Therapeutic formulations from pelargonium sp. and method of use in respiratory viral infections

Abstract

The SARS-CoV-2 pandemic infected 504 million people with over 6.2 million deaths worldwide. Recent variants of SARS-CoV-2 are evolving faster and are more transmissible compared to the strain first reported. Broad-spectrum viral inhibitors that block the initial stages of infection by reducing virus binding and proliferation, thereby reducing disease severity is an unmet global medical need. A standardized polyphenolic-rich compound isolated from Pelargonium sidoides, against recombinant Vesicular Stomatitis Virus (rVSV)-pseudotyped SARS-CoV-2S (spike) of six different variants of SARS-CoV-2. Bi121 was effective in neutralizing all six rVSV-ΔG-SARS-CoV-2S variants expressing different mutations. The antiviral activity was then assessed against different variants of SARS-CoV-2 (USA WA1 / 2020, Hongkong / VM20001061 / 2020, B.1.167.2 (Delta)) and BA.1.1 (Omicron) in two different cell lines (Vero cells and HEK-ACE2) using RT-qPCR and plaque assays. Bi121 showed significant antiviral activity towards all the four SARS-CoV-2 variants tested, suggesting a broad-spectrum activity.

Description

THERAPEUTIC FORMULATIONS FROM PELARGONIUM SP. AND METHOD OF USE IN RESPIRATORY VIRAL INFECTIONSCROSS REFERENCE TO RELATED APPLICATIONSThis application claims priority to U.S. provisional application number 63 / 190,962, entitled Therapeutic Formulations to Treat Respiratory Viral Infections, filed on July 29,2021 , the entire contents of which are hereby incorporated by reference.FIELD OF INVENTIONThe invention relates generally to pharmaceutical compositions and their use. Specifically, the invention discloses phytochemical compounds from a Pelargonium plant for the treatment of respiratory corona viruses.BACKGROUND OF INVENTIONCoronaviruses are the largest group of RNA viruses, formed of an enveloped positive strand of RNA belonging to the Coronaviridae family of helical-capsid enveloped, positive-sense viruses, that causes various respiratory tract and intestinal infections in mammals and birds. (Hosseni-Zare, et al., Targeting severe acute respiratory syndrome-coronavirus (SARS-COV-1) with structurally diverse inhibitors: a comprehensive review. RSC Adv. 2020 Jul 29; 10(47):28287-99; Fehr & Perlman, Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015;1282:1-23; Pillaiyar, et al., Recent discovery and development of inhibitors targeting coronaviruses. Drug Discov Today. 2020 Apr; 25(4):668-88). In 2002, the SARS-CoV (SARS-CoV-1) emerged in China and subsequently resulted in thousands of infections and 801 deaths. (Hosseni-Zare, et al., Targeting severe acute respiratory syndrome-coronavirus (SARS-COV-1) with structurally diverse inhibitors: a comprehensive review. RSC Adv. 2020 Jul 29; 10(47):28287-99; Tong, SARS coronavirus anti-infectives. Recent Pat Antiinfect Drug Discov. 2006 Nov; 1(3):297- 308). The SARS-CoV-2 coronavirus (Wuhan coronavirus, COVID-19) originated in Wuhan in 2019, and has since became a pandemic, spreading exponentially worldwide with over 529 million people infected cases and 6.3 million deaths as of May2022. The virus causes an acute respiratory distress syndrome akin to SARS-CoV-1.SARS-CoV-1 and SARS-CoV-2 belong to the b-coronavirus lineage B, and are more homologous that other coronaviruses with around 80% sequence homology. (Pillaiyar, et al., Recent discovery and development of inhibitors targeting coronaviruses. Drug Discov Today. 2020 Apr; 25(4):668-88; Grifoni, et al., A sequence homology andbioinformatic approach can predict candidate targets for immune responses to SRS- CoV-2. Cell Host Microbe. 2020 Apr 8; 27(4):671-80).A coronavirus is made of various structural proteins, including the spike glycoprotein used to enter cells, envelope proteins used for receptor binding and fusion, viral membrane proteins, nucleoproteins that complex with membrane proteins during viral assembly, replicase polyprotein used for replication and transcription of the viral genome, helicase and protease proteins, and non-structural proteins. (Grifoni, et al., A sequence homology and bioinformatic approach can predict candidate targets for immune responses to SARS-CoV-2. Cell Host Microbe. 2020 Apr 8; 27(4): 671-80; Tanner, et al., The severe acute respiratory syndromw (SARS) coronavirus NTPase / helicase belongs to a distinct class of 5’ to 3’ viral helicases. J Biol Chem. 2003 Oct 10; 278(41 ):39578-82; Muramatsu, et al., SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity. Proc Natl Acad Sci USA. 2016 Nov 15; 113(46):12997-13002; Wu, et al., Antiviral drug discovery against SARS-CoV. Curr Med Chem. 2006; 13(17):2003-20).The S protein of SARS-CoV and SARS-CoV-2 is highly immunogenic and contains two subunits: S1 binds receptors on host cell surfaces and includes a receptor binding domain (RBD), and S2 which fuses to cell membranes. (Li et al., Angiotensin converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003 Nov 27; 426(6965) :450-4). The RBD recognizes and binds to the angiotensin converting enzyme 2 (ACE2), a metallocarboxypeptidase on host cells, with high efficiency, that serves as a functional receptor to mediate cell entry of the virus. (Li et al., Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003 Nov 27; 426(6965) :450-4; Turner, et al., ACEH / ACE2 is a novel mammalian metalllocarboxypeptidase and a homologue of angiotensin converting enzyme insensitive to ACE inhibitors. Can J Physiol Pharmacol. 2002 Apr; 80(4):346-53; Hamming, et al., Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004 Jun; 203(2):631-7; Verdecchia, et al., The pivotal link between ACE2 deficiency and sARS-CoV-2 infection. Eur J Intern Med. 2020 Jun; 76:14-20).While SARS-CoV-2 and SARS-CoV proteins share a high degree of homology, the two viruses possess low homology at the receptor binding domain. While the RBD of the spike protein is a natural target for neutralizing antibodies, the low homology of the RBD potentially explains the 10-20x higher infectivity of SARS-CoV, and also means neutralizing antibodies developed against SARS-CoV are not effective for SARS-CoV- 2. (Buchholz, et al., Contributions of the structural proteins of severe acute respiratorysyndrome coronavirus to protective immunity. Pro Natl Acad Sci USA. 2004 Jun 29;101(26):9804-9; Shang, et al., Structural basis of receptor recognition by SARS- CoV-2. Nature. 2020 May; 581(7807):221-4).Since its first report, several SARS-CoV-2 lineages evolved in the last 24 to 30 months, including Alpha (also called B.1.1.7 (Pango lineage) or GH / 501Y.V1 (GISAID clade)), Beta (also called B.1.251 (Pango lineage) or GH / 501Y.V2 (GISAID clade)), Delta (B.1.617.2 (Pango lineage) or G / 478K.V1 (GISAID clade)), Gamma (P.1 (Pango lineage) or GR / 501Y.V3 (GISAID clade)), and Omicron (B.1.1.529 (Pango lineage) or GR / 484A (GISAID clade)), all of which have been designated as variants of concern. (Rochman, et al., Ongoing global and regional adaptive evolution of SARS-CoV-2. Proc Natl Acad Sci USA. 2021 Jul 20; 118(29):e2104241118; Araf, et al., Omicron variant of SARS-COV-2: genomics, transmissibility, and responses to current COVID- 19 vaccines. J Med Virol. 2022 May; 94(5):1825-32; Fiolet, et al., Comparing COVID- 19 vaccines for their characteristics, efficiency and effectiveness against SARS-COV- 2 and variants of concern: a narrative review. Clin Microbiol Infect. 2022 Feb; 28(2):202-221). Newly designated variants of concern possess concerning properties, including increased transmissibility, more severe disease course, and / or reduced effectiveness of treatments. (Araf, et al., Omicron variant of SARS-COV-2: genomics, transmissibility, and responses to current COVID-19 vaccines. J Med Virol. 2022 May; 94(5):1825-32; Fiolet, et al., Comparing COVID-19 vaccines for their characteristics, efficiency and effectiveness against SARS-COV-2 and variants of concern: a narrative review. Clin Microbiol Infect. 2022 Feb; 28(2):202-221). Evolutionary viral mutations in spike and other proteins in highly evolved lineages may warrant survival benefits to the virus to thwart the human immune system (Tabibzadeh, et al., Evolutionary study of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as an emerging coronavirus: Phylogenetic analysis and literature review. Vet Med Sci. 2021 Mar; 7(2):559-71). Omicron variant carries 46 high prevalence mutations specific to Omicron; Twenty-three of these are localized within the spike (S) protein and the rest localized to the other three viral structural proteins of the virus (Kannan, et al., Omicron SARS-CoV-2 variant: Unique features and their impact on pre-existing antibodies. J Autoimmun.2022 Jan; 126:102779).Veklury (Remdesivir) is the only approved drug for the use in adults and pediatric patients for treatment of COVID-19 requiring hospitalization. Several monoclonal antibodies are authorized to use through Emergency Use Authorization (EUA) for treatment of certain patients with COVID-19 by U.S. Federal Drug Administration. Ritonavir in combination with nirmatrelvir (Paxlovid), developed by Pfizer, was foundto reduce the risk of hospitalization or death by 89% compared to placebo. Molnupiravir (Lagevrio), an oral antiviral manufactured by Merck, was authorized by FDA for the treatment of mild to moderate COVID-19. In people with mild to moderate COVID-19 infection, molnupiravir reduced the risk of hospitalization and death by 30%. Because of the prolific nature of viral infectivity and evolutionary pressure from vaccine-induced adaptive immune response and prospective antiviral treatments, there is a high probability of the emergence of more infectious SARS-CoV-2 variants with potential vaccine and antiviral drug resistance (Hu, et al., Characteristics of SARS- CoV-2 and COVID-19. Nat Rev Microbiol. 2021 Mar; 19(3) :141 -54). This suggests the need for antivirals with broad-spectrum neutralization activity towards various lineages of existing and future SARS-CoV-2 variants.Several single compound antivirals have shown to be effective against SARS-CoV-2 in preclinical studies and are in clinical development. However, these single molecule- single target-based approaches may be challenging in rapidly evolving virus strains of SARS-CoV-2. Several antiviral compounds are in different stages of clinical trials, but broad-spectrum natural compounds that are effective in inhibiting coronavirus growth and replication can help in the fight against COVID-19. Many successful drug products are derived from medicinal herbs and then re-engineered to produce the active compound using synthetic chemistry. A broad-spectrum viral inhibitor that targeting various lineages of SARS-CoV-2 by blocking the initial stage of infection, including virus uptake and proliferation, may reduce the infectious viral load and, thereby, disease severity in patients.To date there are no effective drugs available to treat infection with human corona virus, including SARS-CoV, MERS-CoV or SARS-CoV-2. There is a dire need for therapeutic intervention against SARS-CoV-2 because of the global public health emergency. There are several groups looking into drug repurposing, and it is imperative to bring all the ideas in short time frame on the table to because of the scale of the calamity.SUMMARY OF THE INVENTIONPelargonium reniforme ( P . reniforme) and the closely related species, P, sidoides, are plant species indigenous to areas of Africa having cordate leaves that form a basal rosette or dark red to black. The plants are traditional remedies used by Zulu, Basuto, Xhosa, and Mfengi tribes to treat various gastrointestinal disorders, liver disorders, colds and fever, fatigue and tuberculosis. (Kolodziej, Traditionally used Pelargonium species: Chemistry and biological activity of umckaloabo extracts and their constituents. Curr Top Phytochem. 2000;3:77-93). Chemical analyses ofextracts from the plants has resulted in the characterization of about 85 metabolites, including phenolic and cinnamic acids, tannins, fiavonoids, and coumarins in both plant species. (Kolodziej, Traditionally used Pelargonium species: Chemistry and biological activity of umckaloabo extracts and their constituents. Curr Top Phytochem. 2000;3:77-93; Seidel & Taylor, In vitro activity of extracts and constituents of Pelargonium against rapidly growing mycobacteria. Int J Antimicrob Agents. 2004 Jun; 23(6):613-9; Kolodziej, et al. Tannins and related compounds induce nitric oxide synthase and cytokines gene expressions in Leishmania major- infected macrophagelike RAW 264.7 cells. Bioorg Med Chem. 2005 Dec 1 ; 13(23):6470-6). Notably, various flavones have been isolated from the aerial portions of P. reniforme and P. sidoides. (Latte, et al., O-galloyl-C-glycosylflavones from Pelargonium reniforme. Phytochemistry. 2002 Feb; 59(4) :419-24; Goedecke, et al., A phenol glucoside, uncommon coumarins and fiavonoids from Pelargonium sidoides DC. Z Naturforsch B. 2005 Feb; 60(6):677-82). However, extracts have been found to possess the aliphatic amine 1 ,3-dimethylamylamine (DMAA; 1,3- dimethylpentylamine), which is an amphetamine derivative having sympathomimetic properties that are linked to myocardial infaction, resulting in bans in New Zealand and U.S. military. (Smith, et al., Acute myocardial infarction associated with dietary supplements containing 1 ,3-dimethylamylamine and Citrus aurantium. Tex Heart Inst J. 2014 Feb; 41(1):70-2).Most antiviral and antibiotic activity has been attributed to coumarins and phenolic acids in the extracts. (Kayser & Kolodziej, Antibacterial activity of extracts and constituents of Pelargonium sidoides and Pelargonium reniforme. Planta Med. 1997 Dec; 63(6) :508-10). However, there is evidence the extracts also enhance immune response, through activating NK cells, and increasing IF-b and NO synthesis. (Kolodziej, et al., Pharmacological profile of extracts of Pelargonium sidoides and their constituents. Phytomedicine. 2003; 10 Suppl 4:18-24; Kayser, et al.,Immunomodulatory principles of Pelargonium sidoides. Phytother Res. 2001 Mar; 15(2):122-6; Lukman, et al., Novel kinase platform for the validation of antitubercular activities of Pelargonium sidoides. BMC Biotechnol. 2020 Sep 29; 20(1 ):50).Traditional P. sidoides extracts (i.e. EPs 7630) are 8 g of extracted plant material in 100 g of 11 % aqueous ethanol. One clinical trial administered a daily dose of 13.5mL of extract (1.2g plant material), with a regimen of three times a day. (Matthys, et al., Efficacy and safety of an extract of Pelargonium sidoides (EPs 7630) in adults with acute bronchitis, a randomised, double-blind, placebo-controlled trial. Phytomedicine. 2003;10 Suppl 4:7-17; Chuchalin et al., Treatment of acute bronchitis in adults witha Pelargonium sidoides preparation (EPs 7630): a randomized, double-blind, placebo- controlled trial. Explore (NY). 