel blockers is selected from amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine.

21. The method of claim 19, wherein the non-hydropyridine calcium channel blockers are selected from phenylalkylamine calcium channel blockers.

22. The method of claim 21 wherein the phenylalkylamine calcium channel blockers are selected from fendiline, gallopamil, and verapamil.

23. The method of claim 19, wherein the benzothiazepine calcium channel blockers are selected from diltiazem.

24. The method of claim 19, wherein the non-selective calcium channel blockers are selected from mibefradil, bepridil, flunarizine, fluspirilene, and fendiline.

25. The method of claim 19, wherein the gabapentinoids are selected from gabapentin and pregab ali n.

26. The method of claim 19, wherein the N-type calcium channel blockers is selected from zi conotide.

27. The method of claim 19, wherein diphenylpiperazine class L-type and T-type calcium channel blockers is selected from lomerizine.

28. The method of claim 18, wherein the avermectin is ivermectin.

29. The method of claim 1, wherein more than one EL03 inhibitor is administered.

30. A method of treating a coronavirus comprising administration of ND-646 together with at least one compound selected from calcium channel blockers, avermectin and salinomycin.

31. The method of claim 30, wherein the calcium channel blocker is selected from dihydropyridine calcium channel blockers, the non-hydropyridine calcium channel blockers,; the benzothiazepine calcium channel blockers,; the non-selective calcium channel blockers, the gabapentinoids, the N-type calcium channel blockers and diphenylpiperazine class L-type and T-type calcium channel blockers.

32. The method of claim 31, wherein the dihydropyridine calcium channel blockers is selected from amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine.

33. The method of claim 31, wherein the non-hydropyridine calcium channel blockers are selected from phenylalkylamine calcium channel blockers.

34. The method of claim 33 wherein the phenylalkylamine calcium channel blockers are selected from fendiline, gallopamil, and verapamil.

35. The method of claim 31, wherein the benzothiazepine calcium channel blockers are selected from diltiazem.

36. The method of claim 31, wherein the non-selective calcium channel blockers are selected from mibefradil, bepridil, flunarizine, fluspirilene, and fendiline.

37. The method of claim 31, wherein the gabapentinoids are selected from gabapentin and pregab ali n.

38. The method of claim 31, wherein the N-type calcium channel blockers is selected from zi conotide.

39. The method of claim 31, wherein diphenylpiperazine class L-type and T-type calcium channel blockers is selected from lomerizine.

40. The method of claim 30, wherein the avermectin is ivermectin.

41. The method of claim 1, 7, 18 or 30 wherein the composition is delivered as a combination treatment, co-administered with one or more antiviral compounds selected from: abacavir, acyclovir, adefovir, amantadine, ampligen, amprenavir, arbidol, atazanavir, atripla, balavir, baloxavir marboxil, biktarvy, boceprevir, cidofovir, cobicistat, combivir, daclatasvir, darunavir, delavirdine, descovy , didanosine, docosanol, dolutegravir, doravirine, ecoliever, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, fusion inhibitors, ganciclovir, ibacitabine, ibalizumab, idoxuridine, imiquimod, imunovir, indinavir, inosine, integrase inhibitors, interferon type i, interferon type ii, interferon type iii, interferon, lamivudine, letermovir, lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfmavir, nevirapine, nexavir, nitazoxanide, norvir, nucleoside analogues, oseltamivir, peginterferon alfa-2a, peginterferon alfa-2b, penciclovir, peramivir, pleconaril, podophyllotoxin, pyramidine, raltegravir, remdesivir, reverse transcriptase inhibitors, ribavirin, rilpivirine, rimantadine, ritonavir, saquinavir, simeprevir, sofosbuvir, stavudine, synergistic enhancers, telaprevir, telbivudine, tenofovir alafenamide, tenofovir disoproxil, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir and zidovudine.

42. A method of identifying drugs for treating viral infections in a mammal comprising screening compounds for activity against EL03 or genes in its associated functional module, such as ACC1, ACC2, ACB1, and EL02.

43. The method of claim 42 wherein the virus is a coronavirus.

44. The method of claim 43 wherein the coronavirus is SARS CoV 2.

45. A method of preventing infection or reducing the severity of a positive strand RNA virus infection in a patient in need thereof comprising the administration of a compound which inhibits fatty acid synthesis identified through the functional module containing EL03.

