WO2021186438A1 - Molecules that target proteins of coronaviruses and uses thereof as anti-viral "cocktail" - Google Patents
Molecules that target proteins of coronaviruses and uses thereof as anti-viral "cocktail" Download PDFInfo
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- WO2021186438A1 WO2021186438A1 PCT/IL2021/050289 IL2021050289W WO2021186438A1 WO 2021186438 A1 WO2021186438 A1 WO 2021186438A1 IL 2021050289 W IL2021050289 W IL 2021050289W WO 2021186438 A1 WO2021186438 A1 WO 2021186438A1
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- 241000711573 Coronaviridae Species 0.000 title claims abstract description 81
- 230000000840 anti-viral effect Effects 0.000 title claims description 99
- 108090000623 proteins and genes Proteins 0.000 title description 20
- 102000004169 proteins and genes Human genes 0.000 title description 12
- 238000000034 method Methods 0.000 claims abstract description 156
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 116
- 239000010452 phosphate Substances 0.000 claims abstract description 116
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 103
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Definitions
- the invention relates to anti-viral compositions and method of using the same. Specifically, the invention related to compositions having antiviral activity against viruses of the Coronaviridae family and method of using the same.
- Coronaviruses are a diverse group of viruses infecting many different animals, and they can cause mild to severe respiratory infections in humans.
- SARS-CoV severe acute respiratory syndrome coronavirus
- MERS-CoV Middle East respiratory syndrome coronavirus
- SARS-CoV-2 shares 79% genome sequence identity with SARS-CoV and 50% with MERS-CoV24. Its genome organization is shared with other betacoronaviruses. Most of the proteins encoded by SARS-CoV-2 have a similar length to the corresponding proteins in SARS-CoV. Of the four structural genes, SARS-CoV-2 shares more than 90% amino acid identity with SARS-CoV except for the spike (S) gene, which diverges.
- SARS-CoV-2 uses the same receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2). Besides human ACE2 (hACE2), SARS-CoV-2 also recognizes ACE2 from pig, ferret, rhesus monkey, civet, cat, pangolin, rabbit, and dog.
- ACE2 angiotensin-converting enzyme 2
- hACE2 human ACE2
- SARS-CoV-2 also recognizes ACE2 from pig, ferret, rhesus monkey, civet, cat, pangolin, rabbit, and dog.
- the broad receptor usage of SARS-CoV-2 implies that it may have a wide host range, and the varied efficiency of ACE2 usage in different animals may indicate their different susceptibilities to SARS-CoV-2 infection.
- the invention provides a method of treating a condition associated with an infection by a virus of the Coronaviridae family, in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, wherein said phosphate donor potentiates the anti-viral activity of the at least one agent, to thereby effectively treat the condition associated with the infection by the virus of the Coronaviridae family.
- the invention further provides a method of slowing and/or preventing progression of a condition associated with an infection by a virus of the Coronaviridae family in a subject, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to prevent said condition .
- the invention further provides a method of reducing a viral load in a subject infected by a virus of the Coronaviridae family, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the viral load.
- the invention further provides a method of reducing clinical manifestations of an infection by a virus of the Coronaviridae family in a subject in need, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the clinical manifestations.
- the invention further provides a method of reducing at least one surrogate marker associated with an infection by a virus of the Coronaviridae family in a subject diagnosed with said infection, comprising administering to said subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the at least one surrogate marker.
- the invention further provides a method of reducing at least one biomarker associated with an infection by a virus of the Coronaviridae family in a subject diagnosed with said infection, comprising administering to said subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the at least one biomarker.
- the invention further provides a therapeutic combination suitable for administration to a subject in need, comprising: a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, wherein the subject in need is diagnosed with an infection by a virus of the Coronaviridae family.
- the invention further provides a pharmaceutical composition comprising a. at least one at least one agent having an anti-viral activity, b. at least one phosphate donor, and c. at least one pharmaceutically acceptable carrier.
- the invention further provides a method for treating a subject afflicted with a condition associated with an infection by a virus of the Coronaviridae family with a pharmaceutical composition of the invention, comprising the steps of: a) administering a therapeutic amount of the pharmaceutical composition to the subject; b) determining whether the subject is a responder by determining the gene expression profile of the subject, and comparing the gene expression profile to a reference gene expression profile to identify the subject as a responder; and c) continuing the administration if the subject is identified as a responder, or modifying treatment of the subject if the subject is not identified as a responder.
- the invention further provides a method for treating a human subject presenting clinical manifestations associated with infection by a virus of the Coronaviridae family with a pharmaceutical composition of the invention, comprising the steps of:(i) determining the gene expression profile of the subject; (ii) identifying the subject as a predicted responder if the gene expression profile is indicative of subject being a responder; and (iii) administering the pharmaceutical composition to the subject only if the subject is identified as a predicted responder.
- Fig. 1 is a schematic view of Corona viruses enter human cells
- Fig .2 is an exemplary embodiment of the interface of a first agent: antibiotics having RNA-binding site and Clarithromycin or Azithromycin binding to the pocket;
- Fig. 3 is an exemplary embodiment of phosphate enhancement of antiviral-drug and acyclovir binding to the RNA-dependent-RNA- polymerase of SARS-Cov-2; and Fig. 4 is an exemplary embodiment of Azithromycin dose of 500mg per day and multi-target attack of spike glyco-protein by antibiotics and anti-viral drugs.
- the invention provides method of treating a condition associated with an infection by a virus of the Coronaviridae family, in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, wherein said phosphate donor potentiates the anti-viral activity of the at least one agent, to thereby effectively treat the condition associated with the infection by the virus of the Coronaviridae family.
- agent having an anti-viral activity refers, without limitation, to an agent that kills a virus or that suppresses its ability to replicate and, hence, inhibits its capability to multiply and/or reproduce. It can be interchangeably referred as anti-viral drug or anti-viral substance or anti-viral compound.
- the non-limiting list of agents having anti-viral activity includes acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine.
- phosphate donor or "phosphate donor molecule” refers, without limitation to a chemical entity comprising a covalently attached/bound phosphate moiety.
- the non- limiting list of phosphate donors includes dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine- phosphate, inositol monophosphate, and phytic acid (inositol hexakisphosphate ).
- the therapeutically effective amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day.
- the therapeutically effective amount of the at least one agent having an anti-viral activity is 250mg/day to 5000mg/day; 500mg/day to 5000 mg/day; 750mg/day to 5000 mg/day; 1000mg/day to 5000 mg/day; 1200mg/day to 5000 mg/day; 1400mg/day to 5000 mg/day; 1700mg/day to 5000 mg/day; 1850mg/day to 5000 mg/day; 2000mg/day to 5000 mg/day; 2200mg/day to 5000 mg/day; 2400mg/day to 5000 mg/day; 2600mg/day to 5000 mg/day.
- the therapeutically effective amount of the at least one agent having an anti-viral activity is 1000mg/day to 3000mg/day; 1100mg/day to 2900 mg/day; 1200mg/day to 2800 mg/day; 1300mg/day to 2700 mg/day; 1400mg/day to 2600 mg/day; 1500mg/day to 2500 mg/day; 1600mg/day to 2400 mg/day.
- the therapeutically effective amount of the at least one agent having an anti-viral activity is is 250mg/day; 500mg/day; 750 mg/day; 1000 mg/day; 1200 mg/day; 1300 mg/day; 1400mg/day; 1500 mg/day; 1600mg/day; 1700 mg/day; 1800mg/day; 1900 mg/day; 2000mg/day; 2100 mg/day; 2200mg/day; 2300 mg/day; 2400mg/day; 2600 mg/day; 2700mg/day; 2800 mg/day; 2900mg/day; 3000 mg/day.
- the therapeutically effective amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day.
- the therapeutically effective amount of the at least one phosphate donor is 0.25 mg/day to 50mg/day; 0.5 mg/day to 50mg/day; 0.75 mg/day to 50mg/day; 1 mg/day to 50mg/day; 1.25 mg/day to 50mg/day; 1.5mg/day to 50mg/day; 1.75mg/day to 50mg/day; 2mg/day to 50mg/day; 2.25mg/day to 50mg/day; 2.5mg/day to 50mg/day; 2.75mg/day to 50mg/day; 3mg/day to 50mg/day; 3.5mg/day to 50mg/day; 4mg/day to 50mg/day; 4.5mg/day to 50mg/day; 5mg/day to 50mg/day; 5
- the therapeutically effective amount of the at least one phosphate donor is 1mg/day to 15mg/day; 1.5mg/day to 14.5 mg/day; 2mg/day to 14 mg/day; 2.5mg/day to 13.5 mg/day; 3mg/day to 13mg/day; 4mg/day to 12 mg/day; 5mg/day to 11mg/day; 6mg/day to 10mg/day.
- the therapeutically effective amount of the at least one phosphate donor is 1mg/day; 2mg/day; 2.5 mg/day; 3mg/day; 3.5mg/day; 4mg/day; 4.5mg/day; 5mg/day; 5.5mg/day; 6mg/day; 6.5mg/day; 7mg/day; 7.5mg/day; 8mg/day; 8.5mg/day; 9mg/day; 9.5mg/day; 10mg/day; 10.5mg/day; 11mg/day;
- the antiviral agent is acyclovir
- the phosphate donor is dexamethasone phosphate
- the daily dose of the anti-viral agent and/or phosphate donor can be administered at once, or, alternatively can be split into several administration and/or can be given according to any desired regimen.
- the anti-viral agent and the phosphate donor are administered simultaneously.
- the anti-viral agent and the phosphate donor are administered independently of each other.
- the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
- the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
- the subject is a mammalian subject.
- the term "mammalian” is interchangeable with "mammal”.
- the mammalian subject is a human subject.
- the non- limiting list of conditions associated with an infection by a virus of the Coronaviridae family includes acute respiratory distress syndrome (ARDS), common cold, pneumonia, bronchitis, severe acute respiratory syndrome, and Middle East respiratory syndrome .
- the above method further comprises administering to the subject a therapeutically effective amount of at least one antimicrobial agent.
- the term "antimicrobial agent” refers, without limitation, to drugs, chemicals, or other substances that either kill or slow the growth of microbes.
- the antimicrobial agents of the invention are antibacterial drugs, antifungal agents, and antiparasitic drugs.
- the antimicrobial agent is macrolide.
- a non-limiting list of the antimicrobial agents of the invention includes Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin,
- the antimicrobial agent is azithromycin.
- the dosing regimen of the antimicrobial agent is any state-of-the-art regimen and any administration regime.
- the invention provides a method of slowing and/or preventing progression of a condition associated with an infection by a virus of the Coronaviridae family in a subject, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to prevent said condition .
- said phosphate donor potentiates the anti-viral activity of the at least one agent.
- the phrase "slowing and/or preventing progression” refers, without limitation, to the influence of the treatment on the clinical course of the disease.
- illness severity of SARS- CoV-2 ranges from mild to critical, while mild to moderate disease is categorized as mild symptoms up to mild pneumonia; severe disease has manifestations of dyspnea, hypoxia, or more than 50% lung involvement on imaging; and critical disease has manifestations of respiratory failure, shock, or multiorgan system dysfunction, which may result in death (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical- guidance-management-patients.html) .
- the proposed therapy is aimed at slowing and/or preventing the transition from mild to severe and to critical illness.
- the "slowing and/or preventing" progression of the condition according to the embodiments of the above method may be measured using any appropriate questionary, method, scale, diagnostic tool, or any other means that are known in the art or acceptable by the relevant functions and professionals.
- the term “preventing” might but does not necessarily mean recovery from the illness. As such, the term “preventing” relates to the situation when the patient does not present symptoms and/or signs and/or manifestations of the next "stage” of illness severity as defined by the appropriate and acceptable parameters for the specific disease condition.
- the term “slowing”, or attenuating is can, without limitation, prolong the time of transition into the next "stage” of illness severity, thus providing greater window of opportunity for extensive care and recovery.
- the non- limiting list of conditions associated with an infection by a virus of the Coronaviridae family includes acute respiratory distress syndrome (ARDS), common cold, pneumonia, bronchitis, severe acute respiratory syndrome, and Middle East respiratory syndrome .
- ARDS acute respiratory distress syndrome
- common cold pneumonia
- bronchitis severe acute respiratory syndrome
- Middle East respiratory syndrome Middle East respiratory syndrome
- the non- limiting list of agents having anti-viral activity includes acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine.
- the non-limiting list of phosphate donors includes dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine- phosphate, inositol monophosphate, and phytic acid (inositol hexakisphosphate ).
- the antiviral agent is acyclovir
- the phosphate donor is dexamethasone-phosphate.
- the effective amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day. In one embodiment, the effective amount of the at least one agent having an anti-viral activity is 250mg/day to 5000mg/day; 500mg/day to 5000 mg/day; 750mg/day to 5000 mg/day; 1000mg/day to 5000 mg/day; 1200mg/day to 5000 mg/day; 1400mg/day to 5000 mg/day; 1700mg/day to 5000 mg/day; 1850mg/day to 5000 mg/day; 2000mg/day to 5000 mg/day; 2200mg/day to 5000 mg/day; 2400mg/day to 5000 mg/day; 2600mg/day to 5000 mg/day.
- the effective amount of the at least one agent having an anti-viral activity is 1000mg/day to 3000mg/day; l100mg/day to 2900 mg/day; 1200mg/day to 2800 mg/day; 1300mg/day to 2700 mg/day; 1400mg/day to 2600 mg/day; 1500mg/day to 2500 mg/day; 1600mg/day to 2400 mg/day.
- the effective amount of the at least one agent having an anti-viral activity is 250mg/day; 500mg/day; 750 mg/day; 1000 mg/day; 1200 mg/day; 1300 mg/day; 1400mg/day; 1500 mg/day; 1600mg/day; 1700 mg/day; 1800mg/day; 1900 mg/day; 2000mg/day;
- the effective amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day. In one embodiment, the effective amount of the at least one phosphate donor is 0.25 mg/day to 50mg/day; 0.5 mg/day to 50mg/day; 0.75 mg/day to 50mg/day; 1 mg/day to 50mg/day; 1.25 mg/day to 50mg/day; 1 .5mg/day to 50mg/day; 1.75mg/day to 50mg/day; 2mg/day to 50mg/day; 2.25mg/day to 50mg/day; 2.5mg/day to 50mg/day; 2.75mg/day to 50mg/day; 3mg/day to 50mg/day; 3.5mg/day to 50mg/day; 4mg/day to 50mg/day; 4 .5mg/day to 50mg/day; 5mg/day to 50mg/day;
- the effective amount of the at least one phosphate donor is 1mg/day to 15mg/day; 1.5mg/day to 14.5 mg/day; 2mg/day to 14 mg/day; 2.5mg/day to 13.5 mg/day; 3mg/day to 13mg/day; 4mg/day to 12 mg/day; 5mg/day to 11mg/day; 6mg/day to 10mg/day.
- the effective amount of the at least one phosphate donor is 1mg/day; 2mg/day; 2.5 mg/day; 3mg/day; 3.5mg/day; 4mg/day; 4.5mg/day; 5mg/day; 5.5mg/day; 6mg/day; 6.5mg/day; 7mg/day; 7.5mg/day; 8mg/day; 8.5mg/day; 9mg/day; 9.5mg/day; 10mg/day; 10.5mg/day; 11mg/day;
- the daily dose of the anti-viral agent and/or phosphate donor can be administered at once, or, alternatively can be split into several administration and/or can be given according to any desired regimen.
- the anti-viral agent and the phosphate donor are administered simultaneously.
- the anti-viral agent and the phosphate donor are administered independently of each other.
- the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19), SAKS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
- the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
- the above method further comprises administering to the subject a therapeutically effective amount of at least one antimicrobial agent.
- the antimicrobial agent is macrolide.
- a non-limiting list of the antimicrobial agents of the invention includes Azithromycin, Boromycin, Clarithromycin,
- the invention provides method of reducing clinical manifestations of an infection by a virus of the Coronaviridae family in a subject in need, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the clinical manifestations.
- said phosphate donor potentiates the anti- viral activity of the at least one agent.
- clinical manifestations refers, without limitation, to signs and symptoms of the disease that can be either objective, when observed by a physician, or subjective, when perceived by the patient.
- the non- limiting list of agents having anti-viral activity includes acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine.
- the non-limiting list of phosphate donors includes dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine- phosphate, inositol monophosphate, and phytic acid (inositol hexakisphosphate ).