2005 Nov; 1 (6):437-45).An aqueous polyphenolic-rich fraction from Pelargonium sidoides (PS), designated Bi121 , was prepared, with composition containing at least one polyphenol. The composition is defined by the process of extracting at least one polyphenol from the one or more root sections of a Pelargonium plant, via incubating root sections of a Pelargonium plant in water at about 55Ό to about 60*0 and col lecting the supernatant from the incubated root sections to form a polyphenol extract. Useful temperaturesenriched by incubating the polyphenol extract with polyvinylpyrrolidone, to form an enriched polyphenol extract, and filtering the enriched polyphenol extract. The enriched polyphenol extract from the filter using 0.5 ml 0.5 N NaOH to form a final polyphenol extract, forming the composition. The therapeutic composition optionally includes one or more polyphenols, flavonoids, oligoproanthocyanidins, polymeric proanthocyanidins, gallocatechin, epigallocatechin, epigallocatechin gallate, 1,2, 3, 4, 6 pentagalloyl glucose, or combinations thereof. Nonlimiting examples of the constituents include quercetin, quercitrin, hesperidin and hesperitin. In specific embodiments, the constituents include at least one flavonoid, where the flavonoid is at a percent composition of flavonoid in the range of 0.00000025% to 10%.The therapeutic composition optionally includes phenols. Nonlimiting examples of phenols of the invention include gallic acid, phenolic acid, hydroxycinnamic acid, 1-(4- hydroxy-3-methoxyphenyl) ethenone, 3,5-dihydroxybenzoic acid, vanillic acid, ferulic acid, caffeic acid, and combinations thereof. In some embodiments, the therapeutic composition optionally includes leuco-anthocyanidins. oxygenated coumarins, 7- hydroxy-5,6-di-methoxycoumarin; 6,8-dihydroxy-5,7-dimethoxycoumarin, benzoic acid, 6-methoxy-7-(sulfooxy)-2H-1 -benzopyran-2-one, 6,8-bis(sulfooxy)-7-methoxy- 2H-1 -benzopyran-2-one, 7-Hydroxy-6-methoxy-8-(sulfooxy)-2H 1 -benzopyran-2-one and 8-Hydroxy-7-methoxy-6-(sulfooxy)-2H 1-benzopyran-2-one, and combinations thereof. Neoilludin A, neoilludin B, neoilludin C, methylneoilludin A, methylneoilludin B are optionally found in the formulations of the invention. Specific variations of the invention include additional components, such as hexahydroindenes having the general formula:wherein Ri is CH3, OH, or OCH3; wherein R2is OH, CH3, or OCH3, OCH(O) wherein R3is CH2OH, CH20C(0)CH3, CH30C(0)NH2, CH2F, or CH2CN, CH30CH(0), CH30C(0)X, CH30C(0)N(X)2; where X is an akyl, allyl, oxyalkyl, oxyallyl; wherein R4 is H, or OH; wherein R5is OH, or H; wherein R6is O, or C(CH3)2; andwherein A is spirocyclopropane, or Y ; where Y is an alkyl, allyl, amine, H, ether, ester, C(0)CH3,or C(0)0CH3; where Y’ is an alkyl, allyl, amine, H, ether, ester, C(0)CH3, or C(0)0CH3; but wherein Ri is not CH3when R2is OH, and R4 is OH or H, and A is spirocyclopropane; wherein Ri is not OCH3when R2is CH3, and R4 is OH or H, and A is spirocyclopropane; and wherein wherein Ri is not OH when R2is CH3, and R4 is OH or H, and A is spirocyclopropane.Variations of the molecules may be formed by one of skill in the art (Boddy & Bull, Stereoselective synthesis and applications of spirocyclic oxindoles. Org Chem Front. 2021 Mar 7;5( 8):1026084; Wanka, et al., The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives. Chem Rev. 2013 May 8; 113(5): 3516-604). Examples of the molecules include molecules where Ri and R2are not concurrentlythe same moiety and FU and R5are not concurrently the same moiety. Specific examples, which are not intended to limit the scope of the invention, include 1',3',4',6'- tetrahydroxy-2'-(hydroxymethyl)-2',4',6'-trimethyl-1',2',3',4'- tetrahydrospiro[cyclopropane-1 ,5'-inden]-7'(6' / - / )-one, (1 ' , 3' , 4' , 6' -tetrahyd roxy- 2' , 4' , 6'- trimethyl-7'-oxo-1 ',2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl acetate, (1,,3,,6,-trihydroxy-4,-methoxy-2,,4',6,-trimethyl-7,-oxo-1,,2',3,,4,,6,,7'- hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl acetate, 1',3',6'-trihydroxy-2'- (hydroxymethyl)-4'-methoxy-2',4',6'-trimethyl-1',2',3',4'-tetrahydrospiro[cyclopropane- 1 ,5'-inden]-7'(6' / - / )-one, (1 ',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-7'-oxo-1 ',2',3',4',6',7'- hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl carbamate, 2'-(hydroxymethyl)- 2',4',6'-trimethyl-7'-(propan-2-ylidene)-1',2',3',4',6',7'-hexahydrospiro[cyclopropane- 1 ,5'-indene]-1 ',3',4',6'-tetrol, 2'-(fluoromethyl)-2',4',6'-trimethyl-7'-(propan-2-ylidene)- 1 ',2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'-indene]-1 ',3',4',6'-tetrol, 2'-(fluoromethyl)-1',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-1',2',3',4'- tetrahydrospiro[cyclopropane-1 ,5'-inden]-7'(6' / - / )-one, (1 ',3',4',6'-tetrahydroxy-2',4',6'- trimethyl-7'-(propan-2-ylidene)-1',2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'- indene]-2'-yl)acetonitrile, (1',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-7'-oxo-1 ',2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)acetonitrile, (1 ',3',6'- trihydroxy-4’-methoxy-2',4',6'-trimethyl-7'-oxo-T,2',3',4',6',7'- hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl carbamate, or a combination thereof as part of the composition. The invention includes hexahydroindene molecules having the general formula:wherein Ri is CH3, OH, or OCH3; wherein R2is OH, CH3, or OCH3, OCH(O) wherein R3is CH2OH, CH20C(0)CH3, CH30C(0)NH2, CH2F, or CH2CN, CH3OCH(0), CH3OC(0)X, CH30C(0)N(X)2; where X is an akyl, allyl, oxyalkyl, oxyallyl; wherein R4is H, or OH; wherein R5is OH, or H;wherein R6is O, or C(CH3)2; andwherein A is spirocyclopropane, or Y ; where Y is an alkyl, allyl, amine, H, ether, ester, C(0)CH3,orC(0)OCH3; where Y’ is an alkyl, allyl, amine, H, ether, ester, C(0)CH3, orC(0)0CH3; but wherein Ri is not CH3when R2is OH, and R4 is OH or H, and A is spirocyclopropane; wherein Ri is not OCH3when R2is CH3, and R4 is OH or H, and A is spirocyclopropane; and wherein wherein Ri is not OH when R2is CH3, and FU is OH or H, and A is spirocyclopropane.Variations of the molecules may be formed by one of skill in the art and are intended to be included in the invention. Nonlimiting examples include molecules where Ri and R2 are not concurrently the same moiety and R4 and R5are not concurrently the same moiety. Specific examples, which are not intended to limit the scope of the invention, include 1 ',3',4',6'-tetrahydroxy-2'-(hydroxymethyl)-2',4',6'-trimethyl-1 ',2',3',4'- tetrahydrospiro[cyclopropane-1 ,5'-inden]-7'(6' / - / )-one, (1 ',3',4',6'-tetrahydroxy-2',4',6'- trimethyl-7'-oxo-1',2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl acetate, (1,,3,,6,-trihydroxy-4,-methoxy-2,,4,,6'-trimethyl-7,-oxo-1 ',2', 3', 4', 6', 7'- hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl acetate, 1',3',6'-trihydroxy-2'- (hydroxymethyl)-4'-methoxy-2',4',6'-trimethyl-1',2',3',4'-tetrahydrospiro[cyclopropane- 1 ,5'-inden]-7'(6' / - / )-one, (1 ',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-7'-oxo-1 ',2',3',4',6',7'- hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl carbamate, 2'-(hydroxymethyl)- 2',4',6'-trimethyl-7'-(propan-2-ylidene)-1',2',3',4',6',7'-hexahydrospiro[cyclopropane- 1 ,5'-indene]-1 ',3',4',6'-tetrol, 2'-(fluoromethyl)-2',4',6'-trimethyl-7'-(propan-2-ylidene)- 1 ',2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'-indene]-1 ',3',4',6'-tetrol, 2'-(fluoromethyl)-1',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-1',2',3',4'- tetrahydrospiro[cyclopropane-1 ,5'-inden]-7'(6' / - / )-one, (1 ',3',4',6'-tetrahydroxy-2',4',6'- trimethyl-7'-(propan-2-ylidene)-1 ',2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'- indene]-2'-yl)acetonitrile, (1',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-7'-oxo-1 ',2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)acetonitrile, (1 ',3',6'-trihydroxy-4’-methoxy-2',4',6'-trimethyl-7'-oxo-T,2',3',4',6',7'- hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl carbamate.The variations of the composition optionally intercalates RNA duplexes of RNA viruses. The compositions may, without limiting the scope of the claims, intercalate RNA duplexes at A-U stacked bases and interacting with the uracil pyrimidine nitrogen. In some variations, of the composition optionally blocks helicase activity of RNA viruses. The compositions may, without limiting the scope of the claims, interact with glutamate and / optionally asparagine residues on the helicase.The therapeutic composition is optionally further defined by fractionating the final polyphenol extract, by suspending the final polyphenol extract in an aqueous buffer, running a reverse phase high liquid chromatography purification comprising an aqueous buffer and an organic solvent at a 90 / 108 gradient and flow rate 250 pl / m, and collecting a plurality of fractions. Optionally, at least one fraction is reserved. Useful fractions for reserving are those collected at time thirteen minutes to twenty- four minutes, twenty-five minutes to thirty-six minutes, sixty minutes to seventy-two minutes, or a combination thereof.In some embodiments, the therapeutic composition includes a mucoadhesive nanoparticle liquid base, wherein the nanoparticle liquid base is a nanocellulose nanoemulsion stabilized with a polysaccharide. The nanocellulose nanoemulsion is formed of at least one oil or lipid component, at least one surfactant, nanocellulose, and the polysaccharide stabilizer. The at least one oil or lipid component is PEG-ylated liposomes, phosphotidyl, or a combination thereof. In optional variations, the oil includes a second oil. The second oil is optionally castor oil, corn oil, coconut oil, peanut oil, olive oil, mineral oil, linseed oil, essential oil, or combinations thereof.The surfactant can be a single surfactant or a combination of surfactant and a cosurfactant. The surfaciant(s) have a hydrophilic-lipophilic balance (HLB) that is typically between 11 and 16. {Pavoni, et al., An overview of micro- and nanoemulsions as vehicles for essential oils: formulation, preparation and stability. Nanomaterials (Basel). 2020 Jan; 10(1 ):135). Useful surfactants include, but are not limited to, Tween 20, Tween 80, Triton X-100, Triton X-114, Span 80, or combinations thereof. In specific variations of the nanocellulose nanoemulsion, a co-surfactant is used. Useful co- surfactants are optionally short / medium-chain length alcohols, such as glycerol, propylene glycol, polyethylene glycol derivative, and sorbitol. Some specific examples, without limiting the scope of the invention, are ethanol, propan-2-oi, glycerin, PG, and PEG-400. (Pavoni, et al., An overview of micro- and nanoemulsionsas vehicles for essential oils: formulation, preparation and stability. Nanomaterials (Basel). 2020 Jan; 10(1):135).The nanocellulose is nanocellulose crystals, formed from a known source, such as, without limiting the scope of the invention, hydroxyethylceilu!ose, wood cellulose, bacterial cellulose, or mangosteen rind (Fujisawa, et al., Nanoeeliulose-s!abilized Pickering emulsions and their applications. Sci Technol Adv Mater. 2017; 18(1): 959- 71).Useful polysaccharide stabilizers include marine sulfated polysaccharide, mucin, pectin, cellulose or combination thereof Optionally, the nanoparticle liquid base is provided in the range of 0.000025% to 0.5%.The invention further includes a method of preventing or treating a coronaviral infection, comprising administering the therapeutic composition described above to a patent in need thereof. The coronaviral infection is optionally a SARS-CoV infection, MERS-CoV infection, or SARS-CoV-2 infection.The therapeutic composition is optionally administered by nasal inhalation, intravenous infusion, inhaled nanodroplets, or intramuscular injection. For prevention of coronavirus infection, the composition is optionally administered to a human at between 10 pg / kg and 20 pg / kg, or any range therein. Non-limiting doses include 10.0 pg / kg, 10.1 pg / kg, 10.2 pg / kg, 10.25 pg / kg, 10.3 pg / kg, 10.4 pg / kg, 10.5 pg / kg, 10.6 pg / kg, 10.7 pg / kg, 10.75 pg / kg, 10.8 pg / kg, 10.9 pg / kg, 11.0 pg / kg, 11.25 pg / kg, 11.5 pg / kg, 11.75 pg / kg, 12.0 pg / kg, 12.25 pg / kg, 12.5 pg / kg, 12.75 pg / kg, 13.0 pg / kg,13.25 pg / kg, 13.5 pg / kg, 13.75 pg / kg, 14.25 pg / kg, 14.5 pg / kg, 14.75 pg / kg, 15.0 pg / kg, 15.25 pg / kg, 15.5 pg / kg, 15.75 pg / kg, 16.0 pg / kg, 16.25 pg / kg, 16.5 pg / kg,16.75 pg / kg, 17.0 pg / kg, 17.25 pg / kg, 17.5 pg / kg, 17.75 pg / kg, 18.0 pg / kg, 18.25 pg / kg, 18.5 pg / kg, 18.75 pg / kg, 19.0 pg / kg, 19.25 pg / kg, 19.5 pg / kg, 19.75 pg / kg, or 20.0 pg / kg. Where the composition is dosed intranasally, the composition is optionally administered to a human at between 12 pg / kg and 18 pg / kg, or any range therein. Non-limiting doses include 12.0 pg / kg, 12.25 pg / kg, 12.5 pg / kg, 12.75 pg / kg, 13.0 pg / kg, 13.25 pg / kg, 13.5 pg / kg, 13.75 pg / kg, 14.25 pg / kg, 14.5 pg / kg, 14.75 pg / kg, 15.0 pg / kg, 15.25 pg / kg, 15.5 pg / kg, 15.75 pg / kg, 16.0 pg / kg, 16.25 pg / kg, 16.5 pg / kg, 16.75 pg / kg, 17.0 pg / kg, 17.25 pg / kg, 17.5 pg / kg, 17.75 pg / kg, or 18.0 pg / kg. Where the composition is dosed orally, the composition is optionally administered to a human at between 16 pg / kg and 20.0 pg / kg. Non-limiting doses include 16.0 pg / kg, 16.25 pg / kg, 16.5 pg / kg, 16.75 pg / kg, 17.0 pg / kg, 17.25 pg / kg, 17.5 pg / kg, 17.75 pg / kg, 18.0 pg / kg, 18.25 pg / kg, 18.5 pg / kg, 18.75 pg / kg, 19.0 pg / kg, 19.25 pg / kg, 19.5 pg / kg,19.75 pg / kg, or 20.0 pg / kg. Where the inventive composition is dosed intravenously, the composition is optionally administered to a human at between 10 pg / kg and 16 pg / kg, or any range therein. Non-limiting doses include 10.0 pg / kg, 10.1 pg / kg, 10.2 pg / kg, 10.25 pg / kg, 10.3 pg / kg, 10.4 pg / kg, 10.5 pg / kg, 10.6 pg / kg, 10.7 pg / kg, 10.75 pg / kg, 10.8 pg / kg, 10.9 pg / kg, 11.0 pg / kg, 11.25 pg / kg, 11.5 pg / kg, 11.75 pg / kg, 12.0 pg / kg, 12.25 pg / kg, 12.5 pg / kg, 12.75 pg / kg, 13.0 pg / kg, 13.25 pg / kg, 13.5 pg / kg,13.75 pg / kg, 14.25 pg / kg, 14.5 pg / kg, 14.75 pg / kg, 15.0 pg / kg, 15.25 pg / kg, 15.5 pg / kg, 15.75 pg / kg, or 16.0 pg / kg. Where the inventive composition is dosed intramuscularly, the composition is optionally administered to a human at between10.25 pg / kg and 18 pg / kg. Non-limiting doses include 10.25 pg / kg, 10.3 pg / kg, 10.4 pg / kg, 10.5 pg / kg, 10.6 pg / kg, 10.7 pg / kg, 10.75 pg / kg, 10.8 pg / kg, 10.9 pg / kg, 11.0 pg / kg, 11.25 pg / kg, 11.5 pg / kg, 11.75 pg / kg, 12.0 pg / kg, 12.25 pg / kg, 12.5 pg / kg,12.75 pg / kg, 13.0 pg / kg, 13.25 pg / kg, 13.5 pg / kg, 13.75 pg / kg, 14.25 pg / kg, 14.5 pg / kg, 14.75 pg / kg, 15.0 pg / kg, 15.25 pg / kg, 15.5 pg / kg, 15.75 pg / kg, 16.0 pg / kg,16.25 pg / kg, 16.5 pg / kg, 16.75 pg / kg, 17.0 pg / kg, 17.25 pg / kg, 17.5 pg / kg, 17.6 pg / kg,17.75 pg / kg, 17.9 pg / kg, 18.0 pg / kg. For treatment of coronavirus infection, the composition is optionally administered to a human at between 50 pg / kg and 100 pg / kg, or any range therein. Non-limiting doses include 50.0 pg / kg, 50.5 pg / kg, 51 pg / kg, 51.5 pg / kg, 52 pg / kg, 52.5 pg / kg, 53 pg / kg, 53.5 pg / kg, 54 pg / kg, 54.5 pg / kg, 55 pg / kg, 55.5 pg / kg, 56 pg / kg, 57 pg / kg, 58 pg / kg, 59 pg / kg, 60 pg / kg, 62.5 pg / kg, 65 pg / kg, 67.5 pg / kg, 70 pg / kg, 72.5 pg / kg, 75 pg / kg, 77.5 pg / kg, 80 pg / kg, 82.5 pg / kg, 85 pg / kg, 87.5 pg / kg, 90 pg / kg, 91 pg / kg, 92 pg / kg, 93 pg / kg, 94 pg / kg, 95 pg / kg, 95.5 pg / kg, 96 pg / kg, 96.6 pg / kg, 97 pg / kg, 97.5 pg / kg, 98 pg / kg, 98.5 pg / kg, 99 pg / kg, 99.5 pg / kg, or 100.0 pg / kg. Where the composition is dosed intranasally, the composition is optionally administered to a human at between 74 pg / kg and 100 pg / kg, or any range therein. Non-limiting doses include74 pg / kg, 74.5 pg / kg, 75 pg / kg, 75.5 pg / kg, 76 pg / kg, 76.5 pg / kg, 77 pg / kg, 77.5 pg / kg, 80 pg / kg, 82.5 pg / kg, 85 pg / kg, 87.5 pg / kg, 90 pg / kg, 91 pg / kg, 92 pg / kg, 93 pg / kg, 94 pg / kg, 95 pg / kg, 95.5 pg / kg, 96 pg / kg, 96.6 pg / kg, 97 pg / kg, 97.5 pg / kg, 98 pg / kg, 98.5 pg / kg, 99 pg / kg, 99.5 pg / kg, or 100.0 pg / kg. Where the inventive composition is dosed intravenously, the composition is optionally administered to a human at between 50 pg / kg and 80 pg / kg, or any range therein. Non-limiting doses include 50.0 pg / kg, 50.1 pg / kg, 50.2 pg / kg, 50.3 pg / kg, 50.4 pg / kg,50.5 pg / kg, 51 pg / kg, 51.5 pg / kg, 52 pg / kg, 52.5 pg / kg, 53 pg / kg, 53.5 pg / kg, 54 pg / kg,54.5 pg / kg, 55 pg / kg, 55.5 pg / kg, 56 pg / kg, 57 pg / kg, 58 pg / kg, 59 pg / kg, 60 pg / kg,62.5 pg / kg, 65 pg / kg, 67.5 pg / kg, 70 pg / kg, 72.5 pg / kg, 75 pg / kg, 76 pg / kg, 77.0 pg / kg,77.25 pg / kg, 77.5 pg / kg, 77.75 pg / kg, 78 pg / kg, 78.25 pg / kg, 78.5 pg / kg, 78.75 pg / kg, 79 pg / kg, 79.25 pg / kg, 79.5 pg / kg, 79.6 pg / kg, 79.7 pg / kg, 79 / 8 pg / kg, 