WO2024035526A1 - Combined use of nanobody, cyclodextrin and quercetin for protection from enveloped viruses - Google Patents
Combined use of nanobody, cyclodextrin and quercetin for protection from enveloped viruses Download PDFInfo
- Publication number
- WO2024035526A1 WO2024035526A1 PCT/US2023/027904 US2023027904W WO2024035526A1 WO 2024035526 A1 WO2024035526 A1 WO 2024035526A1 US 2023027904 W US2023027904 W US 2023027904W WO 2024035526 A1 WO2024035526 A1 WO 2024035526A1
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- WIPO (PCT)
- Prior art keywords
- composition
- zinc
- viral
- nanobody
- quercetin
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/724—Cyclodextrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Definitions
- Embodiments of the invention generally fall into the category of suppression or prevention of enveloped viral infection.
- a formulation of engineered nanobodies combined with Hydroxypropyl-13-Cyclodextrin and the flavonoid quercetin administered in a nasal/pulmonary route to treat infection with or exposure to an enveloped virus in a therapeutic or prophylactic fashion DISCUSSION OF ART
- the cell plasma membrane of skin and lung epithelia is the first line of defense and when breached, serves as the portal for viral entry into hosts.
- the entry of pathogenic viruses into the host cell could be prevented by using nanobodies such as against SARS-CoV-2 and or small molecules which have been demonstrated to be safe for human use.
- Cholesterol microdomains have been suggested in the cellular entry or infection of HIV, its assembly, and its release from infected cells. Studies further report that plasma membrane cholesterol is also required for a wide range of both bacterial and yeast infections. Furthermore, the literature illustrates that a high-cholesterol diet impairs pulmonary host defense against gram-negative bacteria and Mycobacterium tuberculosis. Taken together, these results support that CD-mediated depletion of plasma membrane cholesterol in epithelial cells (i.e., skin, nasal passage, and lung epithelia) in humans, using topological application, aerosol spray and nebulization, will mitigate both viral entry and secondary bacterial and yeast infections.
- epithelial cells i.e., skin, nasal passage, and lung epithelia
- CDs are a family of cyclic oligosaccharides constituted of a macrocyclic ring of glucose subunits joined by a-1,4 glycosidic bonds. CDs are used for improving the water-solubility and bioavailability of a wide range of drugs.
- the U.S. Food and Drug Administration (FDA) has approved the use of cyclodextrins since 2001. Cyclodextrins were first employed in the food industry in the 1970s, and since they have been used as food additives for carrying food-related lipophiles such as vitamins, aromas, and colorants. PCD has also been used as a cholesterol- reducing agent in food of animal origin such as milk and eggs.
- the first pharmaceutical patent related to CDs and pharmaceutical applicability as complexing agents is dated 1953.
- cyclodextrins are employed in pharmaceutical products primarily to increase water solubility of poorly soluble drug formulations and to enhance drug bioavailability.
- Pharmaceutical products containing CDs comprise nasal spray, oral solutions, solid dosage forms, ocular and dermal formulations, suppositories, and parenteral solutions
- pCD and its derivatives having higher water solubility such as HPpCD, MpCD, and SBE CD.
- Most of the PCD are also approved by the European Medical Agency for all human administration pathways.
- CDs are used in tablets, aqueous parenteral solutions, nasal sprays, and eye drop solutions.
- examples of the use of cyclodextrins in medicines on the European market are p-CD in cetirizine tablets and cisapride suppositories, y-CD in minoxidil solution, and examples of the use of P-cyclodextrin derivatives are SBE-P-CD in the intravenous antimycotic voriconazole, HP- -CD in the antifungal itraconazole, intravenous and oral solutions, and RM- -CD in a nasal spray for hormone replacement therapy by 17p-estradiol.
- alprostadil prostaglandin El, PGE1
- PGE1 prostaglandin El, PGE1
- Cyclodextrins are currently not included in the European Commission Guideline on excipients in the label and package leaflet of medicinal products for human use.
- engineered nanobodies against different target antigens such as the spike protein of the SARS-CoV-2 virus and or to the ACE2 receptor at the host cell surface, binds to the virus or the ACE2 receptor at the host cell plasma membrane, preventing entry of the SARS-CoV-2 virus.
- HPPCD Hydroxypropyl-Beta-Cyclodextrin
- GRAS Generally Recognized As Safe
- FDA U.S. Food and Drug Administration
- a nanobody engineered against a virus or host cell membrane viral receptor is delivered via aerosol spray and/or nebulization.
- the nanobody is combined with either a uniform and/or a wide range of particle sizes of Hydroxypropyl-Beta- Cyclodextrin (HPpCD) in an aqueous phosphate-buffered saline solution at pH 5 to pH 7.5.