- the antiviral agent is acyclovir
- the phosphate donor is dexamethasone-phosphate.
- the effective amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day. In one embodiment, the effective amount of the at least one agent having an anti-viral activity is 250mg/day to 5000mg/day; 500mg/day to 5000 mg/day; 750mg/day to 5000 mg/day; 1000mg/day to 5000 mg/day; 1200mg/day to 5000 mg/day; 1400mg/day to 5000 mg/day; 1700mg/day to 5000 mg/day; 1850mg/day to 5000 mg/day; 2000mg/day to 5000 mg/day; 2200mg/day to 5000 mg/day; 2400mg/day to 5000 mg/day; 2600mg/day to 5000 mg/day.
- the effective amount of the at least one agent having an anti-viral activity is 1000mg/day to 3000mg/day; l100mg/day to 2900 mg/day; 1200mg/day to 2800 mg/day; 1300mg/day to 2700 mg/day; 1400mg/day to 2600 mg/day; 1500mg/day to 2500 mg/day; 1600mg/day to 2400 mg/day.
- the effective amount of the at least one agent having an anti-viral activity is 250mg/day; 500mg/day; 750 mg/day; 1000 mg/day; 1200 mg/day; 1300 mg/day; 1400mg/day; 1500 mg/day; 1600mg/day; 1700 mg/day; 1800mg/day; 1900 mg/day; 2000mg/day; 2100 mg/day; 2200mg/day; 2300 mg/day; 2400mg/day; 2600 mg/day; 2700mg/day; 2800 mg/day; 2900mg/day; 3000 mg/day.
- the effective amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day. In one embodiment, the effective amount of the at least one phosphate donor is 0.25 mg/day to 50mg/day; 0.5 mg/day to 50mg/day; 0.75 mg/day to 50mg/day; 1 mg/day to 50mg/day; 1.25 mg/day to 50mg/day; 1 .5mg/day to 50mg/day; 1.75mg/day to 50mg/day; 2mg/day to 50mg/day; 2.25mg/day to 50mg/day; 2.5mg/day to 50mg/day; 2.75mg/day to 50mg/day; 3mg/day to 50mg/day; 3.5mg/day to 50mg/day; 4mg/day to 50mg/day; 4 .5mg/day to 50mg/day; 5mg/day to 50mg/day;
- the effective amount of the at least one phosphate donor is 1mg/day to 15mg/day; 1.5mg/day to 14.5 mg/day; 2mg/day to 14 mg/day; 2.5mg/day to 13.5 mg/day; 3mg/day to 13mg/day; 4mg/day to 12 mg/day; 5mg/day to 11mg/day; 6mg/day to 10mg/day.
- the effective amount of the at least one phosphate donor is 1mg/day; 2mg/day; 2.5 mg/day; 3mg/day; 3.5mg/day; 4mg/day; 4.5mg/day; 5mg/day; 5.5mg/day; 6mg/day; 6.5mg/day; 7mg/day; 7.5mg/day; 8mg/day; 8.5mg/day; 9mg/day; 9.5mg/day; 10mg/day; 10.5mg/day; 11mg/day; 11.5mg/day; 12mg/day; 12 .5mg/day; 13mg/day; 13.5mg/day; 14mg/day; 14.5mg/day; 15mg/day.
- the daily dose of the anti-viral agent and/or phosphate donor can be administered at once, or, alternatively can be split into several administration and/or can be given according to any desired regimen.
- the anti-viral agent and the phosphate donor are administered simultaneously.
- the anti-viral agent and the phosphate donor are administered independently of each other.
- the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
- the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
- the above method further comprises administering to the subject a therapeutically effective amount of at least one antimicrobial agent.
- the antimicrobial agent is macrolide.
- a non-limiting list of the antimicrobial agents of the invention includes Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin, Flurithromycin, Ivermectin, Josamycin, Midecamycin, Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin. Any acceptable dose and administration regimen of the antimicrobial agent according to the embodiments of the invention can be used.
- the invention provides a method of reducing a viral load in a subject infected by a virus of the Coronaviridae family, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the viral load.
- viral load refers, without limitation, to a numerical expression of the quantity of virus in a given volume of fluid.
- the non- limiting list of agents having anti-viral activity includes acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine .
- the non- limiting list of phosphate donors includes dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine- phosphate, inositol monophosphate, and phytic acid (inositol hexakisphosphate ).
- the effective amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day. In one embodiment, the effective amount of the at least one agent having an anti-viral activity is 250mg/day to 5000mg/day; 500mg/day to 5000 mg/day; 750mg/day to 5000 mg/day; 1000mg/day to 5000 mg/day; 1200mg/day to 5000 mg/day; 1400mg/day to 5000 mg/day; 1700mg/day to 5000 mg/day; 1850mg/day to 5000 mg/day; 2000mg/day to 5000 mg/day; 2200mg/day to 5000 mg/day; 2400mg/day to 5000 mg/day; 2600mg/day to 5000 mg/day.
- the effective amount of the at least one agent having an anti-viral activity is 1000mg/day to 3000mg/day; 1100mg/day to 2900 mg/day; 1200mg/day to 2800 mg/day; 1300mg/day to 2700 mg/day; 1400mg/day to 2600 mg/day; 1500mg/day to 2500 mg/day; 1600mg/day to 2400 mg/day.
- the effective amount of the at least one agent having an anti-viral activity is 250mg/day; 500mg/day; 750 mg/day; 1000 mg/day; 1200 mg/day; 1300 mg/day; 1400mg/day; 1500 mg/day; 1600mg/day; 1700 mg/day; 1800mg/day; 1900 mg/day; 2000mg/day; 2100 mg/day; 2200mg/day; 2300 mg/day; 2400mg/day; 2600 mg/day;
- the effective amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day. In one embodiment, the effective amount of the at least one phosphate donor is 0.25 mg/day to 50mg/day; 0.5 mg/day to 50mg/day; 0.75 mg/day to 50mg/day; 1 mg/day to 50mg/day; 1.25 mg/day to 50mg/day; 1 .5mg/day to 50mg/day; 1.75mg/day to 50mg/day; 2mg/day to 50mg/day; 2.25mg/day to 50mg/day; 2.5mg/day to 50mg/day; 2.75mg/day to 50mg/day; 3mg/day to 50mg/day; 3.5mg/day to 50mg/day; 4mg/day to 50mg/day; 4 .5mg/day to
- the effective amount of the at least one phosphate donor is 1mg/day to 15mg/day; 1.5mg/day to 14.5 mg/day; 2mg/day to 14 mg/day; 2.5mg/day to 13.5 mg/day; 3mg/day to 13mg/day; 4mg/day to 12 mg/day; 5mg/day to 11mg/day; 6mg/day to 10mg/day.
- the effective amount of the at least one phosphate donor is 1mg/day; 2mg/day; 2.5 mg/day; 3mg/day; 3.5mg/day; 4mg/day; 4.5mg/day; 5mg/day; 5.5mg/day; 6mg/day; 6.5mg/day; 7mg/day; 7.5mg/day; 8mg/day; 8.5mg/day; 9mg/day; 9.5mg/day; 10mg/day; 10.5mg/day; 11mg/day; 11.5mg/day; 12mg/day; 12 .5mg/day; 13mg/day; 13.5mg/day; 14mg/day; 14.5mg/day; 15mg/day.
- the daily dose of the anti-viral agent and/or phosphate donor can be administered at once, or, alternatively can be split into several administration and/or can be given according to any desired regimen.
- the anti-viral agent and the phosphate donor are administered simultaneously.
- the anti-viral agent and the phosphate donor are administered independently of each other.
- the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
- the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
- the above method further comprises administering to the subject a therapeutically effective amount of at least one antimicrobial agent.
- the antimicrobial agent is macrolide.
- a non-limiting list of the antimicrobial agents of the invention includes Azithromycin, Boromycin, Clarithromycin,
- the viral log is reduced by at least 1.3 log to 10 log. According to some embodiments of the above method, the viral log is reduced by at least 1.3 log, 1.5 log, 1.7 log, 2 log, 2.25 log, 2.5 log, 2.75 log, 3 log, 3.25 log, 3.751og, 4 log, 4.25 log, 4.5 log, 4.75 log, 5 log, 5.25 log, 5.5 log, 5.75 log, 6 log; 6.25 log, 6.5 log, 6.75 log, 7 log, 7.25 log, 7.5 log, 7.75 log, 8 log, 8.25 log, 8.5 log, 8.75 log, 9 log, 9.25 log, 9.5 log, 9.75 log, 10 log.
- the invention provides a method of reducing at least one surrogate marker associated with an infection by a virus of the Coronaviridae family in a subject diagnosed with said infection, comprising administering to said subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the at least one surrogate marker.
- surrogate marker refers, without limitation, to a measure of effect of a specific treatment that may correlate with a real clinical endpoint but does not necessarily have a guaranteed relationship.
- the non-limiting list of possible surrogate markers includes DMA, mRNA, antigen, antibody, and any combination thereof.
- the invention provides a method of reducing at least one biomarker associated with an infection by a virus of the Coronaviridae family in a subject diagnosed with said infection, comprising administering to said subject c. at least one agent having an anti-viral activity, and d. at least one phosphate donor, in an amount effective to reduce the at least one biomarker, wherein said phosphate donor potentiates the anti-viral activity of the at least one agent.
- biomarker refers, without limitation, to A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention . This definition encompasses therapeutic interventions and can be derived from molecular, histologic, radiographic, or physiologic characteristics
- biomarkers of the invention includes SLP1, ID01, SLC7A11, PTGS2,MR1, PNP, ABCG2, CXCL8, MMP1, ARG1, CCL2, BCL2L1, CTSB, HEXB, ARSA, and MAN2B2 and/or other genes.
- the invention provides therapeutic combination suitable for administration to a subject in need, comprising: a. at least one agent having an anti-viral activity; b. at least one phosphate donor; wherein the subject in need is diagnosed with an infection by a virus of the Coronaviridae family.
- therapeutic combination is meant to be understood, without limitation, as a combination of a number of components: at least one agent having an anti-viral activity with at least one phosphate donor that is administered to a subject in need to provide a desirable therapeutic effect.
- the at least two components can be given in a single formulation or each as a separate medicament; they can be administered simultaneously, or alternatively, can have each a specific dosing regimen and/or administration regime.
- the combination according to the embodiments of the invention can be a synergistic combination, while the combined effect is larger than the additive effect of each individual drug. In one embodiment, the combination has an additive effect on the clinical outcome.
- the non- limiting list of agents having anti-viral activity includes acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine.
- the non-limiting list of phosphate donors includes dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine-phosphate, inositol monophosphate, and phytic acid (inositol hexakisphosphate).
- the antiviral agent is acyclovir
- the phosphate donor is dexamethasone phosphate.
- the amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day. In one embodiment, the amount of the at least one agent having an anti-viral activity is
- the amount of the at least one agent having an anti-viral activity is 1000mg/day to 3000mg/day;
- the amount of the at least one agent having an anti-viral activity is
- the amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day. In one embodiment, the amount of the at least one phosphate donor is 0.25 mg/day to 50mg/day; 0.5 mg/day to 50mg/day; 0.75 mg/day to 50mg/day; 1 mg/day to 50mg/day; 1.25 mg/day to 50mg/day; 1 .5mg/day to 50mg/day; 1.75mg/day to 50mg/day; 2mg/day to 50mg/day; 2.25mg/day to 50mg/day; 2.5mg/day to 50mg/day; 2.75mg/day to 50mg/day; 3mg/day to 50mg/day; 3.5mg/day to 50mg/day; 4mg/day to 50mg/day; 4 .5mg/day to
- the amount of the at least one phosphate donor is 1mg/day to 15mg/day; 1.5mg/day to 14.5 mg/day; 2mg/day to 14 mg/day; 2.5mg/day to 13.5 mg/day; 3mg/day to 13mg/day; 4mg/day to 12 mg/day; 5mg/day to 11mg/day; 6mg/day to 10mg/day.
- the amount of the at least one phosphate donor is 1mg/day; 2mg/day; 2.5 mg/day; 3mg/day; 3.5mg/day; 4mg/day; 4.5mg/day; 5mg/day; 5.5mg/day; 6mg/day; 6.5mg/day; 7mg/day; 7.5mg/day; 8mg/day; 8.5mg/day; 9mg/day;
- the above combination further comprises at least one antimicrobial agent.
- the antimicrobial agent is macrolide.
- a non-limiting list of the antimicrobial agents of the invention includes Azithromycin, Boromycin, Clarithromycin,
- the virus of the Coronaviridae family is selected from the group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
- the virus of the Coronaviridae family is selected from the group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
- the virus of the virus of the Coronaviridae family is selected from the group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
- Coronaviridae family is SARS-CoV-2 (COVID-19).
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a. at least one at least one agent having an anti-viral activity, b. at least one phosphate donor, and c. at least one pharmaceutically acceptable carrier
- the non-limiting list of agents having anti-viral activity includes acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV- 100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir ala
- the non-limiting list of phosphate donors includes dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine-phosphate, inositol monophosphate, and phytic acid (inositol hexakisphosphate).
- the antiviral agent is acyclovir
- the phosphate donor is dexamethasone phosphate.
- the amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day. In one embodiment, the amount of the at least one agent having an anti- viral activity is 250mg/day to 5000mg/day; 500mg/day to 5000 mg/day; 750mg/day to 5000 mg/day; 1000mg/day to 5000 mg/day; 1200mg/day to 5000 mg/day; 1400mg/day to 5000 mg/day; 1700mg/day to 5000 mg/day; 1850mg/day to 5000 mg/day; 2000mg/day to 5000 mg/day; 2200mg/day to 5000 mg/day; 2400mg/day to 5000 mg/day; 2600mg/day to 5000 mg/day.
- the amount of the at least one agent having an anti-viral activity is 1000mg/day to 3000mg/day; 1100mg/day to 2900 mg/day; 1200mg/day to 2800 mg/day; 1300mg/day to 2700 mg/day; 1400mg/day to 2600 mg/day; 1500mg/day to 2500 mg/day; 1600mg/day to 2400 mg/day. In one embodiment, the amount of the at least one agent having an anti- viral activity is 250mg/day; 500mg/day; 750 mg/day; 1000 mg/day; 1200 mg/day; 1300 mg/day; 1400mg/day; 1500 mg/day;
- the amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day. In one embodiment, the amount of the at least one phosphate donor is 0.25 mg/day to 50mg/day; 0.5 mg/day to 50mg/day; 0.75 mg/day to 50mg/day; 1 mg/day to 50mg/day; 1.25 mg/day to 50mg/day; 1.5mg/day to 50mg/day; 1.75mg/day to 50mg/day; 2mg/day to 50mg/day; 2.25mg/day to 50mg/day; 2.5mg/day to 50mg/day; 2.75mg/day to 50mg/day; 3mg/day to 50mg/day; 3 .5mg/day to 50mg/day; 4mg/day to 50mg/day; 4.5mg/day to 50mg/day; 5mg/day to 50mg/day; 5 .5m
- the amount of the at least one phosphate donor is 1mg/day; 2mg/day; 2.5 mg/day; 3mg/day; 3.5mg/day; 4mg/day; 4.5mg/day; 5mg/day; 5.5mg/day; 6mg/day; 6.5mg/day; 7mg/day; 7.5mg/day; 8mg/day; 8.5mg/day; 9mg/day; 9.5mg/day; 10mg/day; 10.5mg/day; 11mg/day;
- the above pharmaceutical composition further comprises at least one antimicrobial agent.
- the antimicrobial agent is macrolide.
- a non-limiting list of the antimicrobial agents of the invention includes Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin, Flurithromycin, Ivermectin, Josamycin, Midecamycin, Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin.
- the virus of the Coronaviridae family is selected from the group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
- the virus of the Coronaviridae family is selected from the group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
- the virus of the virus of the Coronaviridae family is selected from the group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
- Coronaviridae family is SARS-CoV-2 (COVID-19).
- the pharmaceutical composition according to the embodiments of the invention may be a fixed dosage form composition.
- the pharmaceutical composition is a solid composition, a liquid composition, or a semi-solid composition.
- the pharmaceutical composition is designed for oral administration, intra-muscular administration, intravenous administration, intraperitoneal administration, intranasal administration, intramucosal administration, or transdermal administration.
- the pharmaceutical composition is in the form of a tablet, a capsule, a powder, a powder for suspension, a powder for reconstitution, granules, a syrup, a suspension, and a dispersion.