79.9 pg / kg, or80 pg / kg. Where the inventive composition is dosed intramuscularly, the composition is optionally administered to a human at between 55 pg / kg and 95 pg / kg. Non-limiting doses include 55.0 pg / kg, 55.1 pg / kg, 55.2 pg / kg, 55.3 pg / kg, 55.4 pg / kg, 55.5 pg / kg, 56 pg / kg, 56.5 pg / kg, 57 pg / kg, 57.5 pg / kg, 58 pg / kg, 59 pg / kg, 60 pg / kg, 62.5 pg / kg, 65 pg / kg, 67.5 pg / kg, 70 pg / kg, 72.5 pg / kg, 75 pg / kg, 77.5 pg / kg, 80 pg / kg, 82.5 pg / kg, 85 pg / kg, 87.5 pg / kg, 90 pg / kg, 91 pg / kg, 92 pg / kg, 93 pg / kg, 92.25 pg / kg, 92.5 pg / kg, 92.75 pg / kg, 93 pg / kg, 93.25 pg / kg, 93.5 pg / kg, 93.75 pg / kg, 94 pg / kg, 94.25 pg / kg, 94.5 pg / kg, 94.6 pg / kg, 94.7 pg / kg, 94.8 pg / kg, 94.9 pg / kg, or 95 pg / kg.A method of manufacturing the therapeutic formulation described above is also provided. The method includes providing one or more root sections of a Pelargonium plant and extracting at least one polyphenol from the one or more root sections of a Pelargonium plant. The at least one polyphenol is extracted by incubating root sections of a Pelargonium plant in water at about 55Ό and collecting the supernata nt from the incubated root sections to form a polyphenol extract. The polyphenols are enriched by incubating the polyphenol extract with polyvinylpyrrolidone; to form an enriched polyphenol extract, filtering the enriched polyphenol extract, and eluting the enriched polyphenol extract with 0.5 ml 0.5 N NaOH to form a final polyphenol extract. In specific embodiments, the Pelargonium plant is Pelagonium sidoides or Pelargonium reniforme.The method optionally also includes fractionating the final polyphenol extract. The polyphenol extract is fractionated by suspending the final polyphenol extract in an aqueous buffer, running a reverse phase high liquid chromatography purification comprising an aqueous buffer and an organic solvent at a 90 / 108 gradient and flow rate 250 pl / m and collecting a plurality of fractions. The aqueous buffer is optionally triethylammonium bicarbonate buffer and the organic solvent acetonitrile. In some variations, the reserved fractions are collected at time thirteen minutes to twenty-four minutes, twenty-five minutes to thirty-six minutes, sixty minutes to seventy-two minutes, or a combination thereof.BRIEF DESCRIPTION OF THE DRAWINGSFor a fuller understanding of the invention, reference should be made to the following detailed description, taken in connection with the accompanying drawings, in which:FIG. 1 is a graph of the HPLC profile of standardized polyphenolic rich Bi121 with fifteen characteristic compound peaks.FIG. 2 is a graph showing the cytotoxicity of Bi121 at varying dilution factors.FIG. 3 is an image of showing uninfected Vero cells (left) compared to Vero cells infected by SARS-CoV-248 hours post infection.FIGs. 4(a) through 4(e) are graphs showing the anti SARS-CoV2 effect of different Bi121 fractions. Vero cells were pretreated at indicated concentration with (a) fraction F0 (0 min to 12 min) and fraction F1 (12 min to 24 min); (b) fraction F2 (24 min to 36 min) and fraction F3 (36 min to 48 min); (c) fraction F4 (48 min to 60 min) and fraction F5 (60 min to 72 min); (d) fraction F6 (72 min to 84 min) and fraction F7 (84 min to 96 min); (e) fraction F8 (96 min to 108 min) and the polyphenol enhanced extract. After 2 h pretreatment, the cells were infected with SARS-CoV-2 at an MOI of 0.01. 48 h post infection MTT assay was performed to determine the cell viability. Cell viability was calculated after normalizing the data with uninfected control. % Viral inhibition was calculated by normalizing the viability of treated cells with respect to viability of untreated controls as follow; % Viral lnhibition= [(cell viability after treatment-cell viability of untreated) / cell viability of untreated]*100. A minimum of 10% viral inhibition was set as cut off value to determine the potential antiviral fraction.FIGs. 5(a) through 5(c) are graph results from liquid chromatography / mass spectroscopy / mass spectroscopy (LC / MS / MS) performed on fractions F2, F3, F5. The exemplary graphs show (a) the liquid chromatography results with the maximum peak was observed having a retention time of 32.99 minutes; (b) a graph of the mass spectrometry from LC / MS / MS results of ; (c) and the LC / MS graph.Figs. 6(a) through 6(c) are tables showing the main constituents of fraction 1 from the liquid chromatography fractionation of crude P. sidoides extract.Figs. 7(a) through 7(c) are tables showing the main constituents of fraction 2 from the liquid chromatography fractionation of crude P. sidoides extract.Figs. 8(a) and 8(b) are tables showing the main constituents of fraction 3 from the liquid chromatography fractionation of crude P. sidoides extract.9(a) through 9(f) are graphs showing Vero E6 and HEK-ACE2 cell response to indicated SARS-CoV-2 strains for (a) Vero E6 RT-qPCR results depicting viral RNA copy numbers; (b) Vero E6 standard plaque assay depicting titres; (c) Vero E6 TCID50 estimation depicting titres; (d) HEK-ACE2 RT-qPCR results depicting viral RNA copy numbers; (e) HEK-ACE2 standard plaque assay depicting titres; and (f) HEK-ACE2 TCID50 estimation depicting titres. Cells were pre-treated for 2 h with Bi121 (1 :40 dilution) or left untreated and were subsequently infected at a MOI of 0.05 for Vero E6 and 0.1 for HEK-ACE2 cells for 1 h. 48 h afterwards, supernatant was harvested for RNA isolation or serially diluted to perform plaque assay and TCID50 estimation. SARS-CoV-2 RNA was isolated from 140 mI_ of supernatant and levels of SARS-CoV-2 specific N-gene was assessed by RT-qPCR. Potential antiviral activity was assessed by comparing compound treated well to untreated and represented as RNA copy numbers.FIG. 10 is a graph showing cellular response to Omicron strain of SARS-CoV-2, as determined by RT-qPCR. Vero E6 cells were pre-treated for 2 h with Bi121 (1 :40 dilution) or left untreated and were subsequently infected SARS-CoV-2 Omicron strain at an MOI of 0.5 for 1 h. After 1 h, viral inoculum was washed, and medium was supplemented with fresh media (DMEM with 2% FBS) containing Bi121 or left untreated (UT). Post-infection at 48 h, medium supernatant was harvested and processed for RNA isolation. SARS-CoV-2 RNA was isolated from 140 pi of supernatant and levels of SARS-CoV-2 specific N-gene was assessed by RT-qPCR. Potential antiviral activity was assessed by comparing compound treated well to untreated and represented as RNA copy numbers. Bars represent the mean of two independent experiments (N=2).**, p<0.001 ; by unpaired student t-test.FIG. 11 is a computer generated image of the proposed interaction between neoilludin B and nsp13 helicase of SARS-CoV2.FIG. 12 is a computer generated image of the proposed interaction between neoilludin B and nsp13 helicase of SARS-CoV2 using the Desmond modeling system (Schrodinger, Inc., New York, NY, USA).FIG. 13 is a graph showing cellular response to SARS-CoV-2 infection at various viral exposure timepoints. HEK-ACE2 cells were pretreated with Bi121 (1 :40 dilution) 2 h or left untreated and were subsequently infected with SARS-CoV-2, Hongkong / VM20001061 / 2020, at an MOI of 0.1 for 1 h. Viral inoculum were washed, and medium was replaced with fresh media (DMEM with 2% FBS) containing Bi121 at indicated time points; immediately upon the medium wash (ON), 2 hours, 8 hours. 48 h post infection. RNA was isolated, and levels of SARS-CoV-2 specific N-gene was assessed by RT-qPCR and potential antiviral activity determined by comparing compound treated wells to untreated and represented as RNA copy numbers. Error bar represents standard deviation from the mean of two independent experiments (N=2).**, p<0.001 , by unpaired student’s f-test.FIGs. 14(a) through 9(f) are graphs showing cellular response to various spike protein mutations; (a) rVSV-AG-SARS-CoV-2 S WT; (b) B.1.1.7; (c) B.1.351 ; (d) B.1.617; (e) B.1.427; and (f) D614G. Bi121 dilution (50 mI_) was mixed with 50 mI_ rVSV-AG-SARS- CoV-2 S variants in a 1 :1 ratio for 1 h at 37Ό. Afterwar d, the viral-Bi121 mix was addedto Vero E6 cells for 24h incubation at 37Ό. Neutralization activity of Bi121 (black line) was assessed and compared to cytotoxicity (gray line).DETAILED DESCRIPTION OF THE INVENTIONAs used herein, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a mixture of two or more compounds and the like, unless specified to the contrary.As used herein, “about” means approximately or nearly and in the context of a numerical value or range set forth means+l- 15% of the numerical.The term “administration”, “administering”, and variants thereof (e.g., “administering” a compound) is used throughout the specification to describe the delivery or introduction of the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents, "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agentsCompounds of the subject invention be administered a number of ways including, but not limited to, oral, parenteral (such term referring to intravenous and intra-arterial as well as other appropriate parenteral routes), intrathecal, intraventricular, intraparenchymal (including into the spinal cord, brainstem or motor cortex), intracisternal, intracranial, intrastriatal, intranigral, and transdermal, among others which term allows a compound of the subject invention to be carried to the ultimate target site where needed. A compound of the subject invention can be administered in the form of active compound, admixtures, or compositions thereof. The compositions according to the present invention may be used without adjuvant, without bioabsorption enhancing agent, without diluent. Alternatively, compositions according to the present invention may include one or more of the adjuvant, bio-absorption enhancing agent, and diluent.Administration will often depend upon the type of vaccine, such as dendritic cell vaccines as compared to small molecule antigen vaccines, epitope vaccines, DNA vaccines, recombinant DNA vaccines, messenger RNA (mRNA) vaccines, subunit vaccines, recombinant vaccines, conjugate vaccines, or toxoid vaccines, as well as the disease or condition targeted by the vaccine. For example, administration may preferably be via administration into the cerebral spinal fluid or by direct administration into the affected tissue in the brain, intratumoral for solid cancers / proliferativedisorders, or be via a parenteral route, for example, intravenously, for systemic diseases.The therapeutic compound is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight, and other factors known to medical practitioners. As such, the precise dosage will vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system health, etc.), the disease, the route of administration, the duration of the treatment desired, and the treatment being affected.As used herein “animal” means a multicellular, eukaryotic organism classified in the kingdom Animalia or Metazoa. The term includes, but is not limited to, mammals. Nonlimiting examples include rodents, aquatic mammals, domestic animals such as dogs and cats, farm animals such as sheep, pigs, cows and horses, and humans. Wherein the terms “animal” or “mammal” or their plurals are used, it is contemplated that it also applies to any animals.The terms "comprising", "consisting of" and "consisting essentially of" are defined according to their standard meaning. The terms may be substituted for one another throughout the instant application in order to attach the specific meaning associated with each term.As used herein, the term “therapeutically effective amount” refers to concentrations or amounts of components of the invention that treat, inhibit, or alleviate one or more symptoms of the viral infection, with or without other adjuvants, to elicit the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In reference to a disease, illness, condition, infection, an effective amount comprises an amount sufficient to prevent or ameliorate the disease. In some embodiments, an effective amount is an amount sufficient to delay development of disease. The therapeutically effective amount can, when used for proliferative disorder therapy, result in the amelioration of cancer or other proliferative disorders or one or more symptoms thereof, prevent advancement of cancer or other proliferative disorder, or cause regression of cancer or other proliferative disorder.A "prophylactically effective amount" refers to concentrations or amounts of components such as the compound(s) of the invention along with an active vaccine compound or agent, with or without other adjuvants, that are sufficient to result in the prevention, recurrence, or spread of disease. The prophylactically effective amountmay refer to the amount sufficient to prevent initial disease, recurrence or spread of the disease or the occurrence of the disease in a patient, including, but not limited, to patients particularly susceptible to the disease, or occurrence of disease in another patient, i.e. spread of disease.As used herein, "treatment" refers to obtaining beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of infection, stabilization (i.e., not worsening) of the state of infection, preventing or delaying spread of the disease (such as pathogen growth or replication), preventing or delaying occurrence or recurrence of the disease, delay or slowing of disease progression and amelioration of the disease state. The methods of the invention contemplate any one or more of these aspects of treatment. The term treatment, as used in this definition only, is intended to mean that regiment described is continued until the underlying disease is resolved, whereas therapy requires that the regiment alleviate one or more symptoms of the underlying disease. Prophylaxis means that regiment is undertaken to prevent a possible occurrence, such as where a pre-cancerous lesion is identified.The term "patient" is used herein to describe members of the animal kingdom, such as but not milted to primates including humans, gorillas and monkeys; rodents, such as mice, fish, reptiles and to whom treatment, including prophylactic treatment, with the composition(s) according to the present invention, is provided. The patient may be any animal requiring therapy, treatment, or prophylaxis, or any animal suspected of requiring therapy, treatment, or prophylaxis. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal.A "safe and effective amount" refers to the quantity of a component that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit / risk ratio when used in the manner of this invention.A "pharmaceutically acceptable" component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio.The pharmaceutical compositions of the subject invention can be formulated according to known methods for preparing pharmaceutically useful compositions.As used herein, the phrase "pharmaceutically acceptable carrier" means any of the standard pharmaceutically acceptable carriers, such as a solvent, suspending agentor vehicle, for delivering the compound or compounds in question to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. The pharmaceutically acceptable carrier can include diluents, adjuvants, and vehicles, as well as implant carriers, and inert, non-toxic solid or liquid fillers, diluents, or encapsulating material that does not react with the active ingredients of the invention. Liposomes and micelles are also a pharmaceutical carrier. Examples of carriers include, but are not limited to, phosphate buffered saline, physiological saline, water, and emulsions, such as oil / water emulsions. The carrier can be a solvent or dispersing medium containing, for example, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Formulations are described in a number of sources that are well known and readily available to those skilled in the art. For example, Remington's Pharmaceutical Sciences (Martin E W