- HPpCD Hydroxypropyl-Beta- Cyclodextrin
- the solution further contains 0.01% Benzylkonium chloride as a preservative.
- the solution may be prophylactically administered to protect the airways, including lungs of human subjects, from all enveloped virus infections including infections from SARS-CoV-2 and its variants.
- 3CD) containing solution is administered via the pulmonary route for the prevention of the entry of SARS-CoV-2 or other enveloped viruses into lung epithelial cells.
- the flavonoid quercetin a naturally occurring plant-based over the counter zinc ionophore that is “Generally Recognized As Safe” (GRAS) by the U.S. Food and Drug Administration (FDA)
- GRAS Generally Recognized As Safe
- FDA U.S. Food and Drug Administration
- phosphate buffered solutions at a concentration of 1-20 micrograms/ml to enable the cellular entry of zinc to protect host cells against viruses by inhibiting RNA binding, RNA synthesis, viral polyprotein cleavage, viral replication, and viral protease enzyme inactivation, among others.
- any of the described embodiments is administered to a patient for the prevention of both viral entry and replication.
- the engineered nanobody against the virus or the virus receptor at the host cell membrane combined with Hydroxypropyl-Beta-Cyclodextrin (HPpCD) and quercetin in a aqueous phosphate buffered saline solution at pH 5 to pH 7.5 containing 0.01% Benzylkonium chloride as preservative is administered via aerosol spray or nebulization
- the present invention is administered dermally either as a treatment or as a means of sanitization.
- the invention provides the use of a formulation containing cyclodextrine, quercetin and zinc, at appropriate concentrations to mitigate infections by enveloped viruses like SARS-CoV-2, influenza and HIV/AIDS. While the different forms of cyclodextrin prevent the entry of coated virus into host cells by extracting and sequestering cholesterol molecules at the virus coat and at the host cell plasma membrane, the natural plant-based ionophore quercetin in the formulation, enables cellular entry of zinc, inhibiting viral replication by altering polymerase activity in the host cell.
- cyclodextrin as a drug in phosphate buffered saline solutions, will allow the extraction of cholesterol molecules from enveloped virus membranes and the host cell membrane, altering their respective lipid and protein composition and distribution, thus preventing virus entry into host cells.
- quercetin a naturally occurring plant-based over the counter zinc ionophore, enables the cellular entry of zinc to protect host cells against the virus by inhibiting RNA binding, RNA synthesis, viral polyprotein cleavage, viral replication, and viral protease enzyme inactivation, among others.
- the invention provides the use of a formulation containing engineered nanobodies against different target antigens of enveloped viruses and host cell membrane, in combination with Hydroxypropyl-Beta-Cyclodextrin (HPpCD) and the flavonoid quercetin, at appropriate concentrations to mitigate infections by enveloped viruses like SARS-CoV-2 and influenza, when administered via the nasal/pulmonary route.
- HPpCD Hydroxypropyl-Beta-Cyclodextrin
- flavonoid quercetin flavonoid quercetin
- Nanobodies are a subclass of antibodies composed of a single polypeptide chain with versatile molecular binding scaffolds found in the camel species, as opposed to the large y-shaped conventional antibodies found in other mammalian species including humans.
- nanobodies may be engineered against different target antigens.
- a nanobody using conventional techniques, may be engineered against the spike protein of the SARS-CoV-2 virus and/or to the ACE2 receptor.
- the nanobody binds to the virus surface or the ACE2 receptor of the host cell preventing viral entry, the HPpCD in the formulation serves to prevent the entry of the enveloped virus into host cells by extracting and sequestering cholesterol molecules at the virus envelop and at the host cell plasma membrane.
- variable domains of the camelidaie variable domain (VHH) nanobodies are humanized to target and bind to one or more domains of one or more target viruses.
- protection from viral infection may last from 6-8 months.
- a viral spike protein is targeted. Spike proteins are readily identifiable from known motifs and are available through databases such as those run by the U.S. National Institutes of Health and the American Chemical Society. Nanobodies targeted to multiple regions in the spike protein bind and prevent entry of the virus into the host cell, thus providing protection from multiple viral variants.
- Benzalkonium chloride widely used as a preservative in nasal sprays and nebulization has been reported to cause sinonasal mucosal injury, nasal squamous metaplasia, ciliary dysmotility, genotoxicity, and other adverse effects. Data also suggests the toxic effects of phenylcarbinol, another commonly used preservative. Despite this evidence, these preservatives continue to be used at higher concentrations even in over-the-counter preparations. Acidification (pH 2.5) of nasal, inhalable, and topical ophthalmic preparations have been demonstrated to maintain sterility without the need for preservatives.