- the invention provides the above pharmaceutical composition for use as a medicament. According to some embodiments, the invention provides the above pharmaceutical composition for use in the treatment of a condition associated with an infection by a virus of the Coronaviridae family, in a subject in need of such treatment.
- the condition associated with the infection by a virus of the Coronaviridae family is selected from the group consisting ofacute respiratory distress syndrome (ARDS), common cold, pneumonia, bronchitis, severe acute respiratory syndrome, and Middle East respiratory syndrome.
- ARDS acute respiratory distress syndrome
- common cold common cold
- pneumonia bronchitis
- severe acute respiratory syndrome severe acute respiratory syndrome
- Middle East respiratory syndrome Middle East respiratory syndrome
- the invention provides method for treating a subject afflicted with a condition associated with an infection by a virus of the Coronaviridae family with a pharmaceutical composition according to the embodiments of the invention, comprising the steps of: a) administering a therapeutic amount of the pharmaceutical composition to the subject; b) determining whether the subject is a responder by determining the gene expression profile of the subject, and comparing the gene expression profile to a reference gene expression profile to identify the subject as a responder; and c) continuing the administration if the subject is identified as a responder, or modifying treatment of the subject if the subject is not identified as a responder.
- the term "responder” is meant to be understood, without limitation, as a subject who, based on his gene expression profile, namely specific biomarkers, is likely to respond to the proposed treatment.
- genetic profile of the Responder is characterized by upregulation and/or downregulation of certain genes
- genetic profile of the Non-Responder is characterized by different pattern of gene expression.
- the reason for the differentiated response can be a result of various cellular pathway and processes.
- the change in genetic profile may be triggered, without limitation, by administration of the proposed therapeutics and/or by the infection itself.
- the variability in the response of different people to viral infection and may lead to differential gene expression and different response to therapeutic tool.
- administration of similar therapeutics to different people may lead to different gene expression pattern which becomes a determinant of the clinical outcome.
- the invention further provides a method for treating a human subject presenting clinical manifestations associated with infection by a virus of the Coronaviridae family with a pharmaceutical composition according to the embodiments of the invention, comprising the steps of:(i) determining the gene expression profile of the subject;(ii) identifying the subject as a predicted responder if the gene expression profile is indicative of subject being a responder; and(iii) administering the pharmaceutical composition to the subject only if the subject is identified as a predicted responder
- a non-limiting list of clinical manifestations includes fever, cough, dyspnea, hypoxia, more than 50% lung involvement on imaging, respiratory failure, shock, multiorgan system dysfunction, malaise, fatigue, sputum/secretion, neurological symptoms, dermatological manifestations, anorexia, myalgia, sneezing, sore throat, rhinitis, goosebumps, headache, chest pain and diarrhea.
- Acyclovir is the pro-drug undergoing two/three-step phosphorylation before its binding (as the Acyclovir triphosphate) to the viral (the HSV) DMA Dependent RNA Polymerase.
- One key enzyme is the viral thymidine kinase which is present in this family of viruses. However the thymidine kinase is not reported in the beta- coronavirus family.
- bioinformatics tools we also have demonstrated the absence of the thymidine kinase in the beta- coronavirus SARS CoV-2. This explains why acyclovir did not suppressed coronaviruses in-vitro experiments.
- RNA Dependent RNA Polymerases RdRp
- RNA-polymerase specific RNA-polymerase specific and, therefore, it can be considered as better candidate for targeting SARS-CoV-2.
- Remdesivir is also designed as the pro-drug. After initial metabolic cleavage, the remdesivir intermediate phosphorylates and binds to SARS-CoV-2 RNA- polymerase.
- pro-drugs with same anti-viral mechanism: Ribavirin and Zidovudine.
- Example 1 Homology modeling of SARS-CoV-2 Targets.
- CoVid-2 we data-mined the Protein Data Bank with FDA approved antibiotics, namely, Doxycycline, Azithromycin, Clarithromycin, Amikacin, Tobramycin, etc. as queries. Structures were further studied and compared using different structure superimposing servers Vector Alignment Search Tool (VAST), PDBefold,
- VAST Vector Alignment Search Tool
- Combinatorial Extension CE
- threading servers PHYRE, 3D- Position Specific Scoring Matrix (3DPSSM). Hits with bound antibiotics/antiviral drugs were selected, and multiple structure-based sequence alignments were performed. Based on these alignments, structures from PDB were selected as multiple templates and used for further modelling based on SWISS-MODEL, MODELLER, and iTASSER protocols.
- the modules from OpenBabel suite and Chimera vl.11.2 were used to prepare ligand molecules for docking.
- 3D structures of antiviral/antibiotics molecules were taken from PDB (such as Doxycycline, Azithromycin, Clarithromycin, Amikacin, Tobramycin, etc.). All possible ionization states and tautomers were generated and prepared for docking study.
- Molecular conformers were generated and docked to the areas identified as binding sites, using AutoDock4 and AutoDock Vina docking protocols. Docking strategy included writing per-residue interaction energy values in order to determine key residues involved in antibiotics binding and selectivity.
- RNA binding site with the viral RNA the SARS-CoV-2 surface binding to the human cell receptor ACE2 binding site
- Figure 1 All the anti-pneumonia agents, particularly, antibiotics we collected (Table 1). Most interesting there were molecules with a mechanism of actions to RNA, such as a binding to the 50S subunit of the bacterial ribosome, thus, inhibiting translation of mRNA.
- antibiotics are known to have RNA binding property and may prevent virus from two functions: (1) virus particle re- assembly by binding of the S-glycoprotein to the viral surface, and (2) binding of this glycoprotein to human/host ACE2 receptor ( Figures 2-4). Table 1. antibiotics drugs candidates:
- Example 2 Antiviral cocktail based on Acyclovir and Dexamethasone Phosphate against COVID-19.
- a new pharmaceutical combination was designed, aimed to enhance the pharmaco-therapeutic potential of Acyclovir in the treatment of patients infected by SAKS-CoV-2.
- An additional phosphate donor was antibiotic Fosfomycin (the phosphoenolpyruvate analogue with the phosphate group bound to epoxypropyl moiety. Fosfomycin is old well- tolerated antimicrobial drug.
- this small molecule may enter inter-helical pores of viral surface proteins, in particular, the S-glycoprotein and thus may be in the pharmacological synergism with acyclovir action.
- This biochemical and pharmacological synergism of the Acyclovir & Dexamethasole and Acyclovir & Fosfomycin compositions provided with promising opportunity in the current urgent need of novel methods to stop the outburst of the SARS-CoV-2.
- Example 3 POC Testing for Human Coronavirus OC43 (hCoV-OC43) Attenuation by Acyclovir 6 Dexamethasone Phosphate Liquid Formula
- the aim of the study was POC testing of the antiviral potential of a formula containing acyclovir and dexamethasone phosphate, on human coronavirus OC43 (hCoV-OC43), by cytopathogenic effect (CPE) monitoring and cell viability assay.
- hCoV-OC43 human coronavirus OC43
- CPE cytopathogenic effect
- Fetal Bovine Serum (FBS; Biological Industries, Cat # 04- 127-1A)
- Human coronavirus OC43 (hCoV-OC43; stock titer: 6.36x106 TCID50/ml)
- MRC5 cells (4.1) were grown in MEM medium (4.5) supplemented with 2mM L-Alanyl-L-Glutamine (4.2), 1%
- acyclovir- dexamethasone- phosphate formula was prepared as follows: 1.8 mg acyclovir (2.1) were dissolved in 1ml sterile DDW at 370C (to reach a final concentration of 8mM) . In parallel, l.1mg dexamethasone phosphate (2.2) were dissolved in 1ml 0.1M NaOH (to reach a final concentration of 100 ⁇ /mL).
- MTT viability assay On day 6 of the test, the growth medium was removed from each well. Next, 5 mg/ml MTT compound (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide, in PBS) was diluted 1:7.5 in MEM, and 150 ⁇ l of the diluted MTT were added per well as replacement medium. The plate was then incubated for 2 hours at 370C and 5% CO2. Following incubation, medium + MTT was removed, and 100 ⁇ DMSO were added per well. The plate was incubated for 15 minutes at room temperature following DMSO addition, and was read by SPECTRAFluor Plus plate reader (Tecan) at 560nm. MTT assay results are presented in Table 3.
- acyclovir- dexamethasone phosphate formula stock solution was prepared as described above (final concentrations: 4mM acyclovir, ImM dexamethasone phosphate) .
- the formula stock solution was filter sterilized through a Minisart syringe filter (0.2 ⁇ m filter; 4.7), and was then diluted to provide 4 concentrations as follows:
- NC-c negative control
- the MRC5 96-well plate was then returned to the incubator for 3 additional days at 350C and 5% CO 2 , and monitored every 24 hours under the microscope .
- Cell viability was determined by MTT assay on day 6 of the experiment.
- MTT viability assay on day 6 of the experiment the growth medium was removed from each well. Next, the procedure as described in section was performed. MTT assay results are presented in Table 4.
- NC-tox negative control (i.e cells incubated with MEM medium only)
- % Cell viability indicating viable cells per sample. Cell viability per each sample was calculated as percentage of the average MTT result of each triplicate, from the average of NC wells MTT results, which was regarded as representing 100% cell viability.
- Cytotoxicity test results (as presented in Table 5): the assay was performed diluting the formula to 4 concentrations (as shown in Table 3). In the assay substantial cell death was observed when concentration I of the formula was applied to MRC5 cells and less than 50% death when dilution II was applied to the cells. These results indicate a potential anti-tumor activity of the formula at high concentrations. When dilutions III and IV were applied to the cells, there was no cell death observed. Based on these results it was decided to apply to the infected MRC5 cells, in the acyclovir-dexamethasone phosphate antiviral activity experiment, the formula concentrations: II, III, IV, as well as an additional 2-fold dilution of concentration IV (i.e.
- % Cell viability indicating viable cells per sample. Cell viability per each sample was calculated as percentage of the average MTT result of each treatment concentration + hCoV-OC43 infection, from the average of MTT result of the same treatment concentration with no hCoV-OC43 infection.
- Initial viral TCID50 the viral inoculum used to infect the cells on day 1 of the experiment.
- Viral log reduction is calculated by dividing the initial viral TCID50 by the end viral TCID50 in each sample.
- CPE / outset day the viral cytopathogenic effects as observed under the microscope during the 6 days of experiment.
- +-- " minimal CPE. Day indicates the outset day of observed CPE.
- the results indicate that the tested formula, as tested in the current study, does hamper hCoV-OC43 infectivity and reduce viral load by 1.5 log following 2 dose treatment, and incubation for 3 days following treatment (as indicated in Table 4).
- CPE viral cytopathogenic effects
- CXCL8 (also referred to as IL-8) is a chemokine considered a potential prognostic biomarker for acute respiratory distress syndrome (ARDS) clinical course.
- CXCL8 plays a vital role in the early control of respiratory tract infection due to its chemotactic activity for neutrophils and monocytes.
- the activity of CXCL8 is strongly reliant on the transcription factor AP-1 and is associated with the spike and nucleocapsid proteins of SARS-CoV-2.
- CXCL8 stimulates the formation of the highly immunogenic and toxic neutrophil extracellular traps (NETs) that lead to inflammation and apoptosis of epithelial/endothelial cells.
- NETs highly immunogenic and toxic neutrophil extracellular traps
- CXCL8 is consistently up-regulated in the bronchoalveolar lavage fluid (BALF) of severe COVID-19 patients.
- BALF bronchoalveolar lavage fluid
- CXCL8 could be used as a biomarker for severe COVID-19 cases as they are not found to be up-regulated in peripheral blood mononuclear cell (PBMC) of mild COVID-19 patients. Therefore, inhibitors of CXCL8 could be considered as possible therapeutic modalities for severe COVID-19.
- PBMC peripheral blood mononuclear cell
- Acyclovir and Azithromycin are the most effective FDA-approved drugs that could be used for controlling the expression of CXCL8. Our studies suggest that a combination of these two drugs could be useful for treating severe COVID-19 cases to reduce the chances of ARDS.
- Non-severe COVID-19 (DE based on PBMC data)
- Example 4 Clinical trial evaluating safety and efficacy of the combination of Acyclovir 6 dexamethasone phosphate on clinical manifestation of COVID-19 infection
- phase I including approximately 10 patients
- phase II double blinded study including about 50-100 moderate COVID- 19 patients.
- a at least one endpoint of the study is assessing antiviral effect of the combination versus standard of care treatment .
- range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
- the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
- the term "patient” or “subject” is meant to include any mammal.
- a "mammal,” as used herein, refers to any animal classified as a mammal, including but not limited to, humans, experimental animals including monkeys, rats, mice, and guinea pigs, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, and the like.
- a "pharmaceutically acceptable" carrier or excipient 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.
- Treating" or “treatment” of a disease as used herein includes: preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e ., arresting or reducing the development of the disease or its clinical symptoms, or relieving the disease, i.e ., causing regression of the disease or its clinical symptoms.
- a “therapeutically-effective amount” or an “effective amount” means the amount of a compound or a dosage form that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
- the “therapeutically- effective amount” will vary depending on the compound, the disease, and its severity and the age, weight, etc ., of the subject to be treated.
- the term “Pharmaceutically-acceptable salt” refers to salts which retain the biological effectiveness and properties of compounds which are not biologically or otherwise undesirable .
- Pharmaceutically acceptable salts refer to pharmaceutically acceptable salts of the compounds, which salts are derived from a variety of organic and inorganic counter ions well known in the art.
- the pharmaceutical dosage forms may be prepared as medicaments to be administered orally.
- suitable forms for oral administration include, without limitation, tablets, capsules, solutions, syrups and suspensions; such as ready-to-use syrups and suspensions, or reconstituted from solid dosage form such as, without limitation, dry powder.
- the dosage form may contain suitable binders, lubricants, coloring agents, flavoring agents, flow-inducing agents, stabilizing agents, solubilizing agents, antioxidants, buffering agent, chelating agents, and fillers, all collectively or individually fall under the definition of the term "pharmaceutically acceptable carrier” or "pharmaceutically acceptable excipient".
- the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert filler such as gelatin, agar, starch, methyl cellulose, mannitol, xylitol, sorbitol, maltodextrin and the like .
- suitable binders include starch, gelatin, natural sugars such as corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, cellulose based soluble polymers such as but not limited to hydroxypropylomethylcellulose, hydroxypropylcellulose, polyethylene glycol, and the like.
- Glidants used in these dosage forms include sodium benzoate, sodium acetate, polyethylene glycole, and the like.
- Stabilizing (antimicrobial) agents include benzoic acid, and salts thereof, parahydroxybenzoate and salts thereof, sorbic acid and salts thereof and the like.
- Stabilizing (physical) agents include viscosity enhancing polymers such as hydroxyethyl cellulose, xanthan gum and the like .
- SARS- CoV-2 COVID-19 Coronavirus
- Vanpouille C Lisco A
- Derudas M et al.
- a new class of dual-targeted antivirals monophosphorylated acyclovir prodrug derivatives suppress both human immunodeficiency virus type 1 and herpes simplex virus type 2. J Infect Dis.
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Abstract
The present invention provides effective and safe therapeutics and methods thereof for various health conditions associated with infection by the viruses of the Coronaviridae family. Specifically, the invention provides novel therapeutics based on the combinations of anti-viral agents and phosphate donor molecules against SARS-CoV-2 (COVID-19).
Description
MOLECULES THAT TARGET PROTEINS OF CORONAVIRUSES AND
USES THEREOF AS ANTI-VIRAL "COCKTAIL"
FIELD OF THE INVENTION
The invention relates to anti-viral compositions and method of using the same. Specifically, the invention related to compositions having antiviral activity against viruses of the Coronaviridae family and method of using the same.
BACKGROUND OF THE INVENTION
Coronaviruses are a diverse group of viruses infecting many different animals, and they can cause mild to severe respiratory infections in humans. In 2002 and 2012, respectively, two highly pathogenic coronaviruses with zoonotic origin, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), emerged in humans and caused fatal respiratory illness, making emerging coronaviruses a new public health concern in the twenty-first century.