46. The method of claim 45, wherein the RNA virus is selected from enveloped and non- enveloped capsid positive strand RNA viruses.

47. The method of claim 46, wherein the non-enveloped capsid viruses are selected from Picornaviridae, Caliciviridae and Hepeviridae

48. the method of claim 46, wherein the enveloped capsid viruses are selected from Flaviviridae, Togaviridae, Arteriviridae and Coronaviridae.

49. The method of claim 48, wherein the coronavirus is selected from Genus Alphacoronavirus which includes Alphacoronavirus 1, Human coronavirus 229E, Human coronavirus NL63, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Porcine epidemic diarrhea virus, Rhinolophus bat coronavirus HKU2 and Scotophilus bat coronavirus 512 species; the genus Betacoronavirus including Murine coronavirus (MHV): Betacoronavirus 1 (Bovine Coronavirus, Human coronavirus OC43), Hedgehog coronavirus 1, Human coronavirus HKU 1 , Middle East respiratory syndrome-related coronavirus, Murine coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome-related coronavirus (SARS-CoV, SARS-CoV-2) and Tylonycteris bat coronavirus HKU4 species; the Gammacoronavirus genus which includes ; Avian coronavirus and Beluga whale coronavirus SW 1 species and the Deltacoronavirus genus which includes Bulbul coronavirus HKU11 and Porcine coronavirus HKU15 species.

50. The method of claim 45, wherein the composition is selected from one or more of the following felodipine, lomerizine, diclazuril, amiodarone, abamectin, idebenone, salinomycin, or Lorenzo’s Oil.

51. A method of preventing or reducing the severity of an RNA virus comprising inhibiting viral replication in a patient in need thereof comprising the administration of a therapeutically effective amount of at least one calcium channel blockers.

52. The method of claim 51, wherein the calcium channel blockers are selected from the dihydropyridine calcium channel blockers the non- hydropyridine calcium channel blockers the benzothiazepine calcium channel blockers; the non-selective calcium channel blockers the gabapentinoids and the N-type calcium channel blockers.

53. The method of claim 52, wherein the dihydropyridine calcium channel blockers are selected from amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine.

54. The method of claim 52, wherein the non- hydropyridine calcium channel blockers are selected from phenylalkylamine calcium channel blockers.

55. The method of claim 54 wherein the phenylalkylamine calcium channel blockers are selected from fendiline, gallopamil, and verapamil.

56. The method or claim 52, wherein the benzothiazepine calcium channel blockers is selected from diltiazem.

57. The method of claim 52, wherein the non-selective calcium channel blockers are selected from mibefradil, bepridil, flunarizine, fluspirilene, and fendiline.

58. The method of claim 52, wherein the gabapentinoids are selected from such as gabapentin and pregabaline.

59. The method of claim 52, wherein the N-type calcium channel blockers is selected from zi conotide

60. A method of preventing or reducing the severity of an RNA virus comprising inhibiting viral replication in a patient in need thereof by administering a therapeutically effective amount of an Acetyl-CoA carboxylase inhibitor.

61. The method of claim 60, wherein the Acetyl-CoA carboxylase inhibitor is selected from firsocostat or derivatives thereof, Olumacostat glasaretil (CAS 1261491-89-7); TOFA (CAS 54857-86-2); ND-646 (CAS 1434639-57-2); ND-630 (CAS 1434635-54-7) and ND-630 S enantiomer); RS 79948 hydrochloride (CAS 186002-54-0); PF-05175157 (CAS 1301214-47-0) or antibodies to Acetyl-CoA carboxylase.

62. A method of preventing or reducing the severity of an RNA virus comprising administration of an effective amount of remdesivir together with a calcium channel blocker or an abamectin.

63. The method of claim 62, wherein the calcium channel blocker is selected from the dihydropyridine calcium channel blockers, the non- hydropyridine calcium channel blockers, the benzothiazepine calcium channel blockers, the non-selective calcium channel blockers, the gabapentinoids, the N-type calcium channel blockers, and diphenylpiperazine class L-type and T-type calcium channel blockers or firsocostat.

64. The method of claim 63, wherein the dihydropyridine calcium channel blockers is selected from amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine , efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine.

65. The method of claim 63, wherein the non- hydropyridine calcium channel blockers are selected from phenylalkylamine calcium channel blockers.

66. The method of claim 65 wherein the phenylalkylamine calcium channel blockers are selected from fendiline, gallopamil, and verapamil.