- soluble [ CD derivatives such as 2-hydroxypropyl-pCD (HP0CD) and sulfobutylether 0CD sodium salt (SBEpCD), are preferred for use in aqueous pharmaceutical formulations
- Inorganic acids such as phosphoric and citric acid induce CD solubilization.
- Zinc is an essential trace element supporting growth, development, and immune health. Zinc is also known to protect against viruses by inhibiting RNA binding, RNA synthesis, viral polyprotein cleavage, viral replication, and viral protease enzyme inactivation. Zinc however needs to enter the host cell to protect against the virus. Quercetin, a naturally occurring plant-based over the counter zinc ionophore, enables the cellular entry of zinc to protect host cells against the virus. Furthermore, quercetin has shown therapeutic effects against influenza virus.
- ACE2 epithelial cell angiotensin converting enzyme-2
- the present invention utilizes FDA approved concentrations of CDs (1-5%) and quercetin (8-24 micrograms mb’ 1 ) in buffered solutions to retain both high solubility and sterility.
- Mode of administration may be through aerosol spray and/or nebulization, and topical application on body surface using a water-based solution adsorbed to paper, cellulose or fabric.
- the topical application on body surfaces will including the face and neck, to mitigate envelope virus (such as SARS-CoV- 2, influenza, and HIV), bacteria and fungus infections.
- the formulation is adapted for use and introduction to a subject by dispersal, utilizing any known method of measured nasal sprays or inhalers
- the formulation is introduced in form of an aqueous phosphate buffered saline pH 5-7.5 solution, containing 0.01% Benzylkonium chloride as preservative and different concentrations of the active ingredients: 1- 5% cyclodextrin; and the flavonoid quercetin, a naturally occurring zinc ionophore at a concentration of 8-24 pg ml' 1 .
- pH 2.5 citrate buffered aqueous may also be used, where the low pH serves as a preservative and a solvent for cyclodextrin.
- cyclodextrin alone is followed by quercetin and zinc administration (alone or combined), in a water based soluble formulation that prevents both viral entry and replication in host cells, such as the nasal epithelial cells and that of the lung epithelia.
- the formulation may be administered as an aerosol spray or nebulization.
- a particular embodiment contemplates an aqueous phosphate buffered saline pH 7.5 solution containing 0.01% Benzylkonium chloride as preservative, will be used to protect the airways including lungs from all coat virus infections.
- the pH may be citrate buffered at pH 2.5.
- the above formulations may be topically applied; for example, via oils, creams, emulsions and the like the formulations of which are known to those skilled in the art.
- Additional embodiments include application of the above solutions to both sides of cellulose masks. In such medicated masks, any airborne droplets containing the virus will be neutralized on contact with the medicated mask.
- the effective dose and method of administration of a particular embodiment of the instant invention may vary based on the individual patient and stage of any present diseases (e.g., influenza, covid, HIV, other co-morbidities), as well as other factors known to those of skill in the art.
- Therapeutic efficacy and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population).
- the dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
- Pharmaceutical compositions that exhibit large therapeutic indices are preferred.
- the data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use.
- the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
- the dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
- the exact dosage is chosen by an individual physician in view of a patient to be treated. Dosage and administration are adjusted to provide sufficient levels of embodiments of the instant invention to maintain the desired effect (e.g., elimination or reduction of enveloped virus particles or activity in a host). Additional factors that may be taken into account include the severity of any disease state, age, weight, and gender of the patient; diet, time and frequency of the administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.
- Short acting pharmaceutical compositions are administered daily whereas long acting pharmaceutical compositions are administered every 2, 3 to 4 days, every week, or once every two weeks or more.
- the pharmaceutical compositions of the instant invention may be administered once, twice, three, four, five, six, seven, eight, nine, ten or more times per day.
- Normal dosage amounts for active ingredients may vary from approximately 1 to 100,000 micrograms, up to a total dose of about 10 grams, depending upon the route of administration. Desirable dosages include 250 pg, 500 pg, 1 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g, 1.9 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, and 10 g.
- the dosage of the active ingredients described herein are those that provides sufficient quantity to attain a desirable effect, including those above-described effects. Accordingly, the dose of the active ingredients preferably produces a tissue or blood concentration of both about 1 to 800 pM. Preferable doses produces a tissue or blood concentration of greater than about 10 pM to about 500 pM.