[1995] Easton Pa., Mack Publishing Company, 19.sup.th ed.) describes formulations which can be used in connection with the subject invention. The carrier includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. Formulations suitable for parenteral administration include, for example, aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the condition of the sterile liquid carrier, for example, water for injections, prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powder, granules, tablets, etc. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the subject invention can include other agents conventional in the art having regard to the type of formulation in question. The pharmaceutical composition can be adapted for various forms of administration. Administration can be continuous or at distinct intervals as can be determined by a person skilled in the art.The compounds of the present invention include all hydrates and pharmaceutically acceptable salts of the propanoic acids that can be prepared by those of skill in the art, for example by reacting the inventive compound with a sufficiently basic compound, such as an amine, affording a physiologically acceptable anion. Under conditions where the compounds of the present invention are sufficiently basic or acidic to formstable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Suitable inorganic salts may also be formed by reaching the compound with a basic compound, such as a basic salt of ammonium, calcium magnesium, potassium, or sodium, such as ammonium bicarbonate. When reference is made to a compound or administering a compound, the recitation of the compound includes a pharmaceutically acceptable salt thereof.The compounds of the present invention can be formulated as pharmaceutical compositions and administered to a patient, such as a human patient, in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally, by intravenous, intramuscular, topical, or subcutaneous routes.Thus, the present compounds may be systemically administered, e.g., intravenously, in combination with a pharmaceutically acceptable vehicle such as an inert diluent, or to a specific organ, such as the nasal cavity, via inhalation. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water or other suitable solvent, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to includeisotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient presenting the previously sterile-filtered solutions.Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from adsorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. Examples of useful dermatological compositions which can be used to deliver the compounds of the invention to the skin are disclosed in Jacquet, et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith, et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).Useful dosages of the compounds of the present invention can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art (See, Borch et al., U.S. Pat. No. 4,938,949).Accordingly, the invention includes a pharmaceutical composition comprising a compound of the present invention as described above, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. Pharmaceutical compositions adapted for oral, topical or parenteral administration,comprising an amount of one or more compounds effective to treat a bacterial infection, are a preferred embodiment of the invention.This invention addresses the severe need for new classes of compounds to treat or prevent coronaviral infection.Example 1. Preparation of Extract.Pelargonium sidoides (PS) and P. reniforme are medicinal plants indigenous to Africa that contains antiviral compounds: The aqueous ethanolic P. sidoides extract has been used as a traditional medicine for the treatment of various ailments for over a century. (Brendler & Van Wyk, A historical, scientific and commercial perspective on the medicinal use of Pelargonium sidoides (Geraniaceae). J Ethnopharmacol. 2008 Oct 28; 119(3):420-433). A proprietary extract from PS roots known as EPs7630 or Umckaloabo has been evaluated in numerous clinical trials for safety and alleviation of symptoms associated with acute bronchitis and is licensed in Germany for the treatment of upper respiratory tract infections. (Careddu & Pettenazzo, Pelargonium sidoides extract EPs 7630: a review of its clinical efficacy and safety for treating acute respiratory tract infections in children. IntJ Gen Med. 2018 Mar 8;11 :91-8.). PS extract contains numerous metabolites and was reported to inhibit viruses associated with respiratory diseases like influenza viruses, HIV, and herpes virus. (Theisen & Muller, EPsH 7630 (UmckaloaboH), an extract from Pelargonium sidoides roots, exerts antiinfluenza virus activity in vitro and in vivo. Antiviral Res. 2012 May; 94(2) :147-56; Kolodziej, Fascinating metabolic pools of Pelargonium sidoides and Pelargonium reniforme, traditional and phytomedicinal sources of the herbal medicine Umckaloabo. Phytomedicine. 2007; 14 Suppl 6:9-17; Gokge, et al., Effectiveness of Pelargonium sidoides in pediatric patients diagnosed with uncomplicated upper respiratory tract infection: a single-blind, randomized, placebo-controlled study. Eur J Pediatr. 2021 Sep; 180(9):3019-28; Michaelis, et al., Investigation of the influence of EPs H7630, a herbal drug preparation from Pelargonium sidoides, on replication of a broad panel of respiratory viruses. Phytomedicine. 2011 Mar 15, 18(5):384-6. Heifer, et al., The root extract of the medicinal plant Pelargonium sidoides is a potent hiv-1 attachment inhibitor. PLoS One. 2014 Jan 29, 9(1): e87487; Schnitzler, et al., Efficacy of an aqueous Pelargonium sidoides extract against herpesvirus. Phytomedicine. 2008 Dec; 15(12):1108-16). Very recently, EPs7630 was shown to have activity against SARS- CoV-2. (Papies, et ai., Antiviral and immunomodulatory effects of Pelargonium sidoides DC. root extract eps© 7630 in sars-cov-2-infected human lung cells. Front Pharmacol. 2021 Oct 25; 12:757666).Crude P. sidoides (PS) extracts were generated from dried plant roots of PS sourced from South Africa. Roots were ground with a ball mill and 100 g powdered roots were stirred in 600 ml water (ddH20) for 24 h at 55Ό. This aqueous extraction was ultrasonicated (Sonicator 4000, Misonix Inc), and the mixture was centrifuged to get a clear aqueous extract. All PS extract stock solutions were sterilized by filtration (0.2- micron syringe-filter) and stored at -20SC until used for preliminary functional assays or polyphenolic enrichment.For polyphenolic enrichment, 8 ml. of aqueous PS extract was thoroughly mixed with 0.2 gram of polyvinylpyrrolidone (PVPP40, Sigma-Aldrich®, Merck KGaA, Darmstadt, Germany); polyphenols were allowed to adsorb to PVPP at room temperature for 20 min. The mixture was filtered with a 10 kDa filter (Millipore®, Merck KGaA, Darmstadt, Germany), and washed three times with ddH20. Polyphenols were eluted three times each with 0.5 ml 0.5 N NaOH to form an extract (Bi121 ) . The pH of the elute was adjusted to 7.0 using HCI and the polyphenol enriched elution stored at -20SC or dried for next step UHPLC fractionation.A sample of the polyphenol-rich extract (Bi121 ) was separated into nine fractions (F0- F8) using HPLC for molecular characterization and to identify potential anti SARS- CoV2 compounds. The fractionation of polyphenol enriched fraction was carried out using an Agilent AdvanceBio Column (2.7 pm, 2.1 x 250 mm) and an Agilent UHPLC 1290 system. The separation was performed by running a gradient of Solvent B (10 mM TEABC, pH 8.0, 90% acetonitrile (ACN)) and Solvent A (10 mM triethylammonium bicarbonate buffer (TEABC), pH 8.0) at a 90 / 108 gradient and flow rate of 250 pl / m. The eluted fractions were collected according to retention time, with 5 minutes per fraction, into a 96-well plate using a 1260 series auto-sample fraction collector based on the peaks at UV wavelength between 214 nm and 280 nm. A total of nine fractions were collected, having a profile seen in FIG. 5. The fractions were evaporated by using speed vacuum.Example 2. Cytotoxic Analysis of Extract.Polyphenolic enrichment PS extracts were prepared as described in Example 1 , and tested for cytotoxic effects. Vero E6 cells (American Type Culture Collection (ATCC), Manassas VA, USA, Cat. No. CRL-1597) were seeded in multiple black 96-well plates (PerkinElmer, Inc., Waltham, MA, USA, Cat. No. 6005660) 24-hours prior (day -1) at 5.0 x 104cells per well with DMEM medium [10% heat-inhibited fetal calf serum (FCS), 2 mM L-Glutamine, 1x Penicillin / Streptomycin (P / S)] (Sigma-Aldrich®, Merck KGaA, Darmstadt, Germany, Cat. No. SLM-241). On day 0, 2-fold dilutions of Bi121 wereprepared: All the media were removed from the 96-well plate and replaced with 50 pl¬ot serum-free medium (Gibco, VP-SFM (1x)) supplemented with 2 mM L-Glutamine. 50 mI_ of Bi121 dilutions were added in triplicate to Vero E6 cells and incubated at 37Ό for 24h; medium and cells alone wells were also included as controls.50% cytotoxic concentration (CC5o) was determined using Bright-Glo™ Luciferase Assay System (Promega Corp., Madison, Wl, Cat. No. E2610 / E2620 / E2650). 50 pl¬ot Bright-Glo™ Reagent was added to each well, and the contents mixed. After a 2 minute incubation, the luminescence was measured using a luminometer (Promega, Glomax Discover, Cat No GM3000). The results were analyzed XLFit (4 Parameter Logistic Model or Sigmoidal Dose- Response Model) and Bi121 CC5o was determined.Cytotoxicity (CC5o) of Bi121was approximately 10% from 100x dilution through 1000x dilution, as seen in FIG. 2. Above a 10OOx dilution, Bi121 extract displayed a reduction in cytotoxicity to a negligible level at 10,000x dilution. Accordingly, Bi121 used at concentrations that inhibited the virus did not display toxicity to the target cells.Example 3. Antiviral Activity of Fractions.The antiviral activity of various collected fractions along with Bi121 was studied using MTT assay. Briefly, Vero E6 cells (ATCC, Manassas VA, Cat. No. CRL-1597) were seeded in multiple 96-well plates (PerkinElmer, Inc., Waltham, MA, Cat. No. 6005660) 24-hours prior (day -1 ) at 5.0 x 104cells per well with DMEM medium containing 10% FBS with 2 mM L-Glutamine, 1x Penicillin / Streptomycin (P / S) (Sigma-Aldrich®, Merck KGaA, Darmstadt, Germany, Cat. No. SLM-241 ), at a density of 10,000 / well and grown overnight at 37SC.Dilutions of Bi121 extract were prepared in DMEM containing 2% FBS with increasing concentration of each fraction (F0- F-8). The media on Vero cells was replaced with the Bi121 -media for 2 h and the cells subsequently infected with SARS-CoV-2 at an MOI of 0.01. 48 h post infection MTT assay was performed to determine the cell viability. The assay plate was incubated at 37SC for 48 h. After viral infection, cells were visualized under light microscopy for visible cytopathic effects. The SARS-CoV-2 induced cytopathy in Vero cells, as seen in FIG. 3.MTT assay was performed in duplicate to evaluate the inhibition of infection. Briefly, after viral infection, supernatant was removed from the assay plate, and 3-(4,5- dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) reagent was added to each well at final concentration of 1 mg / ml. The plate was allowed to incubate at 37SC for 1 h in dark. The crystals were dissolved in Isopropanol. The absorbance was measured at 570 nm. Cell viability was calculated after normalizing the data withuninfected control. Percentage viral inhibition was calculated by normalizing the viability of treated cells with respect to viability of untreated controls as follow; % Viral Inhibition = [(cell viability after treatment-cell viability of untreated) / cell viability of untreated]*100. A minimum of 10% viral inhibition was set as cut off value to determine the potential antiviral fraction.Viral inhibition assays showed B121.1 and fractions F2, F3 and F5 possess antiviral activity against SARS-CoV-2, as seen in FIGs. 4(b) and 4(c). By comparison, fractions F1 , F4, and F6 through F8 did not significantly affect viral infectivity, as seen in FIGs. 4(a), and 4(c) through 4(e). This suggests the Bi121 extract contains multiple compounds with activity against SARS-CoV-2. Fraction 5 showed 42% viral inhibition at 6.25pg / ml_, however increasing concentration showed lower viral inhibition. Polyphenolic compounds tend to form polymeric compounds which may explain the lesser activity at higher concentration.Example 4. Identification of potential Polyphenol and Flavonoid Species in BΪ121 ExtractPolyphenolic enrichment PS extracts were prepared as described in Example 1 , and the compounds subjected to LC / MS / MS for identification. The fractions were subjected to a detailed molecular identification of the compounds in these fractions using liquid chromatography tandem mass spectrometry (LC / MS / MS) analysis on a Thermo Scientific Orbitrap QExactive Mass Spectrometer and a Thermo Dionex UltiMate 3000 RSLCnano System.Each active fraction is loaded onto a peptide trap cartridge at a flow rate of 5 pL / min. The trapped peptides were eluted onto a reversed-phase 20 cm C18 PicoFrit column (New Objective, Woburn, MA) using a linear gradient of acetonitrile (3-36%) in 0.1% formic acid. The elution duration is 100 min at a flow rate of 0.3 pL / min. Eluted peptides from the PicoFrit column were ionized and sprayed into the mass spectrometer, using a Nanospray Flex Ion Source ES071 (Thermo) under the following settings: spray voltage, 1.6 kV, Capillary temperature, 250Ό.The 3 fractions, F2, F3 and F5, identified as having biological activity in Example 4, all included a dominant compound, of 291.14 Da seen in FIG. 5(a), which was designated as Bi121.2. Comparison of the extracts’ antiviral activity showed all functional extracts possessed the dominant compound, as seen in Table 1.Table 1. Comparison of Bi121 Fraction Antiviral Activity and 298.14 Da Molecule Presence.The LC / MS analysis of active fractions was carried out using a Thermo Scientific Orbitrap QExactive Mass Spectrometer and a Thermo Dionex UltiMate 3000 RSLCnano System. Each active fraction was loaded onto a peptide trap cartridge at a flow rate of 5 pL / min. The trapped peptides were eluted onto a reversed-phase 20 cm C18 PicoFrit column (New Objective, Woburn, MA) using a linear gradient of acetonitrile (3-36%) in 0.1% formic acid. The elution duration was 100 min at a flow rate of 0.3 pL / min. Eluted peptides from the PicoFrit column were ionized and sprayed into the mass spectrometer, using a Nanospray Flex Ion Source ES071 (Thermo, San Jose, CA) using a spray voltage of 1.6 kV, and capillary temperature of 250Ό. The Q Exactive instrument was operated in the data dependent mode to automatically switch between full scan MS and MS / MS acquisition. Survey full scan MS spectra (m / z 150 -600) was acquired in the Orbitrap with 70,000 resolutions (m / z 200) after accumulation of ions to a 1c106target value based on predictive automatic gain control (AGC). Dynamic exclusion was set to 10 s. The 15 most intense multiply charged ions (z > 1 ) were sequentially isolated and fragmented in the octopole collision cell by higher-energy collisional dissociation (HCD) using normalized HCD collision energy 35% with an AGC target 1 x105and a maxima injection time of 100 ms at 17,500 resolutions.MS Raw data files are analyzed by using Compound Discoverer 3.3 software (Thermo, San Jose, CA). MS1 peak area relative quantification is used for determining the relative abundance of each unique compound identified in each active fraction. The mass spectroscopy analysis identified Bi121.2 as Neoilludin B, seen in FIGs. 5(b) and 5(c). An identification of the top hits from fraction 1, seen in FIGs. 6(a) through 6(c), from fraction 2, seen in FIGs. 7(a) through 7(c), and from fraction 3, seen in FIGs. 8(a) and 8(b).Neoilludin B was purified and conducted antiviral tests against two strains of SARS- CoV2 in Vero cells. The results showed that Neoilludin B has potent antiviral activity against delta and omicron strains of SARS-CoV2 without cellular cytotoxicity, as seen in Table 2.Table 2. Comparison Antiviral Activity and 298.14 Da Molecule.Various sesquiterpenoids have been identified in poisonous mushrooms, such as illudin S in Omphalotus japonicus that show potent antiviral and cytotoxic effects. (Lee, et al., Two new fatty acid derivatives, omphalotols A and B and anti -Heliobacter pylori fatty acid derivatives from poisonous mushroom Omphalotus japonicus. Pharmaceuticals (Basel). 2022 Jan 25; 15(2) :139). Neoilludin B is a sesquiterpenoid, identified as an active constituent of P. sidoides extract, as seen above. Analysis of the structure identified similar compounds, seen in Table 3, that have been found to exert a similar activity.Table 3. Structural Comparison of Neoilludin B Analogs.As seen in the Table, the core structure of the five compounds is identical, with minor moiety substitutions to form the different moiecuies. (Aoki, et a!., Constituents of the fruiting body of poisonous mushroom Omphaiotus japonicus. Chem Pharm Bull (Tokyo). 