At the end of 2019, a novel coronavirus designated as SARS-CoV-2 emerged in the city of Wuhan, China, and caused an outbreak of unusual viral pneumonia. Being highly transmissible, this novel coronavirus disease, also known as coronavirus disease 2019 (COVID-19), has spread fast all over the world. It has overwhelmingly surpassed SARS and MERS in terms of both the number of infected people and the spatial range of epidemic areas. The ongoing outbreak of COVID-19 has posed an extraordinary threat to global public health. By metagenomic RNA sequencing and virus isolation from bronchoalveolar lavage fluid (BALE) samples from patients with severe pneumonia, independent teams of Chinese scientists identified that the causative agent of this emerging disease is a betacoronavirus that had never been seen before. On 9 January 2020, the result of this etiological identification was publicly announced. The first genome sequence of the novel coronavirus was published on the Virological website on 10 January 2020, and more nearly complete genome sequences determined by different research institutes were then released via the GISAID database on 12 January.
As a novel betacoronavirus, SARS-CoV-2 shares 79% genome sequence identity with SARS-CoV and 50% with MERS-CoV24. Its genome organization is shared with other betacoronaviruses. Most of the proteins encoded by SARS-CoV-2 have a similar length to the corresponding proteins in SARS-CoV. Of the four structural genes, SARS-CoV-2 shares more than 90% amino acid identity with SARS-CoV except for the spike (S) gene, which diverges.
SARS-CoV-2 uses the same receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2). Besides human ACE2 (hACE2), SARS-CoV-2 also recognizes ACE2 from pig, ferret, rhesus monkey, civet, cat, pangolin, rabbit, and dog. The broad receptor usage of SARS-CoV-2 implies that it may have a wide host range, and the varied efficiency of ACE2 usage in different animals may indicate their different susceptibilities to SARS-CoV-2 infection. At this stage, molecular mechanisms of SARS-CoV-2 infection pathogenesis and virus-host interactions remain largely unclear, and there are no proven effective therapeutics and treatment protocols for COVID-19, although some treatments have shown certain benefits in subpopulations of patients. Thus, it is clear that the world population is exhausted and anxious to find effective and accessible preventive tools, therapeutics, and treatment protocols against COVID-19 and its variants.
SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide effective and safe therapeutics for various health conditions associated with infection by the viruses of the Coronaviridae family.
The invention provides a method of treating a condition associated with an infection by a virus of the Coronaviridae family, in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a. at least one agent having an anti-viral activity, and
b. at least one phosphate donor, wherein said phosphate donor potentiates the anti-viral activity of the at least one agent, to thereby effectively treat the condition associated with the infection by the virus of the Coronaviridae family.
The invention further provides a method of slowing and/or preventing progression of a condition associated with an infection by a virus of the Coronaviridae family in a subject, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to prevent said condition .
The invention further provides a method of reducing a viral load in a subject infected by a virus of the Coronaviridae family, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the viral load.
The invention further provides a method of reducing clinical manifestations of an infection by a virus of the Coronaviridae family in a subject in need, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the clinical manifestations.
The invention further provides a method of reducing at least one surrogate marker associated with an infection by a virus of the
Coronaviridae family in a subject diagnosed with said infection, comprising administering to said subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the at least one surrogate marker.
The invention further provides a method of reducing at least one biomarker associated with an infection by a virus of the Coronaviridae family in a subject diagnosed with said infection, comprising administering to said subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the at least one biomarker.
The invention further provides a therapeutic combination suitable for administration to a subject in need, comprising: a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, wherein the subject in need is diagnosed with an infection by a virus of the Coronaviridae family. The invention further provides a pharmaceutical composition comprising a. at least one at least one agent having an anti-viral activity, b. at least one phosphate donor, and c. at least one pharmaceutically acceptable carrier.
The invention further provides a method for treating a subject afflicted with a condition associated with an infection by a virus of the Coronaviridae family with a pharmaceutical composition of the invention, comprising the steps of: a) administering a therapeutic amount of the pharmaceutical composition to the subject; b) determining whether the subject is a responder by determining the gene expression profile of the subject, and comparing the gene expression profile to a reference gene expression profile to identify the subject as a responder; and c) continuing the administration if the subject is identified as a responder, or modifying treatment of the subject if the subject is not identified as a responder.
The invention further provides a method for treating a human subject presenting clinical manifestations associated with infection by a virus of the Coronaviridae family with a pharmaceutical composition of the invention, comprising the steps of:(i) determining the gene expression profile of the subject; (ii) identifying the subject as a predicted responder if the gene expression profile is indicative of subject being a responder; and (iii) administering the pharmaceutical composition to the subject only if the subject is identified as a predicted responder.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a schematic view of Corona viruses enter human cells;
Fig .2 is an exemplary embodiment of the interface of a first agent: antibiotics having RNA-binding site and Clarithromycin or Azithromycin binding to the pocket;
Fig. 3 is an exemplary embodiment of phosphate enhancement of antiviral-drug and acyclovir binding to the RNA-dependent-RNA- polymerase of SARS-Cov-2; and
Fig. 4 is an exemplary embodiment of Azithromycin dose of 500mg per day and multi-target attack of spike glyco-protein by antibiotics and anti-viral drugs.
DETAILED DESCRIPTION OF THE INVENTION The present invention is now described more fully hereinafter with reference to the accompanying examples, in which embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather these embodiments are provided so that this disclosure will be thorough and complete and will fully convey the scope of the invention to those skilled in the art.
According to some embodiments, the invention provides method of treating a condition associated with an infection by a virus of the Coronaviridae family, in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, wherein said phosphate donor potentiates the anti-viral activity of the at least one agent, to thereby effectively treat the condition associated with the infection by the virus of the Coronaviridae family.
In the context of the embodiments of the invention the term "agent having an anti-viral activity" refers, without limitation, to an agent that kills a virus or that suppresses its ability to replicate and, hence, inhibits its capability to multiply and/or reproduce. It can be interchangeably referred as anti-viral drug or anti-viral substance or anti-viral compound. In one embodiment, the non-limiting list of agents having anti-viral activity includes acyclovir, gancyclovir,
valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine. In the context of the embodiments of the invention, the term "phosphate donor", or "phosphate donor molecule" refers, without limitation to a chemical entity comprising a covalently attached/bound phosphate moiety. In one embodiment, the non- limiting list of phosphate donors includes dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine- phosphate, inositol monophosphate, and phytic acid (inositol hexakisphosphate ). According to some embodiments of the above method, the therapeutically effective amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day. In one embodiment, the therapeutically effective amount of the at least one agent having an anti-viral activity is 250mg/day to 5000mg/day; 500mg/day to 5000 mg/day; 750mg/day to 5000 mg/day; 1000mg/day to 5000 mg/day; 1200mg/day to 5000 mg/day; 1400mg/day to 5000 mg/day; 1700mg/day to 5000 mg/day; 1850mg/day to 5000 mg/day; 2000mg/day to 5000 mg/day; 2200mg/day to 5000 mg/day; 2400mg/day to 5000 mg/day; 2600mg/day to 5000 mg/day. In one embodiment, the therapeutically effective amount of the at least one agent having an anti-viral activity is 1000mg/day to 3000mg/day; 1100mg/day to 2900 mg/day; 1200mg/day to 2800 mg/day; 1300mg/day to 2700 mg/day; 1400mg/day to 2600 mg/day; 1500mg/day to 2500 mg/day; 1600mg/day to 2400 mg/day. In one embodiment, the therapeutically effective amount of the at least one agent having an anti-viral activity is is 250mg/day; 500mg/day; 750 mg/day; 1000 mg/day; 1200 mg/day; 1300 mg/day; 1400mg/day; 1500 mg/day; 1600mg/day; 1700 mg/day; 1800mg/day; 1900 mg/day; 2000mg/day; 2100 mg/day; 2200mg/day; 2300 mg/day;
2400mg/day; 2600 mg/day; 2700mg/day; 2800 mg/day; 2900mg/day; 3000 mg/day.
According to some embodiments of the above method, the therapeutically effective amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day. In one embodiment, the therapeutically effective amount of the at least one phosphate donor is 0.25 mg/day to 50mg/day; 0.5 mg/day to 50mg/day; 0.75 mg/day to 50mg/day; 1 mg/day to 50mg/day; 1.25 mg/day to 50mg/day; 1.5mg/day to 50mg/day; 1.75mg/day to 50mg/day; 2mg/day to 50mg/day; 2.25mg/day to 50mg/day; 2.5mg/day to 50mg/day; 2.75mg/day to 50mg/day; 3mg/day to 50mg/day; 3.5mg/day to 50mg/day; 4mg/day to 50mg/day; 4.5mg/day to 50mg/day; 5mg/day to 50mg/day; 5 .5mg/day to 50mg/day; 6mg/day to 50mg/day; 6.5mg/day to 50mg/day; 7mg/day to 50mg/day; 7 .5mg/day to 50mg/day; 8mg/day to 50mg/day; 8.5mg/day to 50mg/day; 9mg/day to 50mg/day; 9.5mg/day to 50mg/day; 10mg/day to 50mg/day. In one embodiment, the therapeutically effective amount of the at least one phosphate donor is 1mg/day to 15mg/day; 1.5mg/day to 14.5 mg/day; 2mg/day to 14 mg/day; 2.5mg/day to 13.5 mg/day; 3mg/day to 13mg/day; 4mg/day to 12 mg/day; 5mg/day to 11mg/day; 6mg/day to 10mg/day. In one embodiment, the therapeutically effective amount of the at least one phosphate donor is 1mg/day; 2mg/day; 2.5 mg/day; 3mg/day; 3.5mg/day; 4mg/day; 4.5mg/day; 5mg/day; 5.5mg/day; 6mg/day; 6.5mg/day; 7mg/day; 7.5mg/day; 8mg/day; 8.5mg/day; 9mg/day; 9.5mg/day; 10mg/day; 10.5mg/day; 11mg/day;
11.5mg/day; 12mg/day; 12 .5mg/day; 13mg/day; 13.5mg/day; 14mg/day; 14.5mg/day; 15mg/day.
According to some embodiment of the above method, the antiviral agent is acyclovir, and the phosphate donor is dexamethasone phosphate.
According to some embodiment of the above method, the daily dose of the anti-viral agent and/or phosphate donor can be administered at once, or, alternatively can be split into
several administration and/or can be given according to any desired regimen. In one embodiment, the anti-viral agent and the phosphate donor are administered simultaneously. In one embodiment, the anti-viral agent and the phosphate donor are administered independently of each other.
According to some embodiments of the above method, the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1. In one embodiment, the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19). According to some embodiments of the above method, the subject is a mammalian subject. As used herein, the term "mammalian" is interchangeable with "mammal". In one embodiment, the mammalian subject is a human subject.
According to some embodiments of the above method, the non- limiting list of conditions associated with an infection by a virus of the Coronaviridae family includes acute respiratory distress syndrome (ARDS), common cold, pneumonia, bronchitis, severe acute respiratory syndrome, and Middle East respiratory syndrome . According to some embodiments, the above method further comprises administering to the subject a therapeutically effective amount of at least one antimicrobial agent. As used herein, the term "antimicrobial agent", refers, without limitation, to drugs, chemicals, or other substances that either kill or slow the growth of microbes. Among the antimicrobial agents of the invention are antibacterial drugs, antifungal agents, and antiparasitic drugs. In one embodiment, the antimicrobial agent is macrolide. A non-limiting list of the antimicrobial agents of the invention includes Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin,
Flurithromycin, Ivermectin, Josamycin, Midecamycin, Miocamycin,
Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin,
Troleandomycin, and Tylosin. According to some embodiment of the
above method, the antimicrobial agent is azithromycin. According to some embodiments of the above method, the dosing regimen of the antimicrobial agent is any state-of-the-art regimen and any administration regime. According to some embodiments, the invention provides a method of slowing and/or preventing progression of a condition associated with an infection by a virus of the Coronaviridae family in a subject, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to prevent said condition . In one embodiment, said phosphate donor potentiates the anti-viral activity of the at least one agent. As used herein, the phrase "slowing and/or preventing progression" refers, without limitation, to the influence of the treatment on the clinical course of the disease. For example, illness severity of SARS- CoV-2 (COVID-19) ranges from mild to critical, while mild to moderate disease is categorized as mild symptoms up to mild pneumonia; severe disease has manifestations of dyspnea, hypoxia, or more than 50% lung involvement on imaging; and critical disease has manifestations of respiratory failure, shock, or multiorgan system dysfunction, which may result in death (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical- guidance-management-patients.html) . In the context of the invention, the proposed therapy is aimed at slowing and/or preventing the transition from mild to severe and to critical illness. The "slowing and/or preventing" progression of the condition according to the embodiments of the above method may be measured using any appropriate questionary, method, scale, diagnostic tool, or any other means that are known in the art or acceptable by the relevant functions and professionals. The term "preventing" might but does not necessarily mean recovery
from the illness. As such, the term "preventing" relates to the situation when the patient does not present symptoms and/or signs and/or manifestations of the next "stage" of illness severity as defined by the appropriate and acceptable parameters for the specific disease condition. The term "slowing", or attenuating is can, without limitation, prolong the time of transition into the next "stage" of illness severity, thus providing greater window of opportunity for extensive care and recovery. According to some embodiments of the above method, the non- limiting list of conditions associated with an infection by a virus of the Coronaviridae family includes acute respiratory distress syndrome (ARDS), common cold, pneumonia, bronchitis, severe acute respiratory syndrome, and Middle East respiratory syndrome .
According to some embodiments of the above method, the non- limiting list of agents having anti-viral activity includes acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine. According to some embodiments of the above method, the non-limiting list of phosphate donors includes dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine- phosphate, inositol monophosphate, and phytic acid (inositol hexakisphosphate ). According to some embodiments of the above method, the antiviral agent is acyclovir, and the phosphate donor is dexamethasone-phosphate.
According to some embodiments of the above method, the effective amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day. In one embodiment, the
effective amount of the at least one agent having an anti-viral activity is 250mg/day to 5000mg/day; 500mg/day to 5000 mg/day; 750mg/day to 5000 mg/day; 1000mg/day to 5000 mg/day; 1200mg/day to 5000 mg/day; 1400mg/day to 5000 mg/day; 1700mg/day to 5000 mg/day; 1850mg/day to 5000 mg/day; 2000mg/day to 5000 mg/day; 2200mg/day to 5000 mg/day; 2400mg/day to 5000 mg/day; 2600mg/day to 5000 mg/day. In one embodiment, the effective amount of the at least one agent having an anti-viral activity is 1000mg/day to 3000mg/day; l100mg/day to 2900 mg/day; 1200mg/day to 2800 mg/day; 1300mg/day to 2700 mg/day; 1400mg/day to 2600 mg/day; 1500mg/day to 2500 mg/day; 1600mg/day to 2400 mg/day. In one embodiment, the effective amount of the at least one agent having an anti-viral activity is 250mg/day; 500mg/day; 750 mg/day; 1000 mg/day; 1200 mg/day; 1300 mg/day; 1400mg/day; 1500 mg/day; 1600mg/day; 1700 mg/day; 1800mg/day; 1900 mg/day; 2000mg/day;
2100 mg/day; 2200mg/day; 2300 mg/day; 2400mg/day; 2600 mg/day; 2700mg/day; 2800 mg/day; 2900mg/day; 3000 mg/day.
According to some embodiments of the above method, the effective amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day. In one embodiment, the effective amount of the at least one phosphate donor is 0.25 mg/day to 50mg/day; 0.5 mg/day to 50mg/day; 0.75 mg/day to 50mg/day; 1 mg/day to 50mg/day; 1.25 mg/day to 50mg/day; 1 .5mg/day to 50mg/day; 1.75mg/day to 50mg/day; 2mg/day to 50mg/day; 2.25mg/day to 50mg/day; 2.5mg/day to 50mg/day; 2.75mg/day to 50mg/day; 3mg/day to 50mg/day; 3.5mg/day to 50mg/day; 4mg/day to 50mg/day; 4 .5mg/day to 50mg/day; 5mg/day to 50mg/day; 5.5mg/day to 50mg/day; 6mg/day to 50mg/day; 6 .5mg/day to 50mg/day; 7mg/day to 50mg/day; 7.5mg/day to 50mg/day; 8mg/day to 50mg/day; 8.5mg/day to 50mg/day; 9mg/day to 50mg/day; 9.5mg/day to 50mg/day; 10mg/day to 50mg/day. In one embodiment, the effective amount of the at least one phosphate donor is 1mg/day to 15mg/day; 1.5mg/day to 14.5 mg/day; 2mg/day to 14 mg/day; 2.5mg/day to 13.5 mg/day; 3mg/day to 13mg/day; 4mg/day to 12 mg/day; 5mg/day to 11mg/day;
6mg/day to 10mg/day. In one embodiment, the effective amount of the at least one phosphate donor is 1mg/day; 2mg/day; 2.5 mg/day; 3mg/day; 3.5mg/day; 4mg/day; 4.5mg/day; 5mg/day; 5.5mg/day; 6mg/day; 6.5mg/day; 7mg/day; 7.5mg/day; 8mg/day; 8.5mg/day; 9mg/day; 9.5mg/day; 10mg/day; 10.5mg/day; 11mg/day;
11.5mg/day; 12mg/day; 12 .5mg/day; 13mg/day; 13.5mg/day; 14mg/day; 14.5mg/day; 15mg/day.