- Preferable doses are, for example, the amount of active ingredients required to achieve a tissue or blood concentration or both of 10 pM, 15 pM, 20 pM, 25 pM, 30 pM, 35 pM, 40 pM, 45 pM, 50 pM, 55 pM, 60 pM, 65 pM, 70 pM, 75 pM, 80 pM, 85 pM, 90 pM, 95 pM, 100 pM, 110 pM, 120 pM, 130 pM, 140 pM, 150 pM, 160 pM, 170 pM, 180 pM, 190 pM, 200 pM, 220 pM, 240 pM, 250 pM, 260 pM, 280 pM, 300 pM, 320 pM, 340 pM, 360 pM, 380
- the pharmacologically active compounds of this invention can be processed in accordance with conventional methods of galenic pharmacy to produce medicinal agents for administration to patients (e g., mammals including humans).
- sequence explicitly contemplates DNA, cDNA, RNA and resulting peptide chains encoded thereby in both sense and antisense directions. To know one is to know the others via the standard rules of complementarity and codon encoding as exemplified in standardized DNA, RNA, and amino acid codon tables.
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Abstract
Disclosed are engineered nanobodies against different target antigens such as the spike protein of the SARS-CoV-2 virus and or to the ACE2 receptor at the host cell surface, binds to the virus or the ACE2 receptor at the host cell plasma membrane, preventing entry of the SARS-CoV-2 virus. The nanobodies are included in a composition comprising: a cyclodextrin; a zinc ionophore; a zinc-containing compound; and, benzalkonium.
Description
COMBINED USE OF NANOBODY, C YCLODEXTRIN AND QUERCETIN FOR
PROTECTION FROM ENVELOPED VIRUSES
APPLICATION CROSS-REFERENCE
[0001J The instant application is a continuation-in-part of U.S. Patent Application Serial No. 17/890,754, filed on August 18, 2022, which claims the benefit of U.S. Provisional Patent Application Serial No. 63/235,772, filed on August 22, 2021, U.S. Provisional Patent Application Serial No. 63/294,067, filed on December 27, 2021, and U.S. Provisional Patent Application Serial No. 63/308,782, filed on February 10, 2022, and which is also a continuation-in-part of U.S. Patent Application Serial No. 17/472,604, filed on September 11, 2021, which is a continuation-in-part of U.S. Patent Application Serial No. 17/207,250, filed on March 19, 2021, and which claims the benefit of U.S. Provisional Patent Application Serial No. 63/029,458, filed May 23, 2020, U.S. Provisional Patent Application Serial No. 63/019,312, filed May 2, 2020, and U.S. Provisional Patent Application Serial No. 63/235,772, filed on August 22, 2021. The instant application further claims priority to U.S. Provisional Patent Application Serial No. 63/396,040, filed August 8, 2022. The entirety of all the above referenced are hereby incorporated by reference.
BACKGROUND
TECHNICAL FIELD
[0002] Embodiments of the invention generally fall into the category of suppression or prevention of enveloped viral infection. In some embodiments there is provided a formulation of engineered nanobodies combined with Hydroxypropyl-13-Cyclodextrin and the flavonoid quercetin administered in a nasal/pulmonary route to treat infection with or exposure to an enveloped virus in a therapeutic or prophylactic fashion.
DISCUSSION OF ART
[0003] Viruses enter hosts via the epithelium. The cell plasma membrane of skin and lung epithelia is the first line of defense and when breached, serves as the portal for viral entry into hosts. The entry of pathogenic viruses into the host cell could be prevented by using nanobodies such as against SARS-CoV-2 and or small molecules which have been demonstrated to be safe for human use.
[0004] Studies in the past two decades report the various cell membrane binding and entry mechanisms utilized by viruses to infect. Irrespective of the different mechanisms involved in viral entry into host cells, the initiating critical process is binding of the virus to the cell plasma membrane. Without binding of virus to the cell plasma membrane, there would be no viral entry into the host.