2020; 68(5): 436-42).The properties of certain compounds according to the present invention, were assessed in-silico using the Swiss ADME computational platform. (Swiss Institute of Bioinformatics, Lausanne, Switzerland). Computer models have been adopted as a valid alternative to experimental procedures for prediction of ADME. (Daina, et al., Swiss ADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017 Mar 3;7:42717). SwissADME is a pool of predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, using lipophilicity, size, polarity, solubility, flexibility and saturation. The neoilludin and methylneolilludin molecules, along with bioisosteres, were analyzed for various pharmacologic properties.Table 4a. Structure of the bioisosteres used in in silico testing of hexahydroindene substitutions at 2’ and 7’ positions.1 neoilludin (A / B / C); 1',3',4',6'-tetrahydroxy-2'-(hydroxymethyl)-2',4',6'-trimethyl- 1',2',3',4'-tetrahydrospiro[cyclopropane-1,5'-inden]-7'(6' / - / )-one2 (1 ',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-7'-oxo-1 ',2',3',4',6',7'-hexahydrospiro [cyclopropane-1 ,5'-inden]-2'-yl)methyl acetate3 (1 ',3',6'-trihydroxy-4'-methoxy-2',4',6'-trimethyl-7'-oxo-1 ',2',3',4',6',7'-hexahydro spiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl acetate4 methylneoilludin (A / B); 1',3',6'-trihydroxy-2'-(hydroxymethyl)-4'-methoxy-2',4',6'- trimethyl-1',2',3',4'-tetrahydrospiro[cyclopropane-1 ,5'-inden]-7'(6' / - / )-one 5 (1 ',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-7'-oxo-1 ',2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl carbamate7 2'-(hydroxymethyl)-2',4',6'-trimethyl-7'-(propan-2-ylidene)-1',2\3\4\6',7'- hexahydrospiro [cyclopropane- 1 ,5'-indene]-1',3',4',6'-tetrol8a 2'-(fluoromethyl)-2',4',6'-trimethyl-7'-(propan-2-ylidene)-1',2',3',4',6',7'- hexahydrospiro [cyclopropane- 1 ,5'-indene]-1 ',3',4',6'-tetrol8b 2'-(fluoromethyl)-1 ',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-1 ',2',3',4'-tetrahydrospiro [cyclopropane-1 ,5'-inden]-7'(6' / - / )-one9a (1 ',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-7'-(propan-2-ylidene)-1 ',2',3',4',6',7'-hexa hydrospiro[cyclopropane-1 ,5'-indene]-2'-yl)acetonitrile 9b (1 ',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-7'-oxo-1 ',2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)acetonitrile11 (1 ',3',6'-trihydroxy-4’-methoxy-2',4',6'-trimethyl-7'-oxo-1 ',2',3',4',6',7'- hexahydrospiro [cyclopropane- 1 ,5'-inden]-2'-yl)methyl carbamate Table 4b. In silico results of bioisostere analysis (illudin bioisosteres).*Abbott bioavailability score (Martin, A bioavailability score. J Med Chem. 2005 May 5; 48(9):3164-70)Solubility range is calculated from ESOL, Ali and SILICOS-IT models#Topological Polar Surface Area logPo / w range is calculated from iLOGP, XLOGP, WLOGP, MLOGP, and SILICOS- IT models†Lipinski (Lipinski, et al., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001 Mar 1 ; 46(1 -3):3-26)*Ghose (Ghose, et al., A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem. 1999 Jan; 1 (1 ):55-68)**Verber (Verber, et al., Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002 Jun 6; 45(12):2615-23)††Egan (Egan, et al., Prediction of drug absorption using multivariate statistics. J Med Chem. 2000 Oct 19; 43(21 ):3867-77) # Muegge (Muegge, et al., Simple selection criteria for drug-like chemical matter. JMed Chem. 2001 Jun 7; 44(12):1841-6)Table 4b. In silico results of bioisostere analysis (illudin bioisosteres).Example 5. In Silico Analysis of Spirocyclopropane MoietyThe effect of modifying the spirocyclopropane moiety of the molecule was analyzed using some of the molecules and bioisosteres analyzed in Example 4, using the Swiss ADME computational platform. (Swiss Institute of Bioinformatics, Lausanne, Switzerland). The structure of the molecules tested is shown in Table 5a, with the in silico properties shown in Table 5b and 5c.Table 5a. Structure of the in silico molecules having 5’ substitutions, subjected to SwissADME.Table 5b. In silico results of bioisostere analysis.*Abbott bioavailability score (Martin, A bioavailability score. J Med Chem. 2005 May 5; 48(9):3164-70)Solubility range is calculated from ESOL, Ali and SILICOS-IT models#Topological Polar Surface Area logPo / w range is calculated from iLOGP, XLOGP, WLOGP, MLOGP, and SILICOS- IT models†Lipinski (Lipinski, et al., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001 Mar 1 ; 46(1 -3):3-26)*Ghose (Ghose, et al., A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem. 1999 Jan; 1 (1 ):55-68)**Verber (Verber, et al., Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002 Jun 6; 45(12):2615-23)††Egan (Egan, et al., Prediction of drug absorption using multivariate statistics. J Med Chem. 2000 Oct 19; 43(21 ):3867-77)nMuegge (Muegge, et al., Simple selection criteria for drug-like chemical matter. J Med Chem. 2001 Jun 7; 44(12):1841-6)Table 4b.Example 6. Variant Cross-ReactivityAfter observing the cytopathic blocking effect of Bi121 in various dilutions (results not shown), the antiviral activity of Bi121 was assessed against different SARS-CoV-2 variants 2 using RT-qPCR, plaque assay, and TCID50 estimation in two different cell lines (Vero E6 cells and HEK-ACE2). The three SARS-COV-2 variants tested were: USA WA1 / 2020, Hongkong / VM20001061 / 2020, B.1.167.2 (Delta). All experiments entailing live SARS-CoV-2 followed the approved standard operating procedures for viral biosafety level 3 facility at IISc, and approved by its biosafety committee (Center for Infectious Disease Research at the Indian Institute of Sciences (IISc.), Bangalore, India).Vero E6 cells (ATCC, Manassas VA, Cat. No. CRL-1597) were cultured in DMEM (Sigma-Aldrich®, Merck KGaA, Darmstadt, Germany, Cat. No. SLM-241) at 37Ό in an atmosphere containing 5% CO2. The day preceding the experiment, the reporter cells were seeded with DMEM medium containing 10% FBS with 2 mM L-Glutamine, 1x Penicillin / Streptomycin (P / S), at 5.0 x 104 cells per well of a 6 well plate, at a density of 10,000 / well and grown overnight at 37Ό. HEK-ACE2 ce Ms (Xell AG, Stukenbrock, Germany, Cat. No. 851-0001) were cultured in DMEM at 37T3 in an atmosphere containing 5% CO2. The day preceding the experiment, the reporter cells were diluted in DMEM containing 10% FBS with 2 mM L-Glutamine, 1x Penicillin / Streptomycin (P / S), and seeded at 5.0 x 104cells per well of 6 well plates at a density of 10,000 / well.The cells were pre-treated for 2 h with Bi121 (1 :40 dilution) or left untreated and were subsequently infected with a SARS-CoV-2 strain; USA-WA1 / 2020 Hong Kong / VM20001061 / 2020 B.1.617.2; at a MOI of 0.1 for 1 h. Viral inoculum were washed, and medium was replaced with fresh media (DMEM with 2% FBS) containing Bi121 or left untreated (UT). Post-infection at 48 h, medium supernatant was harvested and processed for RNA isolation or serially diluted to perform plaque assay and TCID50 estimation.For RNA extraction and reverse transcription quantitative PCR (RT-qPCR), viral RNA was extracted from the cell supernatant using QIAamp Viral RNA mini kit (Qiagen GmbH, Hilden, Germany, Cat. No. 52,906) as recommended by the manufacturer.Briefly, the samples were brought to room temperature and 140 pl_ of media from each flask of immortalized cells was collected and the samples transferred to a microcentrifuge vial containing 560 mI_ of lysis buffer and 6.2 mg of poly A carrier RNA. (Qiagen GmbH, Hilden, Germany, lysis buffer: Cat. No. 19073; carrier RNA: Cat. No. 1017647). The microcentrifuge vial was pulse-vortexed for about 15 seconds and incubated at room temperature for 10 minutes. 560 mI_ of 96% ethanol was added to the sample, the vial was pulse-vortexed for about 15 seconds and 630 mI of the solution added to the QIAamp Mini column in a 2 ml vial. The sample was centrifuged at 6000 x g (8000 rpm) for 1 min and the column washed with 500 mI of first wash buffer (Qiagen GmbH, Hilden, Germany, Cat. No. 19081) at 6000 x g (8000 rpm) for 1 min. The column was washed with 500 mI of second wash buffer (Qiagen GmbH, Hilden, Germany, Cat. No. 19072) at 6000 x g (8000 rpm) for 1 min, followed by elution with 60 mI of elution buffer (Qiagen GmbH, Hilden, Germany, Cat. No. 1020953) at 6000 x g (8000 rpm) for 1 min. The collected RNA viral copies were quantified using C1000 Thermal Cycler and the CFX96 Real-time system (RT PCR) (Bio-Rad). Standards were prepared by serial dilution of 2019-nCoV_N_Positive Control (IDT, Cat# 10,006,625) at different concentration and Control RNA from heat-inactivated SARS- CoV-2 (BEI Resources, Cat# NR-52347) was used as RT-qPCR positive control.The isolated RNA was then converted into cDNA templates for PCR using the BioRad’s iScript™ gDNA clear DNA synthesis kit (Hercules, CA, Cat. No. 1725035). To prepare primer mixes for the PCR reaction, for 2019-nCov CDC EUA kit (Integrated DNA Technologies, Inc., Coarlville, IA, Cat# 10,006,770), N1 primer-probe combination was used: 2019-nCoV_N1-F (GACCCCAAA ATCAGCGAAAT) (SEQ ID NO: 1), 2019- nCoV_N1-R R(T CTGGTT ACT GCC AGTT -G AAT CT G) (SEQ ID NO: 2), and 2019- nCoV_N1-P (FAM-ACCCCGCATTACGTTTGGTGGACC-BHQ1) (SEQ ID NO: 3); for HCoV OC43 RNA copies forward primer (5’-ATGT -T AGGCCG AT AATT GAGG ACT AT - 3’) (SEQ ID NO: 4) and reverse primer (5’-AATGTAAAGATGGCCGCGTATT-3’) (SEQ ID NO: 5). The reactions were carried out using 20 mI_ of PowerUp™ SYBR®Green Master Mix (Thermo Scientific, Thermo Fisher Scientific Inc., Waltham, MA, Cat. No. A25742) per sample, 5 mI_ of extracted viral RNA, TaqMan Fast Virus 1-Step master mix (ThermoFisher Scientific, Cat# 4,444,434) and 2 mI_ of the appropriate primer per RNA sample were mixed. The samples were run using QuantStudio 3 system (Applied Biosystems, ThermoFisher Scientific). The thermal cycling reactions consisted of an initial denaturation at 940 for 2 min followed by 32 cycles of denaturation at 940 for 30s), annealing at 580 for 30s, and extension at 72° C for 60s), with a single final extension at 740 for 2 min. Intracellular level of v iral RNA was normalized withGAPDH using forward primer (5'-GGTGGTCTCCTCTGACTTCAACA-3') (SEQ ID NO: 6) and reverse primer (5'-GTTGCTGTAGC-CAAATTCGTTGT-3') (SEQ ID NO: 7).Bi121 showed significant activity towards all the three SARS-CoV-2 variants tested in the cell lines. In Vero E6 and HEK-ACE2 cells, Bi121 at 1 :40 dilution significantly reduced viral replication (4-5 log reduction) compared to untreated by RT-qPCR, in USA-WA1 / 2020, Hongkong / VM20001061 / 2020, and B.1.167.2 (Delta) strains, as seen in FIGs. 9(a) and 5(d). Bi121 likewise resulted in a 4-5 log reduction in USA- WA1 / 2020 and Hongkong / VM20001061 / 2020 in the plaque assay, as seen in FIGs. 9(b) and 9(e), and TCIDso estimation, as seen in FIGs. 9(c) and 9(f). However, Bi121 resulted in a 2-3 log reduction in B.1.167.2 (Delta) replication in Vero E6 and HEK- ACE2 cells when analyzing the plaque assay, as seen in FIGs. 9(b) and 9(e), and TCIDso estimation, as seen in FIGs. 9(c) and 9(f).The antiviral activity was next analyzed on SARS-CoV-2 omicron strain isolated at IISc, Bengaluru, India by RT-qPCR. Vero E6 cells were seeded at 5.0 x 104cells per well as discussed above, and pre-treated for 2 h with Bi121 (1 :40 dilution) or left untreated. After pre-treatment, the cells were infected with SARS-CoV-2 Omicron strain at an MOI of 0.5 for 1 h. After 1 h, viral inoculum was washed, and medium was supplemented with fresh media (DMEM with 2% FBS) containing Bi121 or left untreated (UT). After 48 h incubation, the medium supernatant was harvested and processed for RNA isolation, as discussed above, from 140 pi of supernatant and levels of SARS-CoV-2 specific N-gene was assessed by RT-qPCR.Similar to the activity against other strains of SARS, Bi121 significantly reduced viral copies of omicron strain in Vero E6 cells in RT-PCR assays by 5 log reduction, as seen in FIG. 10. This reaffirms the broad spectrum activity of Bi121 against SARS-CoV-2.Example 6. Bi121 Interferes with Early Stages of SARS-CoV-2 Infection.After observing the cytopathic blocking effect of Bi121 in various SARS-CoV-2 variants, the primary mode of Bi121 action on SARS-CoV-2 replication was evaluated by time-of-drug-addition experiments.HEK-ACE2 cells (Xell AG, Stukenbrock, Germany, Cat. No. 851-000) were cultured in DMEM (Sigma-Aldrich®, Merck KGaA, Darmstadt, Germany, Cat. No. SLM-241) at 370 in an atmosphere containing 5% CO 2. The day preceding the experiment, the reporter cells were diluted in DMEM containing 10% FBS with 2 mM L-Glutamine, 1x Penicillin / Streptomycin (P / S), and seeded at 5.0 x 104cells per well of 6 well plates at a density of 10,000 / well.The cells were pre-treated for 2 h with Bi121 (1 :40 dilution) or left untreated and were subsequently infected with SARS-CoV-2, Hongkong / VM20001061 / 2020, at an MOI of 0.1 for 1 h. Viral inoculum were washed, and medium was replaced with fresh media (DMEM with 2% FBS) containing Bi121 at indicated time points; immediately upon the medium wash (ON), 2 hours, 8 hours. 48 h post infection, medium supernatants were harvested and processed for RNA, as discussed in Example 5. Briefly, 140 pl_ of media from each flask of immortalized cells was collected and the samples transferred to a microcentrifuge vial containing 560 mI_ of lysis buffer and 6.2 mg of poly A carrier RNA and mixed. (Qiagen GmbH, Hilden, Germany, lysis buffer: Cat. No. 19073; carrier RNA: Cat. No. 1017647). The microcentrifuge vial was incubated at room temperature for 10 minutes, 560 mI_ of ethanol was added, mixed, and 630 mI of the solution added to the QIAamp Mini column in a 2 ml vial. The sample was centrifuged at 6000 x g (8000 rpm) for 1 min and the column washed twice, followed by elution with 60 mI of elution buffer (Qiagen GmbH, Hilden, Germany, Cat. No. 1020953). The collected RNA was quantified using C1000 Thermal Cycler and the CFX96 Real-time system (Bio- Rad). Standards were prepared by serial dilution of 2019-nCoV_N_Positive Control (IDT, Cat# 10,006,625) at different concentration and Control RNA from heat- inactivated SARS-CoV-2 (BEI Resources, Cat# NR-52347) was used as RT-qPCR positive control. The resulting RNA was then subjected to RT-qPCR.The isolated RNA was then converted into cDNA templates for PCR using the BioRad’s iScript™ gDNA clear DNA synthesis kit (Hercules, CA, Cat. No. 1725035). To prepare primer mixes for the PCR reaction, for 2019-nCov CDC EUA kit (Integrated DNA Technologies, Inc., Coarlville, IA, Cat# 10,006,770), N1 primer-probe combination was used: 2019-nCoV_N1-F (GACCCCAAA ATCAGCGAAAT) (SEQ ID NO: 1), 2019- nCoV_N1-R (TCTGGTTACTGCCAGTT-GAATCTG) (SEQ ID NO: 2), and 2019- nCoV_N1-P (FAM-ACCCCGCATTACGTTTGGTGGACC-BHQ1) (SEQ ID NO: 3); for HCoV OC43 RNA copies forward primer (5’-ATGT -T AGGCCG AT AATT GAGG ACT AT - 3’) (SEQ ID NO: 4) and reverse primer (5’-AATGTAAAGATGGCCGCGTATT-3’) (SEQ ID NO: 5). The reactions were carried out using 20 mI_ of PowerUp™ SYBR®Green Master Mix (Thermo Scientific, Thermo Fisher Scientific Inc., Waltham, MA, Cat. No. A25742) per sample, 5 mI_ of extracted viral RNA, TaqMan Fast Virus 1-Step master mix (ThermoFisher Scientific, Cat# 4,444,434) and 2 mI_ of the appropriate primer per RNA sample were mixed. The samples were run using QuantStudio 3 system (Applied Biosystems, ThermoFisher Scientific). Thermal cycling reactions consisted of an initial denaturation at 940 for 2 min followed by 32 cycles o f denaturation at 920 for 30s), annealing at 560 for 30s, and extension at 720 for 60s), with a single final extensionat 74Ό for 2 min. Intracellular level of viral RNA was normalized with GAPDH using forward primer (5'-GGTGGTCTCCTCTGACTTCAACA-3') (SEQ ID NO: 6) and reverse primer (5'-GTTGCTGTAGC-CAAATTCGTTGT-3') (SEQ ID NO: 7). The data was collected in duplicate from two independent experiments and the data combined as a mean.Bi121, when added 2 h before and after the infection, showed an inhibitory effect (p=0.0011), as seen in FIG. 13. Bi121 , when added 8 h after infection, showed a less pronounced inhibitory effect (p=0.0027). This suggests that Bi121 may interfere in the early steps of SARS-CoV-2 entry and replication. The inhibitory activity of Bi121 may result from multivalent interactions between the polyphenolic molecules to bind tightly to the S-protein of SARS-CoV-2 to prevent the initiation of viral cell entry and multiplication. This effect was shown with various SARS-CoV-2 strains and multiple mutants, suggesting a broader inhibitory action of Bi121.Example 7. BΪ121 Neutralizes Pseudotyped-SARS-CoV-2 S (spike protein)Bi121 was tested against recombinant Vesicular Stomatitis Virus (rVSV)-pseudotyped SARS-CoV-2 S expressing the firefly luciferase (Integrated BioTherapeutics Inc, Rockville, MD) to determine the neutralization capacity of the extract. Briefly, the rVSV with glycoprotein gene (G) deleted