67. The method of claim 63, wherein the benzothiazepine calcium channel blockers is selected from diltiazem.

68. The method of claim 63, wherein the non-selective calcium channel blockers are selected from mibefradil, bepridil, flunarizine, fluspirilene, and fendiline.

69. The method of claim 63, wherein the gabapentinoids are selected from gabapentin and pregab aline.

70. The method of claim 63, wherein the N-type calcium channel blockers are selected from zi conotide.

71. The method of claim 63, wherein the diphenylpiperazine class L-type and T-type calcium channel blockers are selected from lomerizine

72. The method of claim 71, wherein the lomerizine is dosed at l-20mg one or more times per day and the remdesivir is dosed 100-200mg once per day. The method of claim 62, wherein the avermectin is ivermectin.

73. The method of claim 45, 51, or 62 wherein the composition is delivered as a combination treatment, co-administered with an antiviral compound selected from: abacavir, acyclovir, adefovir, amantadine, ampligen, amprenavir, arbidol, atazanavir, atripla, balavir, baloxavir marboxil, biktarvy, boceprevir, cidofovir, cobicistat, combivir, daclatasvir, darunavir, delavirdine, descovy didanosine docosanol, dolutegravir, doravirine, ecoliever, edoxudine, efavirenz, EIDD 1941, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, fusion inhibitors ganciclovir , ibacitabine, ibalizumab, idoxuridine, imiquimod, imunovir, indinavir, inosine, integrase inhibitor, interferon type i, interferon type ii, interferon type iii, interferon, lamivudine, letermovir, lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfmavir, nevirapine, nexavir, nitazoxanide, norvir, nucleoside analogues, oseltamivir, peginterferon alfa-2a, peginterferon alfa-2b, penciclovir, peramivir, pleconaril, podophyllotoxin, pyramidine, raltegravir, remdesivir, reverse transcriptase inhibitor, ribavirin, rilpivirine, rimantadine, ritonavir, saquinavir, simeprevir, sofosbuvir, stavudine, synergistic enhancer, telaprevir, telbivudine, tenofovir alafenamide, tenofovir disoproxil, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir and zidovudine.

74. A method of identifying drugs for treating viral infections in a mammal comprising screening compounds for activity against EL03 or genes in its associated functional module, such as ACC1, ACC2, ACB1, and EL02.

75. The method of claim 75, wherein the virus is a coronavirus.

76. The method of claim 76, wherein the corona virus is SARS CoV 2.

77. A drug for treating SARS COV-2 infections identified by screening compounds for activity against EL03 or genes in its associated functional module, such as ACC1, ACC2, ACB1, and/or EL02.

78. A method of treating a coronavirus infection comprising the administration of ND- 646 to a patient in need thereof.

79. The method of claim 78 wherein at least one compound selected from the group consisting of Salinomycin, Amlodipine, Ivermectine, Lomerizine, Amiodarone, PF- 05175157, Firsocostat, Fenofibrate, Nifedipine and EIDD-1931 is administered with ND-646 to a patient in need thereof/

80. The method of claim 79 wherein Salinomycin is administered with ND-646.

81. The method of claim 79 wherein Amlodipine is administered with ND-646.

82. The method of claim 79 wherein Lomerizine is administered with ND-646.

83. The method of claim 79 wherein Amiodaron is administered with ND-646.

84. The method of claim 79 wherein PF-05175157 is administered with ND-646.

85. The method of claim 79 wherein Firsocostat, is administered with ND-646.

86. The method of claim 79 wherein Fenofibrate is administered with ND-646.

87. The method of claim 79 wherein Nifedipine is administered with ND-646.

88. The method of claim 79 wherein EIDD-1931 is administered with ND-646.

89. The method of claim 79 wherein ND-646 is administered with at least one compound selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, ampligen, amprenavir, arbidol, atazanavir, atripla, balavir, baloxavir marboxil, biktarvy, boceprevir, cidofovir, cobicistat, combivir, daclatasvir, darunavir, delavirdine, descovy didanosine docosanol, dolutegravir, doravirine, ecoliever, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscamet, fosfonet, fusion inhibitors ganciclovir, ibacitabine, ibalizumab, idoxuridine, imiquimod, imunovir, indinavir, inosine, integrase inhibitor, interferon type i, interferon type ii, interferon type iii, interferon, lamivudine, letermovir, lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfmavir, nevirapine, nexavir, nitazoxanide, norvir, nucleoside analogues, oseltamivir, peginterferon alfa-2a, peginterferon alfa-2b, penciclovir, peramivir, pleconaril, podophyllotoxin, pyramidine, raltegravir, remdesivir, reverse transcriptase inhibitor, ribavirin, rilpivirine, rimantadine, ritonavir, saquinavir, simeprevir, sofosbuvir, stavudine, synergistic enhancer, telaprevir, telbivudine, tenofovir alafenamide, tenofovir disoproxil, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir and zidovudine.