[0005] A multitude of studies have established that binding of viruses to the cell plasma membrane is subjected to the presence of docking sites or receptors and their regulation by membrane lipid composition and distribution such as the establishment of domains called rafts. A recent study involving cellular membrane biogenesis, demonstrates that changes in composition of membrane cholesterol, impacts both the chemistry and distribution of plasma membrane proteins and lipids, impacting cell function. That study reported that cells exposed to an increasing concentration of methyl beta cyclodextrin (M-PCD) to deplete cholesterol from the cell plasma membrane demonstrate loss in the uptake of phosphotidyl serine by the cell plasma membrane, while the uptake of phosphatidylethanolamine remain unchanged. Similarly, the loss of cholesterol from the cell plasma membrane resulted in the depletion of membrane fusion proteins such as syntaxin and SNAP25 from the plasma membrane suggesting altered membrane fusogenicity. Therefore changes to the chemistry of the epithelial cell plasma membrane via depletion of sterols/cholesterol by cyclodextrins (CDs), could dictate both the binding of a virus at a cell plasma membrane, and influence both the efficacy and potency of its entry into the host cell
[0006] Further studies demonstrated that depletion of plasma membrane cholesterol in host cells using M-pCD, significantly reduces entry of the pseudorabies and vaccinia virus into cells. Additional studies demonstrated that HIV infectivity is critically dependent on cholesterol. Cholesterol microdomains, called lipid ‘rafts’, have been suggested in the cellular entry or infection of HIV, its assembly, and its release from infected cells. Studies further report that plasma membrane cholesterol is also required for a wide range of both bacterial and yeast infections. Furthermore, the literature illustrates that a high-cholesterol diet impairs pulmonary host defense against gram-negative bacteria and Mycobacterium tuberculosis. Taken together, these results support that CD-mediated depletion of plasma membrane cholesterol in epithelial cells (i.e., skin, nasal passage, and lung epithelia) in humans, using topological application, aerosol spray and nebulization, will mitigate both viral entry and secondary bacterial and yeast infections.
[0007] CDs are a family of cyclic oligosaccharides constituted of a macrocyclic ring of glucose subunits joined by a-1,4 glycosidic bonds. CDs are used for improving the water-solubility and bioavailability of a wide range of drugs. The U.S. Food and Drug Administration (FDA) has approved the use of cyclodextrins since 2001. Cyclodextrins were first employed in the food industry in the 1970s, and since they have been used as food additives for carrying food-related lipophiles such as vitamins, aromas, and colorants. PCD has also been used as a cholesterol- reducing agent in food of animal origin such as milk and eggs.
[0008] The first pharmaceutical patent related to CDs and pharmaceutical applicability as complexing agents is dated 1953. Currently, cyclodextrins are employed in pharmaceutical products primarily to increase water solubility of poorly soluble drug formulations and to enhance drug bioavailability. Pharmaceutical products containing CDs comprise nasal spray, oral solutions, solid dosage forms, ocular and dermal formulations, suppositories, and parenteral solutions Currently, more than 40 pharmaceutical products containing CDs are available in the market worldwide, and many of them utilize pCD and its derivatives having higher water solubility such as HPpCD, MpCD, and SBE CD. Most of the PCD are also approved by the European Medical Agency for all human administration pathways. CDs are used in tablets, aqueous parenteral solutions, nasal sprays, and eye drop solutions. Examples of the use of cyclodextrins in medicines on the European market are p-CD in cetirizine tablets and cisapride suppositories, y-CD in
minoxidil solution, and examples of the use of P-cyclodextrin derivatives are SBE-P-CD in the intravenous antimycotic voriconazole, HP- -CD in the antifungal itraconazole, intravenous and oral solutions, and RM- -CD in a nasal spray for hormone replacement therapy by 17p-estradiol. In Germany and Japan there are infusion products on the market, containing alprostadil (prostaglandin El, PGE1) with a-CD. Cyclodextrins are currently not included in the European Commission Guideline on excipients in the label and package leaflet of medicinal products for human use.
[0009] Despite all the advancements above cataloged, there remains a need to treat infection with or exposure to an enveloped virus in a therapeutic or prophylactic fashion. In particular, there remains a need to stabilize or reduce the amount of virus present in a human or other animal.
BRIEF SUMMARY OF THE INVENTION
[0010] In an embodiment of the invention, engineered nanobodies against different target antigens such as the spike protein of the SARS-CoV-2 virus and or to the ACE2 receptor at the host cell surface, binds to the virus or the ACE2 receptor at the host cell plasma membrane, preventing entry of the SARS-CoV-2 virus.
[0011] In another embodiment of the invention, Hydroxypropyl-Beta-Cyclodextrin (HPPCD), which has been affirmed as “Generally Recognized As Safe” (GRAS) by the U.S. Food and Drug Administration (FDA), is administered in different particle sizes in phosphate buffered solutions at concentration ranges of between one (1) and ten (10) per cent (%). The administration enables the extraction of cholesterol molecules to various extents from enveloped virus membranes, including that of SARS-CoV-2 and its variants, and from host cell membranes of human subjects thus altering their respective lipid and protein profiles and distribution and thus preventing enveloped virus entry into host cells of human subjects
[0012] In another embodiment of the invention, a nanobody engineered against a virus or host cell membrane viral receptor is delivered via aerosol spray and/or nebulization. The nanobody is combined with either a uniform and/or a wide range of particle sizes of Hydroxypropyl-Beta- Cyclodextrin (HPpCD) in an aqueous phosphate-buffered saline solution at pH 5 to pH 7.5. The solution further contains 0.01% Benzylkonium chloride as a preservative. The solution may be prophylactically administered to protect the airways, including lungs of human subjects, from all enveloped virus infections including infections from SARS-CoV-2 and its variants.