According to some embodiment of the above method, the daily dose of the anti-viral agent and/or phosphate donor can be administered at once, or, alternatively can be split into several administration and/or can be given according to any desired regimen. In one embodiment, the anti-viral agent and the phosphate donor are administered simultaneously. In one embodiment, the anti-viral agent and the phosphate donor are administered independently of each other.
According to some embodiments of the above method, the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19), SAKS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1. In one embodiment, the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19). According to some embodiments, the above method further comprises administering to the subject a therapeutically effective amount of at least one antimicrobial agent. In one embodiment, the antimicrobial agent is macrolide. In yet another embodiment, a non-limiting list of the antimicrobial agents of the invention includes Azithromycin, Boromycin, Clarithromycin,
Dirithromycin, Erythromycin, Flurithromycin, Ivermectin,
Josamycin, Midecamycin, Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin. Any acceptable dose and administration regimen of the antimicrobial agent according to the embodiments of the invention can be used.
According to some embodiments, the invention provides method of reducing clinical manifestations of an infection by a virus of
the Coronaviridae family in a subject in need, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the clinical manifestations. In one embodiment, said phosphate donor potentiates the anti- viral activity of the at least one agent. As used herein, the term "clinical manifestations" refers, without limitation, to signs and symptoms of the disease that can be either objective, when observed by a physician, or subjective, when perceived by the patient.
According to some embodiments of the above method, the non- limiting list of agents having anti-viral activity includes acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine. According to some embodiments of the above method, the non-limiting list of phosphate donors includes dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine- phosphate, inositol monophosphate, and phytic acid (inositol hexakisphosphate ). According to some embodiments of the above method, the antiviral agent is acyclovir, and the phosphate donor is dexamethasone-phosphate.
According to some embodiments of the above method, the effective amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day. In one embodiment, the effective amount of the at least one agent having an anti-viral activity is 250mg/day to 5000mg/day; 500mg/day to 5000 mg/day;
750mg/day to 5000 mg/day; 1000mg/day to 5000 mg/day; 1200mg/day to 5000 mg/day; 1400mg/day to 5000 mg/day; 1700mg/day to 5000 mg/day; 1850mg/day to 5000 mg/day; 2000mg/day to 5000 mg/day; 2200mg/day to 5000 mg/day; 2400mg/day to 5000 mg/day; 2600mg/day to 5000 mg/day. In one embodiment, the effective amount of the at least one agent having an anti-viral activity is 1000mg/day to 3000mg/day; l100mg/day to 2900 mg/day; 1200mg/day to 2800 mg/day; 1300mg/day to 2700 mg/day; 1400mg/day to 2600 mg/day; 1500mg/day to 2500 mg/day; 1600mg/day to 2400 mg/day. In one embodiment, the effective amount of the at least one agent having an anti-viral activity is 250mg/day; 500mg/day; 750 mg/day; 1000 mg/day; 1200 mg/day; 1300 mg/day; 1400mg/day; 1500 mg/day; 1600mg/day; 1700 mg/day; 1800mg/day; 1900 mg/day; 2000mg/day; 2100 mg/day; 2200mg/day; 2300 mg/day; 2400mg/day; 2600 mg/day; 2700mg/day; 2800 mg/day; 2900mg/day; 3000 mg/day.
According to some embodiments of the above method, the effective amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day. In one embodiment, the effective amount of the at least one phosphate donor is 0.25 mg/day to 50mg/day; 0.5 mg/day to 50mg/day; 0.75 mg/day to 50mg/day; 1 mg/day to 50mg/day; 1.25 mg/day to 50mg/day; 1 .5mg/day to 50mg/day; 1.75mg/day to 50mg/day; 2mg/day to 50mg/day; 2.25mg/day to 50mg/day; 2.5mg/day to 50mg/day; 2.75mg/day to 50mg/day; 3mg/day to 50mg/day; 3.5mg/day to 50mg/day; 4mg/day to 50mg/day; 4 .5mg/day to 50mg/day; 5mg/day to 50mg/day; 5.5mg/day to 50mg/day; 6mg/day to 50mg/day; 6 .5mg/day to 50mg/day; 7mg/day to 50mg/day; 7.5mg/day to 50mg/day; 8mg/day to 50mg/day; 8.5mg/day to 50mg/day; 9mg/day to 50mg/day; 9.5mg/day to 50mg/day; 10mg/day to 50mg/day. In one embodiment, the effective amount of the at least one phosphate donor is 1mg/day to 15mg/day; 1.5mg/day to 14.5 mg/day; 2mg/day to 14 mg/day; 2.5mg/day to 13.5 mg/day; 3mg/day to 13mg/day; 4mg/day to 12 mg/day; 5mg/day to 11mg/day; 6mg/day to 10mg/day. In one embodiment, the effective amount of the at least one phosphate donor is 1mg/day; 2mg/day; 2.5
mg/day; 3mg/day; 3.5mg/day; 4mg/day; 4.5mg/day; 5mg/day; 5.5mg/day; 6mg/day; 6.5mg/day; 7mg/day; 7.5mg/day; 8mg/day; 8.5mg/day; 9mg/day; 9.5mg/day; 10mg/day; 10.5mg/day; 11mg/day; 11.5mg/day; 12mg/day; 12 .5mg/day; 13mg/day; 13.5mg/day; 14mg/day; 14.5mg/day; 15mg/day.
According to some embodiment of the above method, the daily dose of the anti-viral agent and/or phosphate donor can be administered at once, or, alternatively can be split into several administration and/or can be given according to any desired regimen. In one embodiment, the anti-viral agent and the phosphate donor are administered simultaneously. In one embodiment, the anti-viral agent and the phosphate donor are administered independently of each other.
According to some embodiments of the above method, the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1. In one embodiment, the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
According to some embodiments, the above method further comprises administering to the subject a therapeutically effective amount of at least one antimicrobial agent. In one embodiment, the antimicrobial agent is macrolide. In yet another embodiment, a non-limiting list of the antimicrobial agents of the invention includes Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin, Flurithromycin, Ivermectin, Josamycin, Midecamycin, Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin. Any acceptable dose and administration regimen of the antimicrobial agent according to the embodiments of the invention can be used.
According to some embodiments, the invention provides a method of reducing a viral load in a subject infected by a virus of the Coronaviridae family, comprising administering to the subject a. at least one agent having an anti-viral activity, and
b. at least one phosphate donor, in an amount effective to reduce the viral load. As used herein, the term "viral load" refers, without limitation, to a numerical expression of the quantity of virus in a given volume of fluid. According to some embodiments of the above method, the non- limiting list of agents having anti-viral activity includes acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine .
According to some embodiments of the above method, the non- limiting list of phosphate donors includes dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine- phosphate, inositol monophosphate, and phytic acid (inositol hexakisphosphate ).
According to some embodiments of the above method, the effective amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day. In one embodiment, the effective amount of the at least one agent having an anti-viral activity is 250mg/day to 5000mg/day; 500mg/day to 5000 mg/day; 750mg/day to 5000 mg/day; 1000mg/day to 5000 mg/day; 1200mg/day to 5000 mg/day; 1400mg/day to 5000 mg/day; 1700mg/day to 5000 mg/day; 1850mg/day to 5000 mg/day; 2000mg/day to 5000 mg/day; 2200mg/day to 5000 mg/day; 2400mg/day to 5000 mg/day; 2600mg/day to 5000 mg/day. In one embodiment, the effective amount of the at least one agent having an anti-viral activity is 1000mg/day to 3000mg/day; 1100mg/day to 2900 mg/day; 1200mg/day to 2800 mg/day; 1300mg/day to 2700 mg/day; 1400mg/day to 2600 mg/day; 1500mg/day to 2500 mg/day; 1600mg/day to 2400 mg/day. In one
embodiment, the effective amount of the at least one agent having an anti-viral activity is 250mg/day; 500mg/day; 750 mg/day; 1000 mg/day; 1200 mg/day; 1300 mg/day; 1400mg/day; 1500 mg/day; 1600mg/day; 1700 mg/day; 1800mg/day; 1900 mg/day; 2000mg/day; 2100 mg/day; 2200mg/day; 2300 mg/day; 2400mg/day; 2600 mg/day;
2700mg/day; 2800 mg/day; 2900mg/day; 3000 mg/day.
According to some embodiments of the above method, the effective amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day. In one embodiment, the effective amount of the at least one phosphate donor is 0.25 mg/day to 50mg/day; 0.5 mg/day to 50mg/day; 0.75 mg/day to 50mg/day; 1 mg/day to 50mg/day; 1.25 mg/day to 50mg/day; 1 .5mg/day to 50mg/day; 1.75mg/day to 50mg/day; 2mg/day to 50mg/day; 2.25mg/day to 50mg/day; 2.5mg/day to 50mg/day; 2.75mg/day to 50mg/day; 3mg/day to 50mg/day; 3.5mg/day to 50mg/day; 4mg/day to 50mg/day; 4 .5mg/day to
50mg/day; 5mg/day to 50mg/day; 5.5mg/day to 50mg/day; 6mg/day to 50mg/day; 6 .5mg/day to 50mg/day; 7mg/day to 50mg/day;
7.5mg/day to 50mg/day; 8mg/day to 50mg/day; 8.5mg/day to
50mg/day; 9mg/day to 50mg/day; 9.5mg/day to 50mg/day; 10mg/day to 50mg/day. In one embodiment, the effective amount of the at least one phosphate donor is 1mg/day to 15mg/day; 1.5mg/day to 14.5 mg/day; 2mg/day to 14 mg/day; 2.5mg/day to 13.5 mg/day; 3mg/day to 13mg/day; 4mg/day to 12 mg/day; 5mg/day to 11mg/day; 6mg/day to 10mg/day. In one embodiment, the effective amount of the at least one phosphate donor is 1mg/day; 2mg/day; 2.5 mg/day; 3mg/day; 3.5mg/day; 4mg/day; 4.5mg/day; 5mg/day; 5.5mg/day; 6mg/day; 6.5mg/day; 7mg/day; 7.5mg/day; 8mg/day; 8.5mg/day; 9mg/day; 9.5mg/day; 10mg/day; 10.5mg/day; 11mg/day; 11.5mg/day; 12mg/day; 12 .5mg/day; 13mg/day; 13.5mg/day; 14mg/day; 14.5mg/day; 15mg/day.
According to some embodiment of the above method, the daily dose of the anti-viral agent and/or phosphate donor can be administered at once, or, alternatively can be split into
several administration and/or can be given according to any desired regimen. In one embodiment, the anti-viral agent and the phosphate donor are administered simultaneously. In one embodiment, the anti-viral agent and the phosphate donor are administered independently of each other.
According to some embodiments of the above method, the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1. In one embodiment, the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19). According to some embodiments, the above method further comprises administering to the subject a therapeutically effective amount of at least one antimicrobial agent. In one embodiment, the antimicrobial agent is macrolide. In yet another embodiment, a non-limiting list of the antimicrobial agents of the invention includes Azithromycin, Boromycin, Clarithromycin,
Dirithromycin, Erythromycin, Flurithromycin, Ivermectin,
Josamycin, Midecamycin, Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin. Any acceptable dose and administration regimen of the antimicrobial agent according to the embodiments of the invention can be used.
According to some embodiments of the above method, the viral log is reduced by at least 1.3 log to 10 log. According to some embodiments of the above method, the viral log is reduced by at least 1.3 log, 1.5 log, 1.7 log, 2 log, 2.25 log, 2.5 log, 2.75 log, 3 log, 3.25 log, 3.751og, 4 log, 4.25 log, 4.5 log, 4.75 log, 5 log, 5.25 log, 5.5 log, 5.75 log, 6 log; 6.25 log, 6.5 log, 6.75 log, 7 log, 7.25 log, 7.5 log, 7.75 log, 8 log, 8.25 log, 8.5 log, 8.75 log, 9 log, 9.25 log, 9.5 log, 9.75 log, 10 log. According to some embodiments, the invention provides a method of reducing at least one surrogate marker associated with an infection by a virus of the Coronaviridae family in a subject
diagnosed with said infection, comprising administering to said subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the at least one surrogate marker. As used herein, the term "surrogate marker" refers, without limitation, to a measure of effect of a specific treatment that may correlate with a real clinical endpoint but does not necessarily have a guaranteed relationship. In the context of the invention, the non-limiting list of possible surrogate markers includes DMA, mRNA, antigen, antibody, and any combination thereof.
According to some embodiments, the invention provides a method of reducing at least one biomarker associated with an infection by a virus of the Coronaviridae family in a subject diagnosed with said infection, comprising administering to said subject c. at least one agent having an anti-viral activity, and d. at least one phosphate donor, in an amount effective to reduce the at least one biomarker, wherein said phosphate donor potentiates the anti-viral activity of the at least one agent. As used herein, the term "biomarker" refers, without limitation, to A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention . This definition encompasses therapeutic interventions and can be derived from molecular, histologic, radiographic, or physiologic characteristics
(https://www.ncbi.nlm.nih.gov/pmc/articles/FMC5813375/). A non- limiting list of the biomarkers of the invention includes SLP1,
ID01, SLC7A11, PTGS2,MR1, PNP, ABCG2, CXCL8, MMP1, ARG1, CCL2, BCL2L1, CTSB, HEXB, ARSA, and MAN2B2 and/or other genes.
According to some embodiments, the invention provides therapeutic combination suitable for administration to a subject in need, comprising: a. at least one agent having an anti-viral activity; b. at least one phosphate donor; wherein the subject in need is diagnosed with an infection by a virus of the Coronaviridae family. As used herein, the term "therapeutic combination" is meant to be understood, without limitation, as a combination of a number of components: at least one agent having an anti-viral activity with at least one phosphate donor that is administered to a subject in need to provide a desirable therapeutic effect. In the combination according to the embodiments of the invention, the at least two components can be given in a single formulation or each as a separate medicament; they can be administered simultaneously, or alternatively, can have each a specific dosing regimen and/or administration regime. The combination according to the embodiments of the invention can be a synergistic combination, while the combined effect is larger than the additive effect of each individual drug. In one embodiment, the combination has an additive effect on the clinical outcome.
According to some embodiments of the above combination, the non- limiting list of agents having anti-viral activity includes acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and
zidovudine. According to some embodiments of the above combination, the non-limiting list of phosphate donors includes dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine-phosphate, inositol monophosphate, and phytic acid (inositol hexakisphosphate). According to some embodiments of the above combination, the antiviral agent is acyclovir, and the phosphate donor is dexamethasone phosphate.
According to some embodiments of the above combination, the amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day. In one embodiment, the amount of the at least one agent having an anti-viral activity is
250mg/day to 5000mg/day; 500mg/day to 5000 mg/day; 750mg/day to 5000 mg/day; 1000mg/day to 5000 mg/day; 1200mg/day to 5000 mg/day; 1400mg/day to 5000 mg/day; 1700mg/day to 5000 mg/day; 1850mg/day to 5000 mg/day; 2000mg/day to 5000 mg/day; 2200mg/day to 5000 mg/day; 2400mg/day to 5000 mg/day; 2600mg/day to 5000 mg/day. In one embodiment, the amount of the at least one agent having an anti-viral activity is 1000mg/day to 3000mg/day;
1100mg/day to 2900 mg/day; 1200mg/day to 2800 mg/day; 1300mg/day to 2700 mg/day; 1400mg/day to 2600 mg/day; 1500mg/day to 2500 mg/day; 1600mg/day to 2400 mg/day. In one embodiment, the amount of the at least one agent having an anti-viral activity is
250mg/day; 500mg/day; 750 mg/day; 1000 mg/day; 1200 mg/day;
1300 mg/day; 1400mg/day; 1500 mg/day; 1600mg/day; 1700 mg/day; 1800mg/day; 1900 mg/day; 2000mg/day; 2100 mg/day; 2200mg/day;
2300 mg/day; 2400mg/day; 2600 mg/day; 2700mg/day; 2800 mg/day; 2900mg/day; 3000 mg/day.