was used as the base platform for the pseudotype- based neutralization assays. The VSV-G glycoprotein was transiently expressed by transfection to produce virus particles in HEK293T cells. To create pseudotyped viruses, the VSV-G was substituted with SARS-CoV-2 Spike protein (Full-length Spike protein lacking terminal eighteen amino acids of the cytoplasmic domain), and the resulting virus (rVSV-AG-SARS-CoV-2 S) can be handled at biosafety level 2 and expresses firefly luciferase. Infection efficiency can be measured by quantifying luciferase activity by reading the relative light units (RLU) on a luminometer. Neutralization activity (IC5o) of various dilutions of Bi121 against multiple rVSV-AG- SARS-CoV-2 S variants expressing spike protein mutations, seen in Table 4, were tested in Vero E6 cells. Cytotoxicity of Bi121 (CC50) was assessed (see Example 2).Table 6. Specific mutations of VSV-pseudotyped spike protein that represents various strains of SARS-CoV-2. rVSV-AG-SARS- Specific mutations in the spike protein ofCoV-2 S pseudotyped strainsWuhan Wild TypeB.1.1.7 (Alpha) A570D, D614G, D1118H, delH69-V70,N501Y, P681H, S982A, T716I, delY144B.1.351 (Beta) K417N, E484K, N501Y, D614G, A701V B.1.617 (Delta) L452R, E484QD614G D614GB.1.427 L452R, D614GVero E6 cells were seeded in multiple black 96-well plates 24-hours prior (day -1) at5.00 x 104cells per well with EMEM medium [10% heat-inhibited fetal calf serum(FCS), 2 mM L-Glutamine, 1x Penicillin / Streptomycin (P / S)]. On day 0, 2-fold dilutions of Bi121 were prepared. Luciferase activity was measured (Promega, CellTiter-Glo®2.0 Cell Viability Assay).Aliquots of each Bi121 dilution (50 mI_) were mixed with 50 mI_ rVSV-AG-SARS-CoV-2S variants in a 1 :1 ratio for 1 h at 37Ό. All the medi a were removed from the 96-well plates, and the 100 mI_ mixtures were added in triplicate to Vero E6 cells for 24h incubation at 37Ό; pseudotyped virus only and cells only we Ms were also included as controls. Luciferase activity was measured (Promega, Bright-Glo™ Luciferase AssaySystem) to determine Bi121 IC5o- Neutralization assays were validated using Covid-19+ rat serum (data not shown). Data analyses were conducted using XLFit (4Parameter Logistic Model or Sigmoidal Dose- Response Model). Bi121 effectively neutralized multiple rVSV-AG-SARS-CoV-2 S variants expressing different mutations. Bi121 neutralization against the original strain, as well as S protein mutations B.1.427 and D614G, as seen in Table 3, of SARS-CoV-2 showed an exponential relationship between the neutralization and dilution factor along with anID5O of 207.1 for WT and IC50 of 183 for B.1.427 mutation, as seen in FIGs. 14(a) and 14(e), and an IC50 of 183.8 for D614G, as seen in FIG. 14(f). By comparison, Bi121 showed a sigmoidal relationship between the neutralization and dilution factor forB.1.1.7, B.1.351 , and B.1.617, and an ID50 of around 258.4 for B.1.1.7, as seen in FIG.14(b), of 1350 for B.1.351, as seen in FIG. 14(c), and 999.6 for B.1.617, as seen inFIG. 14(d). As such, Bi121 IC50 values against rVSV-AG-SARS-CoV-2 S WT was 183, as seen in FIG. 14(a), and rVSV-AG-SARS-CoV-2 S Delta was 999.6, as seen in FIG. 14(d). This preliminary screening showed the broad-spectrum neutralizing ability of Bi121 to rVSV-AG-SARS-CoV-2 with various spike protein mutations.Example 8. In Silico Mechanism of ActionIn SARS-CoV2, the RNA-dependent RNA polymerase (RdRp) holoenzyme requires a replication-transcription complex (RTC), which includes the n!3 heiicase (nsp13). (Malone, et al., Structural basis for backtracking by the SARS-CoV2 replication- transcription complex. bioRxiv. 2021 Mar 14; 2021.03.13.435256). The bindings sites of the RdRp and n13 heiicase suggest n13 progression results in the backward tracking of the RdRp. (Id).Neoilludin B chemical structures for both 2D and 3D were obtained (PubChem; Nat’l Center for Biotechnology Information, National Library of Medicine, Nat’l Institutes of Health, Bethesda, MD, USA). The molecule was cross-referenced with “SARS-CoV-2” and “anti-viral” as the search terms in the Therapeutic Target Database and Pharmacogenomics Knowledge Base (PharmGKB). (Bioinformatics and Drug Design Group, National University of Singapore, Queenstown, Republic of Singapore; Zhou, et al., Therapeutic target database update 2022: facilitating drug discovery with enriched comparative data of targeted agents. Nucleic Acids Res. 2022 Jan 7; 50(D1):D1398-D1407; Stanford Univ., Stanford, CA, USA). The target protein information was cross-referenced with known inhibitors and no similarity was found, and additional analysis confirmed those results.Neoilludin B was analyzed using Swiss Target Prediction to predict target molecules. (Daina, et al., Swiss ADME: a free web tool to evaluate pharmacokinetics, drug- likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017 Mar 3;7:42717). The molecule was also analyzed by PharmMapper (East China Univ. Sci & Technol., P.R. China), TargetHunter, ChemMapper (East China Univ. Sci & Technol., P.R. China), and ReverseScreen3D (VeraChem LLC, Germantown, MD, USA) were used to predict the plausible Neoilludin B protein targets. (Wang, et al., PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res. 2017 Jul 3;45(W1):W356-W360; Wang, et al., TargetHunter: an in silico target identification tool for predicting therapeutic potential of small organic molecules based on chemogenomic database. AAPS J. 2013 Apr; 15(2):395^106; Gong, et al., ChemMapper: a versatile web server for exploring pharmacology and chemical structure association based on molecular 3D similarity method. Bioinformatics. 2013 Jul 15; 29(14):1827-1829; Kinnings & Jackson, ReverseScreen3D: a structure-based ligand matching method to identify protein targets. J Chem Inf Model. 2011 Mar 28; 51(3):624-634). The top hits were further subjected to a homology search through the NCBI BLAST (Nat’l Center for Biotechnology Information, National Library of Medicine, Nat’l Institutes of Health, Bethesda, MD, USA) server against the Homo sapiens andSARS-CoV-2 species. (Balvociute & Huson, SILVA, RDP, Greengenes, NCBI and OTT — how do these taxonomies compare? BMC Genomics 2017 Mar 14;18(Suppl 2) :114).The identified targets and homologous proteins were validated using computational analysis. Molecular docking (MD) and MD simulation (MDS) validation pipeline were used to unravel potential targets of Neoilludin B. The 3D structures of SARS-CoV-2 helicase (nsp13) and RNA duplexes were obtained from RCSB PDB (Research Collaboratory for Structural Bioinformatics Protein Data Bank, Piscataway, NJ, USA) with PDB IDs 7NNG and 7KRP respectively. (Rose, et al., The RCSB protein data bank: integrative view of protein, gene and 3D structural information. Nucleic Acids Res. 2017 Jan 4; 45(D1 ):D271 -D281 ).The target structures were cleaned and prepared in Molecular Operating Environment (MOE) software. (Molecular Operating Environment (MOE) version ‘MOE2022’ updated on July 6th2022; Chemical Computing Group ULC, Montral, QC, Canada). (Vilar, et al., Medicinal chemistry and the molecular operating environment (MOE): application of QSAR and molecular docking to drug discovery. Curr Top Med Chem. 2008; 8(18), 1555-72). The water molecules with no hydrogen bindings with the core structure were deleted and errors regarding bond orders and steric clashes were resolved by automated wizard and structure was optimized using default parameters. The standard whole molecule docking was used to compare nonspecific scores as a baseline for the active site / major-minor groove docking. The alkylation potential of the docked structure was assessed by proximity of cyclopropane with nitrogen of nitrogenous bases or amino acid side chain residues.The docked complexes were validated by MD simulations using the Desmond package (Schrodinger, Inc., New York, NY, USA). (Bowers, et al., Scalable algorithms for molecular dynamics simulations on commodity clusters. SC’06: Proc 2006 ACM / IEEE Conf Supercomputing. 2006:43-43). The docked complexes were solvated in the default predefined TIP3P solvent model for both helicase-Neoilludin B and Neoilludin B-RNA / DNA duplex, with the top 5 RNA duplex docked poses were superimposed on a single complex with no overlap among ligands, complexes using the OPLS3e force field. (Le, et al., A chemical proteomic analysis of illudin-interacting proteins. Chemistry. 2019 Sep 25; 25(54):12644-51 ). The orthorhombic box boundary with a 10 A buffer space in all three planes was set. The salt concentration was set to 0.1 M with the access of Na+ / CI ions for keeping the system neutral. The full system was loaded onto the Desmond simulation engine and set to run for 100 ns with default temperature and pressure settings (300K / 1atm) in the OPSL3e forcefield. The simulationtrajectories were analyzed for the Root Mean Square Deviation (RSMD) and fly-off times were documented based on visual inspection.Swiss target prediction, TTD, and PharmGKB servers yielded no significant hits owing to a less characterized class of sesquiterpene chemicals. There are only few reports describing similar molecules, however their mechanism of action is mostly attributed to DNA methylation potential due to the presence of a cyclopropane sub moiety. (Le, et al., A chemical proteomic analysis of illudin-interacting proteins. Chemistry. 2019 Sep 25; 25(54):12644-51 ; Lehmann, et al., Illudin S, the sole antiviral compound in mature fruiting bodies of Omphalotus illudens. J Nat Prod. 2003 Sep; 66(9):1257-8). The top 10 hits of PharmMapper were analyzed and there was Zika virus NS3 helicase (PDB ID 6ADW) bound to 4-(2-Hydroxyethyl)-1 -piperazine ethanesulfonic acid and shared similar pharmacophore feature with Neoilludin B. TargetHunter suggested similarity to reported extended nucleoside inhibition of HIV helicase binding properties. (Yedavalli, Vet al., Ring expanded nucleoside analogues inhibit RNA helicase and intracellular human immunodeficiency virus type 1 replication. J Med Chem. 2008 Aug 28; 51 (16):5043-51 ). Consistently, the docking scores of Neoilludin B with SARS-CoV- 2 helicase (PDB ID 7NNG) were high enough (AG= -57.0163) to corroborate. Additionally, the MD simulations showed a lot of hinge-like movement with helicase target protein with good root mean square deviation of atomic positions (RMSD), as seen in Table 7, and early fly-off (~15ns) of Neoilludin B, it was not due to lack of binding energy but significant variations in binding pockets of the receptor.Table 7. Computational pharmacokinetic propteries of neoilludin from Molecular Operating Environment (MOE).The modeling suggests neoilludin B interacts with Glu261 on the nsp13 helicase, as seen in FIG. 11. The Desmond package modeling confirmed the neoilludin B interaction with nsp13 at Glu261, and indicated additional interactions at Asn265, as shown in FIG. 12. Moreover, the early flyoff time (~15ns) could be due to hinge movements in the target protein, which would likely exhibit higher stability in presence of substrates and ATP. It is possible that in the presence of helicase interacting SARS- CoV-2 NSPs and RNA duplex substrate, the receptor complex will be more stable and effectively blocked by neoilludin B. ChemMapper output pointed to a similar moleculebeing intercalating agents based on previous reports. (Kelner, et al., Characterization of illudin S sensitivity in DNA repair-deficient Chinese hamster cells: unusually high sensitivity of ERCC2 and ERCC3 DNA helicase-deficient mutants in comparison to other chemotherapeutic agents. Biochem Pharmacol. 1994 Jul 19; 48(2):403-9; Ozkan & Tezer, Structure-activity relationship studies on aza analogues of illudins. J Mol Struct-THEOCHEM. 2001 Sept 17; 572(1 -3):15-24; Zoldakova, Biochemical studies of targeted and bimodal analogues of the natural anticancer compounds combretastatin A-4 and illudin M. 2011 (PhD Thesis, Univ Bayreuth). However, there was no significant docking observed with DNA. Conversely, RNA duplex docking showed multiple anchoring points for Neoilludin B (AG= -52.0163), specifically with adjacent A and U in major groove. During early phase of MD simulation at ~30ns the Neoilludin B molecule ‘slide’ between A-U and U-T stacked bases and formed stable intercalated RNA duplex complex with restricted horizontal pendulum like movement through rest of the simulations. Neoilludin B showed a strong pre-intercalation docking interacting with the uracil pyrimidine nitrogen forming a cavity for docking of indene substructure which during simulation acted as a gateway for the stronger intercalation, even though it is well known that A-U bond is stronger than A-T. (Swart, et al., Hydrogen bonds of RNA are stronger than those of DNA, but NMR monitors only presence of methyl substituent in uracil / thymine. J Am Chem Soc. 2004 Dec 29; 126(51 ):16718-9). Further experimental wet validations are required to confirm the mode of action of Neoilludin B against SARS-CoV-2 RNA duplex, however these findings open new venues for targeted drug discovery as there are reports of other RNA duplex specific intercalating agents. (Nakamura, et al., Pyrene is highly emissive when attached to the RNA duplex but not to the DNA duplex: the structural basis of this difference. Nucleic Acids Res. 2005 Oct 19; 33(18):5887-95). Furthermore, intercalating agents have been reported as potent anti-SARS-CoV-2 agents though there are a very few RNA duplex specific nontoxic leads. (Wink, Potential of DNA intercalating alkaloids and other plant secondary metabolites against SARS-CoV2 causing COVID-19. Diversity. 2020 May; 12(5) :175).The computational analysis strongly suggests that Neoilludin B is an RNA duplex specific intercalating agent and therefore suggests broad-spectrum antiviral activity against multiple RNA viruses with RNA duplex as a part of their life cycle, which is absent in the host normal central dogma and ribosomal RNA is heavily complexed with protein molecules. Furthermore, based on the strong docking scores, the Helicase binding pharmacophore can be used as a preliminary hit to search for more potent inhibitors.Example 9. Niosome Delivery SystemsNiosomes are synthetic niosomes that exhibit chemical stability as vesicles, are easy to transport and store, are less expensive to manufacture than other vesicles, and possess increased permeability to the blood brain barrier. It is composed of synthetic amphiphilic surfactants and cholesterol that make up a bilayer membrane that is able to entrap hydrophilic solutions in the aqueous core of the vesicle. The niosomes optionally include polyethyleneglycol (PEG) conjugated lipid.Exemplary surfactants include, without limiting the scope of the invention, crown ether amphiphiles bearing a steroidal moiety, 1,2-dialkyl glycerol polyoxyethylene ether, hexadecyl poly-5-oxyethylene ether, hexadecyl poly-5-oxyethylene ether (C16EO5); octadecyl poly-5-oxyethylene ether (CisE05); hexadecyl diglycerol ether (C16G2); sorbitan monopalmitate (Span 40) and sorbitan monostearate (Span 60), Solulan™ C24 (poly-24-oxyethylene cholesteryl ether), polysorbate 20, Span detergents, Brij detergents, such as Brij-35, and polyoxyethylene. Examples of crown ethers are known in the art (Montserrat, et al., Light-induced charge injection in functional crown ether vesicles. J Am Chem Soc. 1980 Aug 1 ; 102(17):5527-5529; Darwish & Uchegbu, The evaluation of crown ether based niosomes as cation containing and cation sensitive drug delivery systems. IntJ Pharm. 1997 Dec 15; 159(2) :207-213; Uchegbu & Duncan, Niosomes containing N-(2-hydroxypropyl)methacrylamide copolymer- doxorubicin (PK1): effect of method of preparation and choice of surfactant on niosome characteristics and a preliminary study of body distribution. Int J Pharm. 1997 Sep 12; 155(1 ):7-17). Exemplary solvents involved in noisome formation may include glycerol, oil, water, and combinations thereof.Cholesterol stabilizes the vesicles by decreasing the permeability and enhancing solute retention (Uchegbu & Florence, Non-ionic surfactant vesicles (niosomes): physical and pharmaceutical chemistry. Adv Colloid Interface Sci. 1995 Jun 27; 58(1 ):1 -55; Nasseri, Effect of cholesterol and temperature in the elastic properties of niosomal membranes. Int J Pharm. 