[0013] In another embodiment the nanobody and Hydroxypropyl-Beta-Cyclodextrin (HP|3CD) containing solution is administered via the pulmonary route for the prevention of the entry of SARS-CoV-2 or other enveloped viruses into lung epithelial cells.
[0014] In another embodiment, the flavonoid quercetin, a naturally occurring plant-based over the counter zinc ionophore that is “Generally Recognized As Safe” (GRAS) by the U.S. Food and Drug Administration (FDA), is administered in different particle sizes in phosphate buffered solutions at a concentration of 1-20 micrograms/ml to enable the cellular entry of zinc to protect host cells against viruses by inhibiting RNA binding, RNA synthesis, viral polyprotein cleavage, viral replication, and viral protease enzyme inactivation, among others.
[0015] In another embodiment, any of the described embodiments is administered to a patient for the prevention of both viral entry and replication.
[0016] In another embodiment, the engineered nanobody against the virus or the virus receptor at the host cell membrane, combined with Hydroxypropyl-Beta-Cyclodextrin (HPpCD) and quercetin in a aqueous phosphate buffered saline solution at pH 5 to pH 7.5 containing 0.01% Benzylkonium chloride as preservative is administered via aerosol spray or nebulization
[0017] In another embodiment, the present invention is administered dermally either as a treatment or as a means of sanitization.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The invention provides the use of a formulation containing cyclodextrine, quercetin and zinc, at appropriate concentrations to mitigate infections by enveloped viruses like SARS-CoV-2, influenza and HIV/AIDS. While the different forms of cyclodextrin prevent the entry of coated virus into host cells by extracting and sequestering cholesterol molecules at the virus coat and at the host cell plasma membrane, the natural plant-based ionophore quercetin in the formulation, enables cellular entry of zinc, inhibiting viral replication by altering polymerase activity in the host cell. Without subscribing to or limiting to a single theory of operation, it is believed that use of cyclodextrin as a drug in phosphate buffered saline solutions, will allow the extraction of cholesterol molecules from enveloped virus membranes and the host cell membrane, altering their respective lipid and protein composition and distribution, thus preventing virus entry into host cells. The additional use of quercetin, a naturally occurring plant-based over the counter zinc ionophore, enables the cellular entry of zinc to protect host cells against the virus by inhibiting RNA binding, RNA synthesis, viral polyprotein cleavage, viral replication, and viral protease enzyme inactivation, among others.
[0019] The invention provides the use of a formulation containing engineered nanobodies against different target antigens of enveloped viruses and host cell membrane, in combination with Hydroxypropyl-Beta-Cyclodextrin (HPpCD) and the flavonoid quercetin, at appropriate concentrations to mitigate infections by enveloped viruses like SARS-CoV-2 and influenza, when administered via the nasal/pulmonary route.
[0020] Nanobodies are a subclass of antibodies composed of a single polypeptide chain with versatile molecular binding scaffolds found in the camel species, as opposed to the large y-shaped conventional antibodies found in other mammalian species including humans.
[0021] Without limitation to a single individual theory of operation, nanobodies may be engineered against different target antigens. For example, a nanobody, using conventional techniques, may be engineered against the spike protein of the SARS-CoV-2 virus and/or to the ACE2 receptor. The nanobody binds to the virus surface or the ACE2 receptor of the host cell preventing viral entry, the HPpCD in the formulation serves to prevent the entry of the enveloped
virus into host cells by extracting and sequestering cholesterol molecules at the virus envelop and at the host cell plasma membrane.
[0022] However, if some viruses have entered the host cell, the natural plant-based ionophore quercetin in the formulation, enables cellular entry of zinc, inhibiting viral replication by altering polymerase activity in the host cell. Hence, engineered nanobodies in combination with HPpCD and quercetin, serve both as prophylactic treatment and therapeutic drug.
[0023] Without subscribing to or limiting to a particular theory, it is thought such a mixture will provide long term protection from targeted viruses and their variants. In some embodiments variable domains of the camelidaie variable domain (VHH) nanobodies are humanized to target and bind to one or more domains of one or more target viruses. In some embodiments protection from viral infection may last from 6-8 months. In some embodiments a viral spike protein is targeted. Spike proteins are readily identifiable from known motifs and are available through databases such as those run by the U.S. National Institutes of Health and the American Chemical Society. Nanobodies targeted to multiple regions in the spike protein bind and prevent entry of the virus into the host cell, thus providing protection from multiple viral variants.