According to some embodiments of the above combination, the amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day. In one embodiment, the amount of the at least one phosphate donor is 0.25 mg/day to 50mg/day; 0.5 mg/day to 50mg/day; 0.75 mg/day to 50mg/day; 1 mg/day to 50mg/day; 1.25 mg/day to 50mg/day; 1 .5mg/day to 50mg/day; 1.75mg/day to
50mg/day; 2mg/day to 50mg/day; 2.25mg/day to 50mg/day; 2.5mg/day to 50mg/day; 2.75mg/day to 50mg/day; 3mg/day to 50mg/day; 3.5mg/day to 50mg/day; 4mg/day to 50mg/day; 4 .5mg/day to
50mg/day; 5mg/day to 50mg/day; 5.5mg/day to 50mg/day; 6mg/day to 50mg/day; 6 .5mg/day to 50mg/day; 7mg/day to 50mg/day;
7.5mg/day to 50mg/day; 8mg/day to 50mg/day; 8.5mg/day to
50mg/day; 9mg/day to 50mg/day; 9.5mg/day to 50mg/day; 10mg/day to 50mg/day. In one embodiment, the amount of the at least one phosphate donor is 1mg/day to 15mg/day; 1.5mg/day to 14.5 mg/day; 2mg/day to 14 mg/day; 2.5mg/day to 13.5 mg/day; 3mg/day to 13mg/day; 4mg/day to 12 mg/day; 5mg/day to 11mg/day; 6mg/day to 10mg/day. In one embodiment, the amount of the at least one phosphate donor is 1mg/day; 2mg/day; 2.5 mg/day; 3mg/day; 3.5mg/day; 4mg/day; 4.5mg/day; 5mg/day; 5.5mg/day; 6mg/day; 6.5mg/day; 7mg/day; 7.5mg/day; 8mg/day; 8.5mg/day; 9mg/day;
9.5mg/day; 10mg/day; 10.5mg/day; 11mg/day; 11.5mg/day;
12mg/day; 12.5mg/day; 13mg/day; 13.5mg/day; 14mg/day;
14.5mg/day; 15mg/day.
According to some embodiments, the above combination further comprises at least one antimicrobial agent. In one embodiment, the antimicrobial agent is macrolide. In yet another embodiment, a non-limiting list of the antimicrobial agents of the invention includes Azithromycin, Boromycin, Clarithromycin,
Dirithromycin, Erythromycin, Flurithromycin, Ivermectin, Josamycin, Midecamycin, Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin.
According to some embodiments of the above combination, the virus of the Coronaviridae family is selected from the group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1. In one embodiment, the virus of the
Coronaviridae family is SARS-CoV-2 (COVID-19).
According to some embodiments, the invention provides a pharmaceutical composition comprising
a. at least one at least one agent having an anti-viral activity, b. at least one phosphate donor, and c. at least one pharmaceutically acceptable carrier According to some embodiments of the above pharmaceutical composition, the non-limiting list of agents having anti-viral activity includes acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV- 100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine. According to some embodiments of the above pharmaceutical composition, the non-limiting list of phosphate donors includes dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine-phosphate, inositol monophosphate, and phytic acid (inositol hexakisphosphate). According to some embodiments of the above pharmaceutical composition the antiviral agent is acyclovir, and the phosphate donor is dexamethasone phosphate.
According to some embodiments of the above pharmaceutical composition, the amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day. In one embodiment, the amount of the at least one agent having an anti- viral activity is 250mg/day to 5000mg/day; 500mg/day to 5000 mg/day; 750mg/day to 5000 mg/day; 1000mg/day to 5000 mg/day; 1200mg/day to 5000 mg/day; 1400mg/day to 5000 mg/day; 1700mg/day to 5000 mg/day; 1850mg/day to 5000 mg/day; 2000mg/day to 5000 mg/day; 2200mg/day to 5000 mg/day; 2400mg/day to 5000 mg/day; 2600mg/day to 5000 mg/day. In one embodiment, the amount of the at least one agent having an anti-viral activity is 1000mg/day to 3000mg/day; 1100mg/day to 2900 mg/day; 1200mg/day to 2800
mg/day; 1300mg/day to 2700 mg/day; 1400mg/day to 2600 mg/day; 1500mg/day to 2500 mg/day; 1600mg/day to 2400 mg/day. In one embodiment, the amount of the at least one agent having an anti- viral activity is 250mg/day; 500mg/day; 750 mg/day; 1000 mg/day; 1200 mg/day; 1300 mg/day; 1400mg/day; 1500 mg/day;
1600mg/day; 1700 mg/day; 1800mg/day; 1900 mg/day; 2000mg/day; 2100 mg/day; 2200mg/day; 2300 mg/day; 2400mg/day; 2600 mg/day; 2700mg/day; 2800 mg/day; 2900mg/day; 3000 mg/day.
According to some embodiments of the above pharmaceutical composition, the amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day. In one embodiment, the amount of the at least one phosphate donor is 0.25 mg/day to 50mg/day; 0.5 mg/day to 50mg/day; 0.75 mg/day to 50mg/day; 1 mg/day to 50mg/day; 1.25 mg/day to 50mg/day; 1.5mg/day to 50mg/day; 1.75mg/day to 50mg/day; 2mg/day to 50mg/day; 2.25mg/day to 50mg/day; 2.5mg/day to 50mg/day; 2.75mg/day to 50mg/day; 3mg/day to 50mg/day; 3 .5mg/day to 50mg/day; 4mg/day to 50mg/day; 4.5mg/day to 50mg/day; 5mg/day to 50mg/day; 5 .5mg/day to 50mg/day; 6mg/day to 50mg/day; 6.5mg/day to 50mg/day; 7mg/day to 50mg/day; 7 .5mg/day to 50mg/day; 8mg/day to 50mg/day; 8.5mg/day to 50mg/day; 9mg/day to 50mg/day; 9.5mg/day to 50mg/day; 10mg/day to 50mg/day. In one embodiment, the amount of the at least one phosphate donor is 1mg/day to 15mg/day;
1.5mg/day to 14.5 mg/day; 2mg/day to 14 mg/day; 2.5mg/day to 13.5 mg/day; 3mg/day to 13mg/day; 4mg/day to 12 mg/day; 5mg/day to 11mg/day; 6mg/day to 10mg/day. In one embodiment, the amount of the at least one phosphate donor is 1mg/day; 2mg/day; 2.5 mg/day; 3mg/day; 3.5mg/day; 4mg/day; 4.5mg/day; 5mg/day; 5.5mg/day; 6mg/day; 6.5mg/day; 7mg/day; 7.5mg/day; 8mg/day; 8.5mg/day; 9mg/day; 9.5mg/day; 10mg/day; 10.5mg/day; 11mg/day;
11.5mg/day; 12mg/day; 12 .5mg/day; 13mg/day; 13.5mg/day; 14mg/day; 14.5mg/day; 15mg/day.
According to some embodiments, the above pharmaceutical composition further comprises at least one antimicrobial agent. In one embodiment, the antimicrobial agent is macrolide. In yet another embodiment, a non-limiting list of the antimicrobial agents of the invention includes Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin, Flurithromycin, Ivermectin, Josamycin, Midecamycin, Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin. According to some embodiments of the above combination, the virus of the Coronaviridae family is selected from the group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1. In one embodiment, the virus of the
Coronaviridae family is SARS-CoV-2 (COVID-19). The pharmaceutical composition according to the embodiments of the invention may be a fixed dosage form composition. In one embodiment, the pharmaceutical composition is a solid composition, a liquid composition, or a semi-solid composition. In another embodiment, the pharmaceutical composition is designed for oral administration, intra-muscular administration, intravenous administration, intraperitoneal administration, intranasal administration, intramucosal administration, or transdermal administration. In yet another embodiment, the pharmaceutical composition is in the form of a tablet, a capsule, a powder, a powder for suspension, a powder for reconstitution, granules, a syrup, a suspension, and a dispersion.
According to some embodiments, the invention provides the above pharmaceutical composition for use as a medicament. According to some embodiments, the invention provides the above pharmaceutical composition for use in the treatment of a
condition associated with an infection by a virus of the Coronaviridae family, in a subject in need of such treatment.
According to some embodiments of the above pharmaceutical composition, the condition associated with the infection by a virus of the Coronaviridae family is selected from the group consisting ofacute respiratory distress syndrome (ARDS), common cold, pneumonia, bronchitis, severe acute respiratory syndrome, and Middle East respiratory syndrome.
According to some embodiments, the invention provides method for treating a subject afflicted with a condition associated with an infection by a virus of the Coronaviridae family with a pharmaceutical composition according to the embodiments of the invention, comprising the steps of: a) administering a therapeutic amount of the pharmaceutical composition to the subject; b) determining whether the subject is a responder by determining the gene expression profile of the subject, and comparing the gene expression profile to a reference gene expression profile to identify the subject as a responder; and c) continuing the administration if the subject is identified as a responder, or modifying treatment of the subject if the subject is not identified as a responder. As used herein the term "responder" is meant to be understood, without limitation, as a subject who, based on his gene expression profile, namely specific biomarkers, is likely to respond to the proposed treatment. For example, genetic profile of the Responder is characterized by upregulation and/or downregulation of certain genes, while genetic profile of the Non-Responder is characterized by different pattern of gene expression. The reason for the differentiated response can be a result of various cellular pathway and processes. The change in genetic profile may be triggered, without limitation, by administration of the proposed therapeutics and/or by the infection itself. The variability in the response of different people to viral
infection and may lead to differential gene expression and different response to therapeutic tool. The opposite is also possible, while administration of similar therapeutics to different people may lead to different gene expression pattern which becomes a determinant of the clinical outcome.
According to some embodiments, the invention further provides a method for treating a human subject presenting clinical manifestations associated with infection by a virus of the Coronaviridae family with a pharmaceutical composition according to the embodiments of the invention, comprising the steps of:(i) determining the gene expression profile of the subject;(ii) identifying the subject as a predicted responder if the gene expression profile is indicative of subject being a responder; and(iii) administering the pharmaceutical composition to the subject only if the subject is identified as a predicted responder
According to some embodiments of the above methods, compositions and combinations, a non-limiting list of clinical manifestations according to the embodiments of the invention includes fever, cough, dyspnea, hypoxia, more than 50% lung involvement on imaging, respiratory failure, shock, multiorgan system dysfunction, malaise, fatigue, sputum/secretion, neurological symptoms, dermatological manifestations, anorexia, myalgia, sneezing, sore throat, rhinitis, goosebumps, headache, chest pain and diarrhea.
Antiviral agents - mode of action
Acyclovir is the pro-drug undergoing two/three-step phosphorylation before its binding (as the Acyclovir triphosphate) to the viral (the HSV) DMA Dependent RNA Polymerase. One key enzyme is the viral thymidine kinase which is present in this family of viruses.
However the thymidine kinase is not reported in the beta- coronavirus family. By using bioinformatics tools, we also have demonstrated the absence of the thymidine kinase in the beta- coronavirus SARS CoV-2. This explains why acyclovir did not suppressed coronaviruses in-vitro experiments. In spite of these negative in-vitro results, Acyclovir analogs were reported to be useful for suppression of the SARS-CoV-2 activity in human cells. We have proposed the existence ofalternative phosphorylarion sites in CoV-2 for Acyclovir, or involvement of host (Human) kinases in the phosphorylation.
The Acyclovir triphosphate and its derivatives were shown also to bind to RNA Dependent RNA Polymerases (RdRp), which are similar to the DNA-dependent ones from HSV-like viruses, thereby sharing the same catalytic mechanism. Currently another drug is available in-the-market, Remdesivir, is the RNA-polymerase specific and, therefore, it can be considered as better candidate for targeting SARS-CoV-2. Remdesivir is also designed as the pro-drug. After initial metabolic cleavage, the remdesivir intermediate phosphorylates and binds to SARS-CoV-2 RNA- polymerase. There are other structurally similar pro-drugs with same anti-viral mechanism: Ribavirin and Zidovudine.
Example 1: Homology modeling of SARS-CoV-2 Targets.
Methods The sequencing data of COVID-19 were retrieved from Genbank database under the FASTA format for analysis. Homology modelling was performed using Swiss model Webserver
(http://swissmodel.expasy.org/). Swiss model was used for 3D structure prediction and also template selection. The best homology models were selected according to Global Model Quality Estimation (GMQE) and QMEAN statistical parameters. The prediction of ligand binding site for few proteins in the modelled protein structure was made using 3DLigandSite server
(http://www.sbg.bio.ic.ac.uk/3dligandsite/). Quality and accuracy with validation of the predicted models were analyzed performing RAMPAGE for Ramachandran plot analysis.
Procedure Homology modelling of protein targets for antiviral/antibiotics, in particular, of spike glycoprotein from SARS-CoV-2, and RNA- dependent RNA-polymerase (RdRp), was performed based on known templates with similar structure/function. For template selection, the target sequence was searched against Protein Data Bank (PDB) (16) database using PSI-BLAST tool and threading server Protein Homology/analogy Recognition Engine (PHYRE) (17). Based on BLAST and PHYRE analysis, a number of proteins from Viruses/Bacteria/ Fungi were retrieved as top-score hits. In order to get available 3D structures with ligand/drug bound sites as templates for modelling potential targets on SARS-
CoVid-2, we data-mined the Protein Data Bank with FDA approved antibiotics, namely, Doxycycline, Azithromycin, Clarithromycin, Amikacin, Tobramycin, etc. as queries. Structures were further studied and compared using different structure superimposing servers Vector Alignment Search Tool (VAST), PDBefold,
Combinatorial Extension (CE), and threading servers PHYRE, 3D- Position Specific Scoring Matrix (3DPSSM). Hits with bound antibiotics/antiviral drugs were selected, and multiple structure-based sequence alignments were performed. Based on these alignments, structures from PDB were selected as multiple templates and used for further modelling based on SWISS-MODEL, MODELLER, and iTASSER protocols.
The models were further evaluated using Ramachandran plot, ERRAT (Protein structure verification web server) and ProSA (Protein Structure Analysis).
Quality assessment of protein models
The global and per-residue model quality has been assessed using the QMEAN scoring function.
Docking
Docking grids were generated using the receptor grid generation module in AutoDock4 application. Grids were generated with OPLS- like force field, keeping the default values of van der Waals scaling factor set to 0.8 and charge cutoff set to 0.15. The binding sites were defined at the (1) SARS-CoVid-2 spike glycoprotein/hACE and (2) virus RNA interfaces, respectively. For RdRp, the center of ATP-binding region was used for the definition of bindingsite. Cubicboxes of 35Ά dimension centre don these binding sites were generated for each docking model.
The modules from OpenBabel suite and Chimera vl.11.2 were used to prepare ligand molecules for docking. When available, 3D structures of antiviral/antibiotics molecules were taken from PDB (such as Doxycycline, Azithromycin, Clarithromycin, Amikacin, Tobramycin, etc.). All possible ionization states and tautomers were generated and prepared for docking study. Molecular conformers were generated and docked to the areas identified as binding sites, using AutoDock4 and AutoDock Vina docking protocols. Docking strategy included writing per-residue interaction energy values in order to determine key residues involved in antibiotics binding and selectivity. All molecules from our library of FDA approved antiviral/antibiotics were docked to Sitel and Site2 regions (as identified by FTMap), and these docking conformations with the best scores were analyzed. Compounds which showed favorable interactions and good AutoDock Vina score, were then selected for further mechanism-of-action analysis .
Results
Targeting SARS-CoV-2 spike glycoprotein
A multi-target attack was defined on the SARS-CoV-2 spike glycoprotein to three possible binding sites: RNA binding site with the viral RNA, the SARS-CoV-2 surface binding to the human cell receptor ACE2 binding site (Figure 1).
First, all the anti-pneumonia agents, particularly, antibiotics we collected (Table 1). Most interesting there were molecules with a mechanism of actions to RNA, such as a binding to the 50S subunit of the bacterial ribosome, thus, inhibiting translation of mRNA. Such antibiotics are known to have RNA binding property and may prevent virus from two functions: (1) virus particle re- assembly by binding of the S-glycoprotein to the viral surface, and (2) binding of this glycoprotein to human/host ACE2 receptor (Figures 2-4). Table 1. antibiotics drugs candidates:
Example 2: Antiviral cocktail based on Acyclovir and Dexamethasone Phosphate against COVID-19.