2005 Aug 26; 300(1 -2):95-101). In addition, negative charged molecules may be added to the bilayer-producing compounds, such as dicetyl phosphate, cetyl sulphate, phosphatidic acid, phosphatidyl serine, oleic acid, palmitic acid, which provide electrostatic stabilization to the vesicles and prevents vesicle aggregation (Uchegbu & Vyas, Non-ionic Surfactant Based Vesicles (Niosomes) in Drug Delivery. Int J Pharm., 1998 Oct 15; 172(1-2):33-70; Manosroi, et al., Characterization of vesicles prepared with various non-ionic surfactants mixed with cholesterol. Colloids Surf B. 2003 Jul 1 ; 30(1 -2):129-138). The ability of the surfactant to form a vesicle depends on two factors, the HydrophobicLipophilic Balance (HLB) and the Critical Packing Parameter (CPP). The HLB is calculated usingHLB=20 xMh / M (1) where Mh is the molecular mass of the hydrophilic portion of the surfactant, and M is the molecular mass of the whole niosome, giving a result on an arbitrary scale of 0 to 20. For the surfactant sorbitan monostearate, an HLB number between 4 and 8 was found to be compatible with vesicle formation (Uchegbu & Vyas, Non-ionic Surfactant Based Vesicles (Niosomes) in Drug Delivery. Int J Pharm., 1998 Oct 15; 172(1-2):33- 70).The CPP is a dimensionless number that predicts the ability of the amphiphile to form aggregates, with values of 0.5-1.0 predicting that the amphiphile will form a vesicle. (Israelachvili, Intermolecular and Surface Forces: With Applications to Colloidal and Biological Systems. 3d Ed. 2011 , Orlando: Academic Press). CPP is calculated usingCPP=u / / c a0(2) where u=hydrocarbon chain volume, lc=critical hydrophobic chain length (the length above which the chain fluidity of the hydrocarbon may no longer exist), and a0=area of hydrophilic head (Uchegbu & Florence, Non-ionic surfactant vesicles (niosomes): physical and pharmaceutical chemistry. Adv Colloid Interface Sci. 1995 Jun 27; 58(1):1-55).The niosomes are formed from the self-assembly of non-ionic amphiphiles in aqueous media resulting in closed bilayer structures (Uchegbu & Vyas, Non-ionic surfactant based vesicles (niosomes) in drug delivery. Int J Pharm., 1998 Oct 15; 172(1-2):33- 70). The assembly into bilayers is rarely spontaneous and usually involves some input of energy such as physical agitation or heat. Span 60, a surfactant, a cholesterol, and, optionally, dicetyl phosphate and / or sorbitan monosterate, a negatively charged molecule, are added to a flask in an organic solvent at a ratio of 1 :1 :(0.1 ), surfactant to cholesterol to dicetyl phosphate. The solution is mixed by agitation over a 60° C bath until the solids dissolve and the solution transferred to an evaporator, such as a buch'i rotary evaporator with nitrogen gas until a film forms on the flask. The flask is allowed to further dry for at least 12 hours, and the film hydrated using one of the therapeutic composition of Example 1, Example 3, or Example 4 or a combination of the compositions. The solution is further dried in the rotary evaporator until the thin film dissolves and the niosomes extruded at 60° C, resulting in size-limited niosomes containing the composition.These niosomes have been found to exhibit a linear behavior in their size distribution as the concentration of the hydrophilic component increases from 5 millimolar to 15 millimolar. (Alcantar, et al., U.S. Pat. No. 9,522,114).Example 10. Liposome Delivery SystemsNanoparticles offer more stability to the encapsulated drug in biological fluid and protection against enzymatic metabolism. By encapsulating drugs with nanoparticles, the efflux of the drug is minimized, facilitating its entry into the CNS and other human organ systems.Lipid nanoparticles have been shown as an effective transport vehicle to deliver therapeutics to biologic target cells. (Semple et al., Rational design of cationic lipids. Nat Biotechnol. 2010 Feb, 28(2): 172-176). Such lipid nanoparticles are made by mixing a cationic lipid, non-cationic lipid, a polyethyleneglycol (PEG) conjugated lipid, and a structural lipid in a method similar to Example 8.In some variations, the lipid nanoparticles can be synthesized using a mixture of ionizable cationic lipid / phosphatidylcholine / cholesterol / PEG-lipid at a ratio of 50:10:38.5:1.5 mol / mol (cationic lipid: phosphatidylcholine: cholesterol: PEG-lipid), and encapsulate the composition at a compound-to-total lipid ratio of 5:1 (compound to lipid) of -0.05 (wt / wt). In specific variations, the liposomes are synthesized from docosohexanoid acid and oleic acid. The interaction between the liposomes and the cargo usually relies on hydrophobic interactions or charge attractions, particularly in the case of cationic lipid delivery systems (Zelphati, et al., Intracellular delivery of proteins with a new lipid-mediated delivery system. J Biol Chem. 2001 Sep 14, 276(37):35103-35110). In a preferred embodiment, the cationic lipid / phosphatidylcholine / cholesterol / PEG based liposomes are loaded with the compositions of the present invention. The liposomal phytochemical extract, composing polyphenols, is administered nasally. Alternatively, the liposomal is loaded with neoilludin and / or methylneoilludin and / or illudin bioisosteres, and administered nasally.Example 11. Nanoemulsions Pharmaceutical CompositionsIn some embodiments, the compositions are delivered to the human tissues by a nanoemulsion. Nanoemulsions are a novel drug delivery system consisting of emulsified oil and water systems with average droplet sizes ranging from 100 to 500 nm. The capacity of nanoemulsions to dissolve large quantities of low soluble drugs along with their mutual compatibility and ability to protect the drugs from hydrolysis andenzymatic degradation make them ideal drug delivery vectors. The nanoemulsion is formed of nanocellulose with an oil phase of phosphotidyl or PEG-lyated liposomes, described in Example 8, and a surfactant. (Giongo, et al., Development of nanoemulsion containing Pelargonium graveolens oil: characterization and stability study. Inti J Pharm Pharma Sci. 20168(12):271 -6; Pavoni, et al., An overview of micro- and nanoemulsions as vehicles for essential oils: formulation, preparation and stability. Nanomaterials (Basel). 2020 Jan; 10(1 ):135; Rizg, et al., Tailoring of germanium oil- based nanoemulsion loaded with pravastatin as a nanoplatform for wound healing. Polymers (Basel). 2022 May; 14(9) :1912). Emulsifying agents stabilize the nanoemulsion. Nanoemulsion based pharmaceutical API delivery has higher bioavailability and organ distribution compared to traditional excipients. The systems use a surfactant-to-oil ratio of below 2.A solution of carrageneen was formed by dissolving the polysaccharide in distilled water at 5g / L and Tween 80 and nanocellulose crystals added. (Pirozzi, et al., O / W Pickering emulsions stabilized with cellulose nanofibrils produced through different mechanical treatments. Foods. 2021 Aug; 10(8):1886). The PEG-ylated liposomes are mixed with the aqueous phase and the composition is subjected to sonication or high- pressure homogenation. (Pavoni, et al., An overview of micro- and nanoemulsions as vehicles for essential oils: formulation, preparation and stability. Nanomaterials (Basel). 2020 Jan; 10(1 ):135; Jimenez Saelices & Capron, Design of Pickering micro- and nanoemulsions based on the structural characteristics of nanocelluloses. Macromolecules. 2018 Jan 8; 19(2):460-9; Zhang, et al., Nanoemulsions and nanolatexes stabilized by hydrophobically functionalized cellulose nanocrystals. Macromolecules. 2017 Aug 11 ; 50:6032-42). The composition was mixed for 1 h, forming the nanoemulsion.The nanoemulsion compositions can be administered by parenteral (intramuscular, intraperitoneal, intravenous (IV), or subcutaneous injection), oral, nasal, ortransdermal (either passively, or using iontophoresis or electroporation) routes of administration. Preferably, the phytochemical extract, composing polyphenols, is loaded with the carrageneen-Tween 80-nanocellulose crystal composition disclosed above, and administered nasally. Alternatively, the carrageneen-Tween 80-nanocellulose crystal composition is loaded with neoilludin and / or methylneoilludin and / or illudin bioisosteres, and administered nasally.Example 12. Nasal AdjuvantsFor treatment of viral infections, the compositions must enter the patient’s circulatory system, However, absorption through either the nasal passageway or pulmonary system requires passing through the nasal mucosa and nasal epithelium, and is a limiting factor in bioavailability of nasal compositions. (Ghadiri, et al., Strategies to enhance drug absorption via nasal and pulmonary routes. Pharmaceutics. 2019 Mar; 11 (3):113). As such, nasal compositions of the compositions can incorporate absorption enhancing agents.Addition of fatty acids to nasal compositions, namely capric acid and lauric acid, have been shown to increase bioavailability of nasal administered compositions, (Ghadiri, et al., Strategies to enhance drug absorption via nasal and pulmonary routes. Pharmaceutics. 2019 Mar; 11 (3):113). Studies suggest the fatty acids activate phospholipase-C, which hydrolyzes 4,5-bisphosphate (PIP2) and eventually results in increases in intracellular calcium, contraction of actin microfilaments, and opening of tight junctions in the nasal epithelium. (Ghadiri, et al., Strategies to enhance drug absorption via nasal and pulmonary routes. Pharmaceutics. 2019 Mar; 11 (3) :113; Szebenyl, et al., Increases in intracellular calcium via activation of potentially multiple phospholipase C isozymes in mouse olfactory neurons. Front Cell Neurosci. 2014 Oct 21 ; 8:336; Ward, et al., Role of phospholipase C-beta in the modulation of epithelial tight junction permeability. J Pharmacol Exp Ther. 2003 Feb; 304(2) :689-98).Similarly, addition of non-ionic surfactants, such as poloxamer 188, cremophor EL, iaurate sucrose ester (SE), and sucrose cocoate have been shown to increase nasal bioavailabiiity. (Ghadiri, et al., Strategies to enhance drug absorption via nasal and pulmonary routes. Pharmaceutics. 2019 Mar; 11 (3) :113). Poloxamer 188 is a polyoxyethylene-polypropylene block co-polymer flanked at either end by a polyethylene oxide segments, having a general formula of H0(C2H40)a(C3H60)b(C2H40)c (ethane-1 ,2-diol;propane-1 ,2-diol). (Moloughney & Weisleder, Poloxamer 188 (P188) as a membrane resealing reagent in biomedical applications. Recent Pat Biotechnol. 2012 Dec; 6(3) :200-11). Cremophor EL (Kolliphor EL) is a polyethoxylated caster oil (oxirane;propane-1 ,2,3-triol, CAS No. 61791 -12-6). Laurate sucrose esters exist as monoester (sucrose monolaurate, CAS No. 13039-40- 2), diester, triesters and polyesters. (McCartney, et al., Evaluation of sucrose laurate as an intestinal permeation enhancer for macromolecules: e vivo and in vitro studies. Pharmaceutics. 2019 Nov; 11(11) :565; McCartney, et al., Permeability-enhancing effects of three laurate-disaccharide monoesters across isolated rat intestinal mucosae. Int J Pharm. 2021 May 15; 601:120593). Studies on moderately and poor cell-permeable compounds (isosorbide dinitrate, TPSA of 129 A2; sumatriptansuccinate TPSA of 148A2) exhibited substantial improvement in ceil permeability with coadministration of non-ionic surfactants, and improved nasal bioavai!abiiity. (Ghadiri, et al., Strategies to enhance drug absorption via nasal and pulmonary routes. Pharmaceutics. 2019 Mar; 11 (3) :113).Accordingly, the nasal adjuvants, i.e. fatty acids or non-ionic surfactants, are added to the liposomal compositions of Example 10 or the nanoemulsion compositions of Example 11 , thereby enhancing the transdermal nasal delivery of those compositions.Example 13.The Bi121 extract was shown to significantly inhibit various strains of SARS-CoV-2 in African green monkey kidney epithelial cells and human embryonic kidney cells (Vero E6 and HEK-ACE2 cells, respectively), with respect to replication, as identified by RT- PCR, and cell viability. Further, studies indicate that the composition likely acts through limiting or preventing viral access to the cell, as seen in FIG. 13. Inhibition was also observed with the rVSV-AG-SARS-CoV-2 system that represents spike protein mutations of various SARS-CoV-2 lineages, seen in FIG. 14(a) through 14(f), supporting the inference that the composition likely acts through preventing viral access to target cells. Moreover, Bi121 used at concentrations that inhibited the virus did not display toxicity to the target cells.Treatment with the extract, or fraction, before infection or early in the infection showed an inhibitory effect suggesting a treatment as well as a prophylactic measure against SARS-CoV-2. Because the composition was capable of neutralizing the spike protein, though multiple variants of SARS-CoV-2, it denies the virus access to the cell and thus prevents viral replication.Broad-spectrum antiviral against SARS-CoV-2 is a global need as new virus lineages with more immune-thwarting mutations are evolving. (Marie Ferre, et al., Omicron SARS-CoV-2 variant: what we know and what we don’t. Anaesth Crit Care Pain Med. 2022 Feb; 41 (1 ) :100998). Projected epidemiological consequences of the Omicron SARS-CoV-2 show a rapid increase in infections in the EU and US in the coming months. (Giovanetti, et al., Evolution patterns of SARS-CoV-2: snapshot on its genome variants. Biochem Biophys Res Commun, 2021 Jan 29;538:88~91). Although preliminary data indicates that Omicron (B.1.1.529) may have less severe infections, the variant is better and faster in transmission. (Marie Ferre, et al., Omicron SARS- CoV-2 variant: what we know and what we don’t. Anaesth Crit Care Pain Med. 2022 Feb; 41 (1):100998).Bi121 shows use as a strong antiviral without cytotoxic effects and is a thermally stable compound without the need for special logistics support for distribution. This is particularly important for low-resource setting countries that doesn’t have special transportation needs or logistics support. There is significant safety information on use of Pelargonium-based actives for human respiratory applications that warrants a fast- track clinical development. (Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS- CoV-2 and COV!D-19. Nat Rev Microbiol. 2021 ; 19(3) :141-154, doi:10.1038 / s41579- 020-00459-7; Brendler & Van Wyk, A historical, scientific and commercial perspective on the medicinal use of Pelargonium sidoides (Geraniaceae). J Ethnopharmacol. 2008 Oct 28; 119(3):420-433; Careddu & Pettenazzo, Pelargonium sidoides extract EPs 7630: a review of its clinical efficacy and safety for treating acute respiratory tract infections in children. Int J Gen Med. 2018 Mar 8;11 :91 -8; Theisen & Muller, EPsH 7630 (UmckaloaboH), an extract from Pelargonium sidoides roots, exerts antiinfluenza virus activity in vitro and in vivo. Antiviral Res. 2012 May; 94(2) :147-56; Kolodziej, Fascinating metabolic pools of Pelargonium sidoides and Pelargonium reniforme, traditional and phytomedicinal sources of the herbal medicine Umckaloabo. Phytomedicine. 2007; 14 Suppl 6:9-17; Gokge, et al., Effectiveness of Pelargonium sidoides in pediatric patients diagnosed with uncomplicated upper respiratory tract infection: a single-blind, randomized, placebo-controlled study. Eur J Pediatr. 2021 Sep; 180(9) :3019-28).The nasal epithelium is where most respiratory viral infections, including SARS-CoV- 2, initiates the infection. (Hu, etal., Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021 Mar; 19(3) :141 -54). Development of Bi121 in a nasal liquid composition as a preventative treatment on nasal tissue can reduce viral infections by reducing or eliminating viral particles before a systemic infection can occur.In the preceding specification, all documents, acts, or information disclosed does not constitute an admission that the document, act, or information of any combination thereof was publicly available, known to the public, part of the general knowledge in the art, or was known to be relevant to solve any problem at the time of priority.The disclosures of all publications cited above are expressly incorporated herein by reference, each in its entirety, to the same extent as if each were incorporated by reference individually.While there has been described and illustrated specific embodiments of an antiviral composition, it will be apparent to those skilled in the art that variations and modifications are possible without deviating from the broad spirit and principle of thepresent invention. It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described, and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween.SEQUENCE LISTING<110> Biom Therapeutics LLC <120> Therapeutic Formulations From Pelargonium Sp. And Method of Use li Respiratory Viral Infections<130> 20220601-1 <150> 63 / 190,962<151 > 2021-07-29<160> 7 <170> Patentln version 3.5<210> 1 <211 > 20 <212> DNA <213> artificial<220><223> SARS-CoV2 forward primer <400> 1 gaccccaaaa tcagcgaaat 20<210> 2 <211 > 24<212> DNA <213> artificial<220> <223> SARS-CoV2 reverse primer<400> 2tctggttact gccagttgaa tctg 24<210> 3 <211 > 24 <212> DNA <213> artificial<220><223> SARS-CoV2 probe<400> 3 accccgcatt acgtttggtg gacc 24<210> 4 <211 > 26 <212> DNA <213> artificial<220><223> HCoV OC43 forward primer<400> 4 atgttaggcc gataattgag gactat 26<210> 5 <211 > 22 <212> DNA<213> artificial<220><223> HCoV OC43 reverse primer<400> 5 aatgtaaaga tggccgcgta tt 22<210> 6 <211 > 23 <212> DNA<213> artificial<220><223> GADPH control forward primer<400> 6 ggtggtctcc tctgacttca aca 23 <210> 7<211 > 23 <212> DNA <213> artificial <220><223> GADPH control reverse primer<400> 7 gttgctgtag ccaaattcgt tgt 23