[0024] Benzalkonium chloride widely used as a preservative in nasal sprays and nebulization, has been reported to cause sinonasal mucosal injury, nasal squamous metaplasia, ciliary dysmotility, genotoxicity, and other adverse effects. Data also suggests the toxic effects of phenylcarbinol, another commonly used preservative. Despite this evidence, these preservatives continue to be used at higher concentrations even in over-the-counter preparations. Acidification (pH 2.5) of nasal, inhalable, and topical ophthalmic preparations have been demonstrated to maintain sterility without the need for preservatives. This approach of lowering the pH of the formulated CD and quercetin solutions to be used in wipes and aerosol sprays, precludes the use of harmful preservatives at higher concentrations, without compromising sterility of the formulation. Therefore, either low concentration of benzalkonium chloride and or low pH formulations are prepared for use
[0025] Natural CDs such as aCD, PCD, and yCD are hydrophilic in aqueous solutions, however they tend to self-assemble and form complexes. To overcome this limitation, soluble [ CD derivatives such as 2-hydroxypropyl-pCD (HP0CD) and sulfobutylether 0CD sodium salt (SBEpCD), are preferred for use in aqueous pharmaceutical formulations Inorganic acids such as phosphoric and citric acid induce CD solubilization.
[0026] Zinc is an essential trace element supporting growth, development, and immune health. Zinc is also known to protect against viruses by inhibiting RNA binding, RNA synthesis, viral polyprotein cleavage, viral replication, and viral protease enzyme inactivation. Zinc however needs to enter the host cell to protect against the virus. Quercetin, a naturally occurring plant-based over the counter zinc ionophore, enables the cellular entry of zinc to protect host cells against the virus. Furthermore, quercetin has shown therapeutic effects against influenza virus. Additionally, in silica modelling of the interactions between the SARS-CoV-2 viral spike protein and the epithelial cell angiotensin converting enzyme-2 (ACE2) protein, has identified quercetin from a database of 8,000 small molecule candidates of known drugs, metabolites, and natural products, as one of the top 5 most potent compounds for binding to the interface site, and disrupt initiation of viral infection.
[0027] The present invention utilizes FDA approved concentrations of CDs (1-5%) and quercetin (8-24 micrograms mb’1) in buffered solutions to retain both high solubility and sterility. Mode of administration may be through aerosol spray and/or nebulization, and topical application on body surface using a water-based solution adsorbed to paper, cellulose or fabric. The topical application on body surfaces will including the face and neck, to mitigate envelope virus (such as SARS-CoV- 2, influenza, and HIV), bacteria and fungus infections.
[0028] In a particular embodiment, the formulation is adapted for use and introduction to a subject by dispersal, utilizing any known method of measured nasal sprays or inhalers The formulation is introduced in form of an aqueous phosphate buffered saline pH 5-7.5 solution, containing 0.01% Benzylkonium chloride as preservative and different concentrations of the active ingredients: 1- 5% cyclodextrin; and the flavonoid quercetin, a naturally occurring zinc ionophore at a concentration of 8-24 pg ml'1. Depending on requirement, pH 2.5 citrate buffered aqueous may also be used, where the low pH serves as a preservative and a solvent for cyclodextrin.
[0029] In another embodiment, administration of cyclodextrin alone is followed by quercetin and zinc administration (alone or combined), in a water based soluble formulation that prevents both viral entry and replication in host cells, such as the nasal epithelial cells and that of the lung epithelia. The formulation may be administered as an aerosol spray or nebulization. A particular embodiment contemplates an aqueous phosphate buffered saline pH 7.5 solution containing 0.01% Benzylkonium chloride as preservative, will be used to protect the airways including lungs from all coat virus infections. In still another embodiment the pH may be citrate buffered at pH 2.5.
[0030] In additional embodiments the above formulations may be topically applied; for example, via oils, creams, emulsions and the like the formulations of which are known to those skilled in the art. Additional embodiments include application of the above solutions to both sides of cellulose masks. In such medicated masks, any airborne droplets containing the virus will be neutralized on contact with the medicated mask.
[0031] Suitable alterations to the above are readily apparent to those of skill in the art and naturally are encompassed and expressly contemplated. For example, normal manufacturing tolerances may induce variances from the above presented formulations without departing from the broader scope of this invention.