90. The method of claim 79 wherein GN 646 and at least one compound selected from the group consisting of Salinomycin, Amlodipine, Ivermectin, Lomerizine, Amiodarone, PF-05175157, Firsocostat, Fenofibrate, Nifedipine and EIDD-1931 is administered with at least one compound selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, ampligen, amprenavir, arbidol, atazanavir, atripla, balavir, baloxavir marboxil, biktarvy, boceprevir, cidofovir, cobicistat, combivir, daclatasvir, darunavir, delavirdine, descovy didanosine docosanol, dolutegravir, doravirine, ecoliever, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, fusion inhibitors ganciclovir , ibacitabine, ibalizumab, idoxuridine, imiquimod, imunovir, indinavir, inosine, integrase inhibitor, interferon type i, interferon type ii, interferon type iii, interferon, lamivudine, letermovir, lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfmavir, nevirapine, nexavir, nitazoxanide, norvir, nucleoside analogues, oseltamivir, peginterferon alfa-2a, peginterferon alfa-2b, penciclovir, peramivir, pleconaril, podophyllotoxin, pyramidine, raltegravir, remdesivir, reverse transcriptase inhibitor, ribavirin, rilpivirine, rimantadine, ritonavir, saquinavir, simeprevir, sofosbuvir, stavudine, synergistic enhancer, telaprevir, telbivudine, tenofovir alafenamide, tenofovir disoproxil, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir and zidovudine.

91. A method of treating a coronavirus infection comprising administration of remdesivir together with at least one compound selected from calcium channel blockers, avermectins and Acetyl-CoA carboxylase inhibitors.

92. The method of claim 91 wherein the Acetyl-CoA carboxylase inhibitor is selected from firsocostat or derivatives thereof, Olumacostat glasaretil (CAS 1261491-89-7); TOFA (CAS 54857-86-2); ND-646 (CAS 1434639-57-2); ND-630 (CAS 1434635- 54-7) and ND-630 S enantiomer); RS 79948 hydrochloride (CAS 186002-54-0); PF- 05175157 (CAS 1301214-47-0); ND-654 (GS-834356); or antibodies to Acetyl-CoA carboxylase.

93. The method of claim 7 wherein salinomycin is administered in combination with at least one compound selected from the group consisting of ND-646, Amlodipine, Ivermectin, Lomerizine, Amiodarone, PF-05175157, Firsocostat, Fenofibrate, Nifedipine and EIDD-1931 is administered with at least one compound selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, ampligen, amprenavir, arbidol, atazanavir, atripla, balavir, baloxavir marboxil, biktarvy, boceprevir, cidofovir, cobicistat, combivir, daclatasvir, darunavir, delavirdine, descovy didanosine docosanol, dolutegravir, doravirine, ecoliever, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, fusion inhibitors ganciclovir , ibacitabine, ibalizumab, idoxuridine, imiquimod, imunovir, indinavir, inosine, integrase inhibitor, interferon type i, interferon type ii, interferon type iii, interferon, lamivudine, letermovir, lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfmavir, nevirapine, nexavir, nitazoxanide, norvir, nucleoside analogues, oseltamivir, peginterferon alfa-2a, peginterferon alfa-2b, penciclovir, peramivir, pleconaril, podophyllotoxin, pyramidine, raltegravir, remdesivir, reverse transcriptase inhibitor, ribavirin, rilpivirine, rimantadine, ritonavir, saquinavir, simeprevir, sofosbuvir, stavudine, synergistic enhancer, telaprevir, telbivudine, tenofovir alafenamide, tenofovir disoproxil, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir and zidovudine.

94. The method of claim 93 wherein salinomycin is administered with remdesivir.

95. The method of claim 1 further comprising co-administration with a standard of care therapeutic.