Based on the described above key anti-viral mechanism on the structural level, a new pharmaceutical combination was designed, aimed to enhance the pharmaco-therapeutic potential of Acyclovir in the treatment of patients infected by SAKS-CoV-2. This includes Dexamethasone phosphate acting as the phosphate donor for Acyclovir biotransformation. An additional phosphate donor was antibiotic Fosfomycin (the phosphoenolpyruvate analogue with the phosphate group bound to epoxypropyl moiety. Fosfomycin is old well- tolerated antimicrobial drug. According to our structure- based modeling results, this small molecule may enter inter-helical pores of viral surface proteins, in particular, the S-glycoprotein and thus may be in the pharmacological synergism with acyclovir action. This biochemical and pharmacological synergism of the Acyclovir & Dexamethasole and Acyclovir & Fosfomycin compositions provided with promising opportunity in the current urgent need of novel methods to stop the outburst of the SARS-CoV-2.
Example 3: POC Testing for Human Coronavirus OC43 (hCoV-OC43) Attenuation by Acyclovir 6 Dexamethasone Phosphate Liquid Formula
The aim of the study was POC testing of the antiviral potential of a formula containing acyclovir and dexamethasone phosphate, on human coronavirus OC43 (hCoV-OC43), by cytopathogenic effect (CPE) monitoring and cell viability assay.
Samples
1. One vial of 25mg acyclovir
2. One vial of 10mg dexamethasone phosphate, 98%
Samples were were stored at 4°C.
Materials
1. Human MRC5 cells (lung fibroblasts; ATCC, Cat # CCL-171)
2. L-Alanyl-L-Glutamine Solution (200 mM; Biological Industries, Cat # 03-022-1B)4.3. Penicillin-Streptomycin Solution (Biological Industries, Cat # 03-031-1B)
3. Fetal Bovine Serum (FBS; Biological Industries, Cat # 04- 127-1A)
4. MEM-NEAA Medium (Biological Industries, Cat # 01-040-1A)
5. Human coronavirus OC43 (hCoV-OC43; stock titer: 6.36x106 TCID50/ml)
6. Consumables:15mltube(Corning,Cat#430055),filtertips(Axyge n,Cat#TF-300-R-S,TF-200R- S), filter tips (Thermo Fisher, Cat # 94052410), 96-well plate (Greiner Bio One, Cat # 655180), sterile 1.5 ml microcentrifuge tubes (SARSTEDT Cat# 72.690), Minisart syringe filter (0.2 E°m; Sartorius, Cat # 17597-K) Methods and experimental procedures
Cytotoxicity test:
Sample preparation: MRC5 cells (4.1) were grown in MEM medium (4.5) supplemented with 2mM L-Alanyl-L-Glutamine (4.2), 1%
Penicillin-Streptomycin (4.3) and 10% FBS (4.4), in an incubator at 370C and 5% C02. On the day of the experiment the acyclovir- dexamethasone- phosphate formula was prepared as follows: 1.8 mg acyclovir (2.1) were dissolved in 1ml sterile DDW at 370C (to reach a final concentration of 8mM) . In parallel, l.1mg dexamethasone phosphate (2.2) were dissolved in 1ml 0.1M NaOH (to reach a final concentration of 100μΜ/mL). Next, the two solutions were mixed 1:1 to a final volume of 2ml, to generate a stock solution with final concentrations: 4mM acyclovir, ImM
dexamethasone phosphate in 1mL. The 2ml stock solution was filter sterilized through a Minisart syringe filter (0.2μm filter; 4.7). Following filtration, the formula was diluted four (4) times to provide 4 concentrations as follows:
• 800μΜ acyclovir, 200μΜ dexamethasone phosphate
• 400μΜ acyclovir, 100μΜ dexamethasone phosphate
• 200μΜ acyclovir, 50μΜ dexamethasone phosphate
• 100μΜ acyclovir, 25μΜ dexamethasone phosphate
All dilutions were performed in MEM medium (4.5) supplemented with 2mM L-Alanyl- LGlutamine (4.2), 1% Penicillin-Streptomycin (4.3) and 10% FBS (4.4). Table 3 summarizes the acyclovir- dexamethasone phosphate formula preparation and its dilutions.
Experimental procedure
On the day of the experiment, the cell growth medium was removed and 250μl of each of the four (4) dilutions prepared (5.1.1) were added, each in a triplicate, to the cells instead of the removed medium. In parallel, in the same 96-well plate, three (3) additional wells (triplicate) were used as negative control (NC-tox) for the viability assay, in which the media was replaced by 250μl sterile MEM, containing no acyclovir-dexamethasone phosphate formula. Following media replacement in the MRC5 96- well plate, cells were incubated for six (6) days at 370C and 5% C02, and monitored every 24 hours under the microscope. Cell viability was determined by MTT assay on day six (6) of incubation.
MTT viability assay
On day 6 of the test, the growth medium was removed from each well. Next, 5 mg/ml MTT compound (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide, in PBS) was diluted 1:7.5 in MEM, and 150μl of the diluted MTT were added per well as replacement medium. The plate was then incubated for 2 hours at 370C and 5% CO2. Following incubation, medium + MTT was removed, and 100μΙ DMSO were added per well. The plate was incubated for 15 minutes at room temperature following DMSO addition, and was read by SPECTRAFluor Plus plate reader (Tecan) at 560nm. MTT assay results are presented in Table 3.
Acyclovir-dexamethasone phosphate formula antiviral activity experiment
Sample preparation day 1 of the experiment: MRC5 cells were plated in a 96-well plate, and grown as described in above. On the day of the experiment (day 1) cells were either infected with hCoV-OC43 at TCID50 = 3.16x103 for the treatment testing (Tr), or with seven 10-fold serial dilutions of hCoV-OC43 (each in 4 replicates), starting at TCID50 = 3.16x106 to serve as viral infection calibration curve. All viral infections were performed in MEM medium supplemented with 2mM L-Alanyl-L-Glutamine, 1% Penicillin Streptomycin and 2% FBS, and the plate was then placed in an incubator at 35°C and 5% CO2. Twenty four (24) hours post- infection, on day 2, 400μΜ acyclovir, acyclovir- dexamethasone phosphate formula stock solution was prepared as described above (final concentrations: 4mM acyclovir, ImM dexamethasone phosphate) . The formula stock solution was filter sterilized through a Minisart syringe filter (0.2μm filter; 4.7), and was then diluted to provide 4 concentrations as follows:
• 800μΜ acyclovir, 200μΜ dexamethasone phosphate
• 400μΜ acyclovir, 100μΜ dexamethasone phosphate
• 200μΜ acyclovir, 50μΜ dexamethasone phosphate
• 100μΜ acyclovir, 25μΜ dexamethasone phosphate
The stock was then kept at 4°C. All dilutions were performed in MEM medium supplemented with 2mM L-Alanyl-L-Glutamine, 1% Penicillin-Streptomycin, and 2% FBS. Experimental procedure
Day 2 of the experiment: following formula dilutions, the cells were monitored under the microscope. Next, the growth medium of MRC5 cells 96-well plate was removed, and 125μl of each of the four (4) dilutions prepared were added, each in a triplicate, to cells infected the day before instead of the removed medium (treatment; Tr). In parallel, in the same 96-well plate, 125μl of each of the four (4) dilutions prepared were added, each in a triplicate, to wells of uninfected cells instead of the removed medium (negative control; NC). For the calibration curve, in each replicate of 4 wells, 125μl of sterile MEM medium were added, to cells infected the day before instead of the removed medium. Four (4) additional wells of uninfected cells (as replicates) were used as negative control (NC-c) for the calibration curve viability assay, to which 125μl of sterile MEM medium were added. Following media replacement in the MRC596- well plate, the plate was returned to the incubator at 35°C and 5% CO2 for an additional 24hr.
Day 3 of the experiment: twenty four (24) hours post-medium replacement in the MRC5 plate, the cells were monitored under the microscope. Next, the formula stock solution was removed from 40C, and dilutions were made to produce the same 4 concentrations as in section. To the Tr wells, additional 125μl treatment of each of the four formula dilutions were added, each in a triplicate, of cells infected on day 1 of the experiment. To the NC wells additional 125μl treatment of each of the four formula dilutions were added, each in a triplicate, of cells uninfected on day 1 of the experiment. To the calibration curve wells and the NC-c wells additional 125μl of sterile MEM medium
were added. The MRC5 96-well plate was then returned to the incubator for 3 additional days at 350C and 5% CO2, and monitored every 24 hours under the microscope . Cell viability was determined by MTT assay on day 6 of the experiment. MTT viability assay on day 6 of the experiment, the growth medium was removed from each well. Next, the procedure as described in section was performed. MTT assay results are presented in Table 4.
Table 4. Cytotoxicity test results % cell viability upon 6- day treatment with the acyclovir- dexamethasone phosphate formula:
Ac: acyclovir, D.ph: dexamethasone phosphate
NC-tox: negative control (i.e cells incubated with MEM medium only)
% Cell viability: indicating viable cells per sample. Cell viability per each sample was calculated as percentage of the average MTT result of each triplicate, from the average of NC wells MTT results, which was regarded as representing 100% cell viability.
Results and conclusion
Cytotoxicity test results (as presented in Table 5): the assay was performed diluting the formula to 4 concentrations (as shown in Table 3). In the assay substantial cell death was observed when concentration I of the formula was applied to MRC5 cells and less than 50% death when dilution II was applied to the cells. These results indicate a potential anti-tumor activity
of the formula at high concentrations. When dilutions III and IV were applied to the cells, there was no cell death observed. Based on these results it was decided to apply to the infected MRC5 cells, in the acyclovir-dexamethasone phosphate antiviral activity experiment, the formula concentrations: II, III, IV, as well as an additional 2-fold dilution of concentration IV (i.e. Ac 50 μΜ / D.ph 12.5μΜ), in order to minimize cytotoxic effects, but to still allow the formula a large enough range of efficacy. Acyclovir-dexamethasone phosphate formula antiviral activity experiment (CPE and MTT assay results, as presented in Table 5):
Table 5. acyclovir-dexamethasone phosphate formula antiviral activity experiment - CPE & MTT assay results
% Cell viability: indicating viable cells per sample. Cell viability per each sample was calculated as percentage of the average MTT result of each treatment concentration + hCoV-OC43 infection, from the average of MTT result of the same treatment concentration with no hCoV-OC43 infection. Initial viral TCID50: the viral inoculum used to infect the cells on day 1 of the experiment.
Viral log reduction: is calculated by dividing the initial viral TCID50 by the end viral TCID50 in each sample. CPE / outset day: the viral cytopathogenic effects as observed under the microscope during the 6 days of experiment. "+++"= massive CPE, = mild CPE, "+--"= minimal CPE. Day indicates the outset day of observed CPE.
The results indicate that the tested formula, as tested in the current study, does hamper hCoV-OC43 infectivity and reduce viral load by 1.5 log following 2 dose treatment, and incubation for 3 days following treatment (as indicated in Table 4). Furthermore, based on our microscope monitoring during the 6 days of the experiment, viral cytopathogenic effects (CPE) were observed in all wells of the cells infected with hCoVOC43 and then twice treated with the acyclovir-dexamethasone phosphate formula. The CPE started 3 days post-viral infection of the cells, and was observed to a similar extent following all 4 treatments of the formula (i.e. in all 4 concentrations).
In conclusion, in this study, 4 concentrations of a liquid formula containing acyclovir and dexamethasone phosphate were tested as antiviral treatment post cell infection with hCoV- OC43. To that end, we employed a direct method assaying cell viability following their infection with the virus and their treatment in a double dose of the tested formula.Results of this study indicate that the tested treatment increase the viability of MRC5 cells by 10%. Example 3. Differential gene expression analysis of drug targeting genes in severe and non-severe COVID-19:
CXCL8 (also referred to as IL-8) is a chemokine considered a potential prognostic biomarker for acute respiratory distress syndrome (ARDS) clinical course. CXCL8 plays a vital role in the early control of respiratory tract infection due to its chemotactic activity for neutrophils and monocytes. The activity of CXCL8 is strongly reliant on the transcription factor AP-1 and is associated with the spike and nucleocapsid proteins of SARS-CoV-2. CXCL8 stimulates the formation of the highly immunogenic and toxic neutrophil extracellular traps (NETs) that lead to inflammation and apoptosis of epithelial/endothelial cells. Using the differential gene expression analysis and comparative profiling of transcriptome data (Accession number:
CRA002390 for BALF and HRA000520 for PBMC; Beijing Institute of Genomics), we observed that CXCL8 is consistently up-regulated in the bronchoalveolar lavage fluid (BALF) of severe COVID-19 patients. Hence, CXCL8 could be used as a biomarker for severe COVID-19 cases as they are not found to be up-regulated in peripheral blood mononuclear cell (PBMC) of mild COVID-19 patients. Therefore, inhibitors of CXCL8 could be considered as possible therapeutic modalities for severe COVID-19. Based on the previous studies, we collected the FDA-approved drugs that could be effective against the CXCL8. Based on the structural analysis, we found Acyclovir and Azithromycin are the most effective FDA-approved drugs that could be used for controlling the expression of CXCL8. Our studies suggest that a combination of these two drugs could be useful for treating severe COVID-19 cases to reduce the chances of ARDS.
Table 6:
Commons differentially expressed genes between severe and non- severe COVID-19 cases are highlighted. We can see three genes which are upregulated in the non-severe cases are found to downregulated in severe cases while two genes which are
downregulated in non-severe cases are found to upregulated in severe cases.
Example 4: Clinical trial evaluating safety and efficacy of the combination of Acyclovir 6 dexamethasone phosphate on clinical manifestation of COVID-19 infection
A clinical study to asses safety and efficacy of administration of the combination of acyclovir and dexamethasone in moderate COVID-19 patients requiring supplemental oxygen via nasal cannula is conducted. The clinical trial is divided into two phases: phase I including approximately 10 patients and phase II, double blinded study including about 50-100 moderate COVID- 19 patients. A at least one endpoint of the study is assessing antiviral effect of the combination versus standard of care treatment . The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a," "an" and "the" are intended to include plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" or "comprising, " when used in this specification, specify the presence of stated features, integers, steps, operations, elements components and/or groups or combinations thereof, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components and/or groups or combinations thereof. As used herein the terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to". The term "consisting of" means "including and limited to".
As used herein, the term "and/or” includes any and all possible combinations or one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and claims and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein. Well-known functions or constructions may not be described in detail for brevity and/or clarity.
It will be understood that, although the terms first, second, etc., may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. Rather, these terms are only used to distinguish one element, component, region, layer and/or section, from another element, component, region, layer and/or section. Certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.
Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for
convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
Whenever the term "about" is used, it is meant to refer to a measurable value such as an amount, a temporal duration, and the like, and is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. As used herein the term "method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
As used herein the term "patient" or "subject" is meant to include any mammal. A "mammal," as used herein, refers to any
animal classified as a mammal, including but not limited to, humans, experimental animals including monkeys, rats, mice, and guinea pigs, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, and the like. As used herein, a "pharmaceutically acceptable" carrier or excipient 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.
"Treating" or "treatment" of a disease as used herein includes: preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e ., arresting or reducing the development of the disease or its clinical symptoms, or relieving the disease, i.e ., causing regression of the disease or its clinical symptoms.
A "therapeutically-effective amount" or an "effective amount" means the amount of a compound or a dosage form that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically- effective amount" will vary depending on the compound, the disease, and its severity and the age, weight, etc ., of the subject to be treated. As used herein the term "Pharmaceutically-acceptable salt" refers to salts which retain the biological effectiveness and properties of compounds which are not biologically or otherwise undesirable . Pharmaceutically acceptable salts refer to pharmaceutically acceptable salts of the compounds, which salts are derived from a variety of organic and inorganic counter ions well known in the art.
The pharmaceutical dosage forms may be prepared as medicaments to be administered orally. Suitable forms for oral
administration include, without limitation, tablets, capsules, solutions, syrups and suspensions; such as ready-to-use syrups and suspensions, or reconstituted from solid dosage form such as, without limitation, dry powder. The dosage form may contain suitable binders, lubricants, coloring agents, flavoring agents, flow-inducing agents, stabilizing agents, solubilizing agents, antioxidants, buffering agent, chelating agents, and fillers, all collectively or individually fall under the definition of the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient".