Claims

What is claimed is:

1. A therapeutic formulation, comprising: a composition of at least one polyphenol prepared by a process comprising: providing one or more root sections of a Pelargonium plant; extracting at least one polyphenol from the one or more root sections of aPelargonium plant, further comprising: incubating root sections of a Pelargonium plant in water at about 55Ό to about 60Ό; collecting the supernatant from the incubated root sections to form a polyphenol extract; enriching the polyphenols in the polyphenol extract, comprising: incubating the polyphenol extract with polyvinylpyrrolidone; to form an enriched polyphenol extract; filtering the enriched polyphenol extract; eluting the enriched polyphenol extract with 0.5 ml 0.5 N NaOH to form a final polyphenol extract; wherein the composition comprises the final polyphenol extract.

2. The therapeutic formulation of claim 1 , further comprising fractions of the final polyphenol extract, the fractions prepared by a process comprising: suspending the final polyphenol extract in an aqueous buffer; running a reverse phase high liquid chromatography purification comprising an aqueous buffer and an organic solvent at a 90 / 108 gradient and flow rate 250 pl / m; collecting a plurality of fractions; reserving at least one reserved fraction, wherein the reserved fractions are collected at time thirteen minutes to twenty-four minutes, twenty-five minutes to thirty-six minutes, sixty minutes to seventy-two minutes, or a combination thereof.

3. The therapeutic formulation of claim 1, wherein the final polyphenol extract comprises polyphenols, flavonoids, oligoproanthocyanidins, polymeric proanthocyanidins, gallocatechin, epigallocatechin, epigallocatechin gallate, 1 ,2, 3, 4, 6 pentagalloyl glucose, or combinations thereof.

4. The therapeutic formulation of claim 1 , further comprising phenols, wherein the phenols comprise gallic acid, phenolic acid, hydroxycinnamic acid, 1-(4- hydroxy-3-methoxyphenyl) ethenone, 3,5-dihydroxybenzoic acid, vanillic acid, ferulic acid, caffeic acid, and combinations thereof.

5. The therapeutic formulation of claim 1, further comprising leuco- anthocyanidins, oxygenated coumarins, 7-hydroxy-5,6-di-methoxycoumarin; 6,8-dihydroxy-5,7-dimethoxycoumarin, benzoic acid, 6-methoxy-7-(sulfooxy)- 2H-1 -benzopyran-2-one, 6,8-bis(sulfooxy)-7-methoxy-2H-1 -benzopyran-2- one, 7-Hydroxy-6-methoxy-8-(sulfooxy)-2H 1-benzopyran-2-one and 8- Hydroxy-7-methoxy-6-(sulfooxy)-2H 1-benzopyran-2-one, and combinations thereof.6 The therapeutic formulation of claim 1 , further comprising at least one molecule having the formula:wherein Ri is CH3, OH, or OCH3; wherein R2is OH, CH3, or OCH3, OCH(O) wherein R3is CH2OH, CH20C(0)CH3, CH30C(0)NH2, CH2F, or CH2CN, CH3OCH(0), CH3OC(0)X, CH30C(0)N(X)2; where X is an akyl, allyl, oxyalkyl, oxyallyl; wherein R4is H, or OH; wherein R5is OH, or H; wherein R6is O, or C(CH3)2; andwherein A is spirocyclopropane, or Y ; where Y is an alkyl, allyl, amine, H, ether, ester, C(0)CH3,or C(0)OCH3;where Y’ is an alkyl, allyl, amine, H, ether, ester, C(0)CH3, or C(0)0CH3.

7. The therapeutic formulation of claim 1, further comprising a mucoadhesive nanoparticle liquid base, wherein the mucoadhesive nanoparticle liquid base is a nanocellulose nanoemulsion stabilized with a polysaccharide.

8. The therapeutic formulation of claim 7, wherein the nanocellulose nanoemulsion further comprises: at least one oil or lipid component, wherein the oil or lipid component is PEG- ylated liposomes, phosphotidyl, or a combination thereof; at least one surfactant, wherein the at least one surfactant is Tween 80, Tween20, Tween 80, Triton X-100, Triton X-114, Span 80, or a combination thereof; and the nanocellulose is nanocellulose crystals.

9. The therapeutic formulation of claim 1 , further comprising an adjuvant, where the adjuvant is a fatty acid or a non-ionic surfactant; wherein the fatty acid is capric acid or lauric acid; and wherein the non-ionic surfactant is poloxamer 188, cremophor EL, laurate sucrose ester, or sucrose cocoate have been shown to increase nasal bioavai!abiiity.

10. The therapeutic formulation of claim 1, wherein the therapeutic formulation is provided at between 10 ug / kg to 100 ug / kg, between 10 ug / kg to 20 ug / kg, or between 50 ug / kg to 100 ug / kg.

11. A composition comprising: a molecule having the formula:wherein Ri is CH3, OH, or OCH3; wherein R2is OH, CH3, or OCH3, OCH(O); wherein R3is CH2OH, CH20C(0)CH3, CH30C(0)NH2, CH2F, or CH2CN, CH30CH(0), CH30C(0)X, CH30C(0)N(X)2;where X is an akyl, allyl, oxyalkyl, oxyallyl; wherein FU is H, or OH; wherein R5 is OH, or H; wherein R6is O, or C(CH3)2; andYU- wherein A is spirocyclopropane, or Y where Y is an alkyl, allyl, amine, H, ether, ester, C(0)CH3,or C(0)OCH3; where Y’ is an alkyl, allyl, amine, H, ether, ester, C(0)CH3, or C(0)OCH3; wherein Ri is not CH3when R2 is OH, and R4 is OH or H, and A is spirocyclopropane; wherein Ri is not OCH3when R2 is CH3, and R4 is OH or H, and A is spirocyclopropane; and wherein wherein Ri is not OH when R2 is CH3, and R4 is OH or H, and A is spirocyclopropane.

12. The composition of claim 11 , wherein Ri and R2 are not concurrently the same moiety; and wherein R4 and R5 are not concurrently the same moiety.

13. The composition of claim 11 , wherein the molecule is 1 ',3',4',6'-tetrahydroxy-2'-(hydroxymethyl)-2',4',6'-trimethyl-1',2',3',4'-tetrahydrospiro[cyclopropane-1 ,5'- inden]-7'(6' / - / )-one, (1',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-7'-oxo-1 ',2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl acetate, (1',3',6'-trihydroxy-4'-methoxy-2',4',6'-trimethyl-7'-oxo-1',2',3',4',6',7'- hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl acetate, T,3',6'- trihydroxy-2'-(hydroxymethyl)-4'-methoxy-2',4',6'-trimethyl-1',2',3',4'- tetrahydrospiro[cyclopropane-1 ,5'-inden]-7'(6' / - / )-one, (1 ',3',4',6'-tetrahydroxy- 2',4',6'-trimethyl-7'-oxo-T,2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'- inden]-2'-yl)methyl carbamate, 2'-(hydroxymethyl)-2',4',6'-trimethyl-7'-(propan- 2-ylidene)-1 ',2',3',4',6',7'-hexahydrospiro[cyclopropane-1 ,5'-indene]-1 ',3',4',6'- tetrol, 2'-(fluoromethyl)-2',4',6'-trimethyl-7'-(propan-2-ylidene)-T,2',3',4',6',7'- hexahydrospiro[cyclopropane-1 ,5'-indene]-1 ',3',4',6'-tetrol, 2'-(fluoromethyl)-1 ',3',4',6'-tetrahydroxy-2',4',6'-trimethyl-1 ',2', 3', 4'- tetrahydrospiro[cyclopropane-1 ,5'-inden]-7'(6' / - / )-one, (1 ',3',4',6'-tetrahydroxy- 2',4',6'-trimethyl-7'-(propan-2-ylidene)-1',2',3',4',6',7'- hexahydrospiro[cyclopropane-1 ,5'-indene]-2'-yl)acetonitrile, (1 ',3',4',6'- tetrahydroxy-2',4',6'-trimethyl-7'-oxo-1',2',3',4',6',7'- hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)acetonitrile, or (1',3',6'- trihydroxy-4’-methoxy-2',4',6'-trimethyl-7'-oxo-T,2',3',4',6',7'- hexahydrospiro[cyclopropane-1 ,5'-inden]-2'-yl)methyl carbamate.

14. The composition of claims 1 through 13, wherein the composition intercalates RNA duplexes of RNA viruses.

15. The composition of claims 1 through 13, wherein the composition blocks helicase activity of RNA viruses.

16. A method of preventing or treating a coronaviral infection, comprising: providing a therapeutic formulation, wherein the therapeutic formulation is prepared by a process comprising: providing one or more root sections of a Pelargonium plant; extracting at least one polyphenol from the one or more root sections of a Pelargonium plant, further comprising: incubating root sections of a Pelargonium plant in water at about 55Ό to about 60Ό; collecting the supernatant from the incubated root sections to form a polyphenol extract; enriching the polyphenols in the polyphenol extract, comprising: incubating the polyphenol extract with polyvinylpyrrolidone; to form an enriched polyphenol extract; filtering the enriched polyphenol extract; eluting the enriched polyphenol extract with 0.5 ml 0.5 N NaOH to form a final polyphenol extract; wherein the composition comprises the final polyphenol extract; and administering the therapeutic formulation to a patient in need thereof.

17. The method of claim 16, wherein the coronaviral infection is a SARS-CoV infection, MERS-CoV infection, or SARS-CoV-2 infection.

18. The method of claim 16, further comprising suspending the therapeutic formulation in a mucoadhesive nanoparticle liquid base prior to the administering step, wherein the nanoparticle liquid base is a nanocellulose nanoemulsion stabilized with a polysaccharide.

19. The method of claim 18, wherein the polysaccharide is a marine sulfated polysaccharide, mucin, pectin, cellulose or combination thereof.

20. The method of claim 16, wherein the therapeutic formulation is administered by nasal inhalation, intravenous infusion, or intramuscular injection.

21. The method of claim 16, wherein the therapeutic formulation is provided at between 10 ug / kg to 100 ug / kg, between 10 ug / kg to 20 ug / kg, or between 50 ug / kg to 100 ug / kg.

22. A method of manufacturing a therapeutic formulation comprising a composition of at least one polyphenol, comprising: providing one or more root sections of a Pelargonium plant; extracting at least one polyphenol from the one or more root sections of a Pelargonium plant, further comprising: incubating root sections of a Pelargonium plant in water at about 55*0 to about 60Ό; collecting the supernatant from the incubated root sections to form a polyphenol extract; enriching the polyphenols in the polyphenol extract, comprising: incubating the polyphenol extract with polyvinylpyrrolidone; to form an enriched polyphenol extract; filtering the enriched polyphenol extract; eluting the enriched polyphenol extract with 0.5 ml 0.5 N NaOH to form a final polyphenol extract; wherein the composition comprises the final polyphenol extract.

23. The method of the claim 22, further comprising fractionating the final polyphenol extract, wherein the fractionating further comprises: suspending the final polyphenol extract in an aqueous buffer;running a reverse phase high liquid chromatography purification comprising an aqueous buffer and an organic solvent at a 90 / 108 gradient and flow rate 250 pl / m; collecting a plurality of fractions; reserving at least one reserved fraction, wherein the reserved fractions are collected at time thirteen minutes to twenty-four minutes, twenty-five minutes to thirty-six minutes, sixty minutes to seventy-two minutes, or a combination thereof.

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