In the pharmaceutical composition, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert filler such as gelatin, agar, starch, methyl cellulose, mannitol, xylitol, sorbitol, maltodextrin and the like . Suitable binders include starch, gelatin, natural sugars such as corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, cellulose based soluble polymers such as but not limited to hydroxypropylomethylcellulose, hydroxypropylcellulose, polyethylene glycol, and the like. Glidants used in these dosage forms include sodium benzoate, sodium acetate, polyethylene glycole, and the like. Stabilizing (antimicrobial) agents include benzoic acid, and salts thereof, parahydroxybenzoate and salts thereof, sorbic acid and salts thereof and the like. Stabilizing (physical) agents include viscosity enhancing polymers such as hydroxyethyl cellulose, xanthan gum and the like .
All publications, patent applications, patents, and other references mentioned in the disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. In case of conflict, the patent specification, including definitions, will prevail.
In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Throughout this application various publications, published patent applications and published patents are referenced. It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather the scope of the present invention is defined by the appended claims and includes both combinations and sub-combinations of the various features described hereinabove as well as variations and modifications thereof, which would occur to persons skilled in the art upon reading the foregoing description. While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents may occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention. Various embodiments have been presented. Each of these embodiments may of course include features from other embodiments presented, and embodiments not specifically described may include various features described herein.
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Claims
1. A method of treating a condition associated with an infection by a virus of the Coronaviridae family, in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, to thereby effectively treat the condition associated with the infection by the virus of the Coronaviridae family.
2. The method of claim 1, wherein the at least one agent having the anti-viral activity is selected from the group consisting of acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine.
3. The method of claim 1 or 2, wherein the at least one phosphate donor is selected from the group consisting of dexamethasone phosphate, fosfomycin, L-creatine phosphate, and carnitine-phosphate.
4. The method of any one of claims 1 to 3, wherein the therapeutically effective amount of the at least one agent
having an anti-viral activity is from 100mg/day to 5000mg/day.
5. The method of any one of claims 1 to 4, wherein the therapeutically effective amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day.
6. The method of any one of claims 1 to 5, wherein the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
7. The method of claim 6, wherein the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
8. The method of any one of claims 1 to 7, wherein the subject is a mammalian subject.
9. The method of claim 8, wherein the mammalian subject is a human subject.
10. The method of any one of claims 1 to 9, wherein the condition associated with an infection by a virus of the Coronaviridae family is selected from the group consisting of acute respiratory distress syndrome (ARDS), common cold, pneumonia, bronchitis, severe acute respiratory syndrome, and Middle East respiratory syndrome.
11. The method of any one of claims 1 to 10, further comprising administering to the subject a therapeutically effective amount of at least one antimicrobial agent.
12. The method of claim 10, wherein the antimicrobial agent is a macrolide.
13. The method of claim 11, wherein the antimicrobial agent is selected from the group consisting of Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin, Flurithromycin, Ivermectin, Josamycin, Midecamycin, Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin.
14. A method of slowing and/or preventing progression of a condition associated with an infection by a virus of the
Coronaviridae family in a subject, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to slow and/or prevent said condition.
15. The method of claim 14, wherein the at least one agent having the anti-viral activity is selected from the group consisting of acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine.
16. The method of claim 14 or 15, wherein the at least one phosphate donor is selected from the group consisting of dexamethasone phosphate, fosfomycin, L-creatine phosphate, and carnitine-phosphate
17. The method of any one of claims 14 to 16, wherein the amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day
18. The method of any one of claims 14 to 17, wherein the amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day.
19. The method of any one of claims 14 to 18, wherein the virus of the Coronaviridae family selected from the group consisting of SARS-CoV-2 (COVID-19, SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
20. The method of claim 19, wherein the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
21. The method of any one of claims 14 to 20, wherein the subject is a mammalian subject.
22. The method of claim 19, wherein the mammalian subject is a human subject.
23. The method of any one of claims 14 to 22, wherein the condition associated with an infection by a virus of the Coronaviridae family is selected from the group consisting of acute respiratory distress syndrome (ARDS), common cold, pneumonia, bronchitis, severe acute respiratory syndrome, and Middle East respiratory syndrome.
24. The method of any one of claims 13 to 21, further comprising administering to the subject a therapeutically effective amount of at least one antimicrobial agent.
25. The method of claim 24, wherein the antimicrobial agent is a macrolide.
26. The method of claim 24, wherein the antimicrobial agent is selected from the group consisting of Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin, Flurithromycin, Ivermectin, Josamycin, Midecamycin, Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin.
27. A method of reducing clinical manifestations of an infection by a virus of the Coronaviridae family in a subject in need, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the clinical manifestations.
28. The method of claim 25, wherein the at least one agent having the anti-viral activity is selected from the group consisting of acyclovir, gancyclovir, valganciclovir, valacyclovir, famciclovir, penciclovir, vidarabine, cidofovir, ribavirin, adefovir, entecavir, favipiravir, brincidofovir, Idoxuridine, trifluridine, tipiracil, edoxudine, brivudine, FV-100, sorivudine, cytarabine, lamivudine, lobucavir, telbivudine, clevudine, tenofovir disoproxil, tenofovir alafenamide, and zidovudine.
29. The method of claim 27 or 28, wherein the at least one phosphate donor is selected from the group consisting of
dexamethasone phosphate, fosfomycin, L-creatine phosphate, and carnitine-phosphate,
30. The method of any one of claims 27 to 29, wherein the amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day.
31. The method of any one of claims 27 to 30, wherein the amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day.
32. The method of any one of claims 27 to 31, wherein the virus of the Coronaviridae family is selected from the group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
33. The method of claim 32, wherein the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
34. The method of any one of claims 27 to 33, wherein the subject is a mammalian subject.
35. The method of claim 34, wherein the subject is a human subject.
36. The method of any one of claims 27 to 35, wherein the clinical manifestations are selected from the group consisting of fever, cough, dyspnea, hypoxia, more than 50% lung involvement on imaging, respiratory failure, shock, multiorgan system dysfunction, malaise, fatigue, sputum/secretion, neurological symptoms, dermatological manifestations, anorexia, myalgia, sneezing, sore throat, rhinitis, goosebumps, headache, chest pain and diarrhea.
37. The method of any one of claims 27 to 36, further comprising administering to the subject an effective amount of at least one antimicrobial agent.
38. The method of claim 37, wherein the antimicrobial agent is a macrolide.
39. The method of claim 37, wherein the antimicrobial agent is selected from the group consisting of Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin, Flurithromycin, Ivermectin, Josamycin, Midecamycin, Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin.
40. A method of reducing a viral load in a subject infected by a virus of the Coronaviridae family, comprising administering to the subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the viral load.
41. The method of claim 40, wherein the viral load is measured in the body fluids of the subject.
42. The method of claim 40 or 41, wherein the subject is a mammalian subject.
43. The method of claim 42, wherein said subject is a human subject.
44. The method of any one of claims 40 to 43, wherein the at least one agent having the anti-viral activity is selected
from the group consisting of acyclovir, oseltamivir, rimantadine, remdesivir, ribavirin,and zidovudine.
45. The method of claim 40 to 44, wherein the at least one phosphate donor is selected from the group consisting of dexamethasone phosphate, fosfomycin, L-creatine phosphate, and carnitine-phosphate.
46. The method of any one of claims 40 to 45, wherein the amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day.
47. The method of any one of claims 40 to 46, wherein the amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day.
48. The method of any one of claims 40 to 47, wherein the virus of the Coronaviridae family is selected from the group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
49. The method of claim 48, wherein the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
50. The method of any one of claims 40 to 49, further comprising administering to the subject at least one antimicrobial agent.
51. The method of claim 50, wherein the antimicrobial agent is a macrolide.
52. The method of claim 50, wherein the antimicrobial agent is selected from the group consisting of Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin, Flurithromycin, Ivermectin, Josamycin, Midecamycin,
Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin.
53. The method of any one of claims 37 to 48, wherein the viral load is reduced by at least 1.3 log.
54. The method of any one of claims 1 to 53, wherein the at least one agent having the anti-viral activity and the at least one phosphate donor are administered simultaneously.
55. The method of claim 54, wherein the at least one agent having the anti-viral activity and the at least one phosphate donor are administered as a fixed dosage form composition.
56. The method of any one of claims 1 to 53, wherein the at least one agent having the anti-viral activity and the at least one phosphate donor are administered independently of each other.
57. A method of reducing at least one surrogate marker associated with an infection by a virus of the Coronaviridae family in a subject diagnosed with said infection, comprising administering to said subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the at least one surrogate marker.
58. A method of reducing at least one biomarker associated with an infection by a virus of the Coronaviridae family
in a subject diagnosed with said infection, comprising administering to said subject a. at least one agent having an anti-viral activity, and b. at least one phosphate donor, in an amount effective to reduce the at least one biomarker, wherein said phosphate donor potentiates the anti-viral activity of the at least one agent.
59. The method of claim 57 or 58, wherein the virus of the Coronaviridae family is selected from the group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
60. The method of claim 59, wherein the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
61. The method of any one of claims 57 to 60, wherein the at least one agent having the anti-viral activity is selected from the group consisting of acyclovir, oseltamivir, rimantadine, remdesivir, ribavirin,and zidovudine.
62. The method of any one of claims 57 to 61, wherein the at least one phosphate donor is selected from the group consisting of dexamethasone phosphate, fosfomycin, L- creatine phosphate, and carnitine-phosphate.
63. The method of any one of claims 57 to 62, wherein the amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day.
64. The method of any one of claims 57 to 63, wherein the amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day.
65. A therapeutic combination suitable for administration to a subject in need, comprising: a. at least one agent having an anti-viral activity; b. at least one phosphate donor; wherein the subject in need is diagnosed with an infection by a virus of the Coronaviridae family.
66. The combination of claim 65, wherein the at least one agent having the anti-viral activity is selected from the group consisting of acyclovir, oseltamivir, rimantadine, remdesivir, ribavirin,and zidovudine.
67. The combination of claim 65 or 66, wherein the at least one phosphate donor is selected from the group consisting of dexamethasone phosphate, fosfomycin, L-creatine phosphate, carnitine-phosphate.
68. The combination of any one of claims 65 to 67, wherein the amount of the at least one agent having an anti-viral activity is from 100mg/day to 5000mg/day.
69. The combination of any one of claims 65 to 68, wherein the amount of the at least one phosphate donor is from 0.1 mg/day to 50mg/day.
70. The combination of any one of claims 65 to 69, further comprising at least one anti-microbial agent.
71. The combination of claim 70, wherein said at least one anti-microbial agent is a macrolide.
72. The combination of claim 70, wherein said anti-microbial agent is selected from the group consisting of Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin, Flurithromycin, Ivermectin, Josamycin, Midecamycin, Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin.
73. The combination of any one of claims 65 to 72, wherein the virus of the Coronaviridae family is selected from the group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
74. The method of claim 73, wherein the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
75. The combination of any one of claims 65 to 74, wherein the subject is a mammalian subject.
76. The combination of claim 75, wherein the mammalian subject is a human subject.
77. A pharmaceutical composition comprising a. at least one at least one agent having an anti-viral activity, b. at least one phosphate donor, and c. at least one pharmaceutically acceptable carrier
78. The pharmaceutical composition of claim 77, wherein the at least one agent having the anti-viral activity is selected from the group consisting of acyclovir,
oseltamivir, rimantadine, , remdesivir, ribavirin, and zidovudine.
79. The pharmaceutical composition of claim 77 or 78, wherein the at least one phosphate donor is selected from the group consisting of dexamethasone phosphate, fosfomycin, L-creatine phosphate, and carnitine-phosphate.
80. The pharmaceutical composition of any one of claims 77 to 79, further comprising at least one anti-microbial agent.
81. The pharmaceutical composition of claim 80, wherein said at least one anti-microbial agent is a macrolide.
82. The pharmaceutical composition of claim 80, wherein said anti-microbial agent is selected from the group consisting of Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin, Flurithromycin, Ivermectin, Josamycin, Midecamycin, Miocamycin, Oleandomycin, Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin.
83. The pharmaceutical composition of any one of claims 77 to 82 which is a fixed dosage form composition.
84. The pharmaceutical composition of any one of claims 77 to 83 for use as a medicament.
85. The pharmaceutical composition of any one of claims 77 to 84 for use in the treatment of a condition associated with an infection by a virus of the Coronaviridae family, in a subject in need of such treatment.
86. The pharmaceutical composition of claim 85, wherein the virus of the Coronaviridae family is selected from the
group consisting of SARS-CoV-2 (COVID-19), SARS-CoV, MERS, OC43, 229E, NL63, OC43, and HKU1.
87. The method of claim 86, wherein the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
88. The pharmaceutical composition of claim 85 or 87, wherein the subject is a mammalian subject.
89. The pharmaceutical composition of claim 88, wherein the mammalian subject is a human subject.
90. The pharmaceutical composition of any one of claims 85 to 89, wherein the condition associated with the infection by a virus of the Coronaviridae family is selected from the group consisting of acute respiratory distress syndrome (ARDS), common cold, pneumonia, bronchitis, severe acute respiratory syndrome, and Middle East respiratory syndrome.
91. The pharmaceutical composition of any one of claims 85 to 90, further comprising at least one anti-microbial agent.
92. The pharmaceutical composition of claim 91, wherein said at least one anti-microbial agent is a macrolide.
93. The pharmaceutical composition of claim 91, wherein said anti-microbial agent is selected from the group consisting of Azithromycin, Boromycin, Clarithromycin, Dirithromycin, Erythromycin, Flurithromycin, Ivermectin,
Josamycin, Midecamycin, Miocamycin, 01eandomycin,
Rokitamycin, Roxithromycin, Spiramycin, Troleandomycin, and Tylosin.
94. The pharmaceutical composition of any one of claims 77 to 93, selected from solid composition, liquid composition, or semi-solid composition.
95. The pharmaceutical composition of any one of claims 77 to 94 which is designed for oral administration, intra- muscular administraton, intravenous administration, intraperitoneal administration, intranasal administration, intramucosal administration, or transdermal administration.
96. The pharmaceutical composition of any one of claims 77 to 95 in the form of a tablet, a capsule, a powder, a syrup, a suspension, or a dispersion.
97. A method for treating a subject afflicted with a condition associated with an infection by a virus of the Coronaviridae family with a pharmaceutical composition of any one of claims 77 to 83, comprising the steps of: a) administering a therapeutic amount of the pharmaceutical composition to the subject; b) determining whether the subject is a responder by determining the gene expression profile of the subject, and comparing the gene expression profile to a reference gene expression profile to identify the subject as a responder; and c) continuing the administration if the subject is identified as a responder, or modifying treatment of the subject if the subject is not identified as a responder.
98. The method of claim 97, wherein the condition is selected from the group consisting of acute respiratory distress syndrome (ARDS), severe pneumonia, and severe acute respiratory syndrome.
99. The method of claim 97 or 98, wherein the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
100. The method of any one of claims 97 to 99, wherein the subject identified as a responder presents up-regulation of CXCL8 expression in the bronchoalveolar lavage fluid.
101. A method for treating a human subject presenting clinical manifestations associated with infection by a virus of the Coronaviridae family with a pharmaceutical composition of any one of claims 77 to 83, comprising the steps of:(i) determining the gene expression profile of the subject;(ii) identifying the subject as a predicted responder if the gene expression profile is indicative of subject being a responder; and(iii) administering the pharmaceutical composition to the subject only if the subject is identified as a predicted responder.
102. The method of claim 101, wherein the condition is selected from the group consisting of acute respiratory distress syndrome (ARDS), severe pneumonia, and severe acute respiratory syndrome.
103. The method of claim 101 or 102, wherein the virus of the Coronaviridae family is SARS-CoV-2 (COVID-19).
104. The method of any one of claims 101 to 103, wherein the subject identified as a predicted responder presents up- regulation of CXCL8 expression in the bronchoalveolar lavage fluid.
105. The method of any one of claims 1 to 64, wherein the at least one at least one agent having an anti-viral activity is acyclovir.
106. The method of claim 105, wherein the at least one phosphate donor is dexamethasone phosphate.
107. The pharmaceutical composition of any one of claims 77 to 96, wherein the at least one at least one agent having an anti-viral activity is acyclovir.
108. The pharmaceutical composition of claim 107, wherein the at least one phosphate donor is dexamethasone phosphate.
109. The method of any one of claims 97 to 104, wherein the at least one at least one agent having an anti-viral activity is acyclovir.
110. The method of claim 109, wherein the at least one phosphate donor is dexamethasone phosphate.
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