[0032] The effective dose and method of administration of a particular embodiment of the instant invention may vary based on the individual patient and stage of any present diseases (e.g., influenza, covid, HIV, other co-morbidities), as well as other factors known to those of skill in the art. Therapeutic efficacy and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies is used in formulating a range of dosage for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage
varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
[0033] The exact dosage is chosen by an individual physician in view of a patient to be treated. Dosage and administration are adjusted to provide sufficient levels of embodiments of the instant invention to maintain the desired effect (e.g., elimination or reduction of enveloped virus particles or activity in a host). Additional factors that may be taken into account include the severity of any disease state, age, weight, and gender of the patient; diet, time and frequency of the administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.
[0034] Short acting pharmaceutical compositions are administered daily whereas long acting pharmaceutical compositions are administered every 2, 3 to 4 days, every week, or once every two weeks or more. Depending on half-life and clearance rate of the particular formulation, the pharmaceutical compositions of the instant invention may be administered once, twice, three, four, five, six, seven, eight, nine, ten or more times per day.
[0035] Normal dosage amounts for active ingredients may vary from approximately 1 to 100,000 micrograms, up to a total dose of about 10 grams, depending upon the route of administration. Desirable dosages include 250 pg, 500 pg, 1 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g, 1.9 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, and 10 g.
[0036] More specifically, the dosage of the active ingredients described herein are those that provides sufficient quantity to attain a desirable effect, including those above-described effects. Accordingly, the dose of the active ingredients preferably produces a tissue or blood concentration of both about 1 to 800 pM. Preferable doses produces a tissue or blood concentration of greater than about 10 pM to about 500 pM. Preferable doses are, for example, the amount of active ingredients required to achieve a tissue or blood concentration or both of 10 pM, 15 pM, 20 pM, 25 pM, 30 pM, 35 pM, 40 pM, 45 pM, 50 pM, 55 pM, 60 pM, 65 pM, 70 pM, 75 pM, 80 pM, 85 pM, 90 pM, 95 pM, 100 pM, 110 pM, 120 pM, 130 pM, 140 pM, 150 pM, 160 pM, 170 pM, 180 pM, 190 pM, 200 pM, 220 pM, 240 pM, 250 pM, 260 pM, 280 pM, 300 pM, 320 pM, 340
pM, 360 pM, 380 |iM, 400 pM, 420 pM, 440 pM, 460 pM, 480 pM, and 500 pM. Although doses that produce a tissue concentration greater than 800 pM are not necessarily preferred, they are envisioned and can be used with some embodiments of the present invention. A constant infusion of embodiments of the invention can be provided so as to maintain a stable concentration of the therapeutic agents.
[0037] Finally, the written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.
[0038] The pharmacologically active compounds of this invention can be processed in accordance with conventional methods of galenic pharmacy to produce medicinal agents for administration to patients (e g., mammals including humans).
[0039] As used herein the term “sequence” explicitly contemplates DNA, cDNA, RNA and resulting peptide chains encoded thereby in both sense and antisense directions. To know one is to know the others via the standard rules of complementarity and codon encoding as exemplified in standardized DNA, RNA, and amino acid codon tables.
[0040] As used herein, an element or step recited in the singular and proceeded with the word "a" or "an" should be understood as not excluding plural of said elements or steps, unless such exclusion is explicitly stated. Furthermore, references to "one embodiment" of the present invention are not intended to be interpreted as excluding the existence of additional embodiments that also incorporate the recited features Moreover, unless explicitly stated to the contrary, embodiments "comprising," "including," or "having" an element or a plurality of elements having a particular property may include additional such elements not having that property.
[0041] Since certain changes may be made in the above-described invention, without departing from the spirit and scope of the invention herein involved, it is intended that all of the subject matter of the above description shown in the accompanying drawings shall be interpreted merely as examples illustrating the inventive concept herein and shall not be construed as limiting the invention.
Claims
1. A composition comprising: a nanobody; a cyclodextrin; a zinc ionophore; a zinc-containing compound; and, benzalkonium.
2. The composition of claim 1 wherein the nanobody is engineered to attach to a viral protein.
3. The composition of claim 2 wherein the viral protein is a viral spike protein.
4. The composition of claim 3 wherein the viral spike protein is a coronavirus spike protein.
5. The composition of claim 1 wherein the nanobody is engineered to attach to a host cell receptor.
6. The composition of claim 5 wherein the host cell receptor is ACE2.
7. The composition of claim 1 wherein the zinc ionophore is quercetin.
8. The composition of claim 7, wherein: the quercetin is at a concentration of 8 pg mL’1; and the zinc containing compound is zinc chloride at a concentration of 1 mg mL'1.
9. The composition of claim 1 wherein the composition is buffered between pH 2.5-7.5
10 The composition of claim 1 wherein the cyclodextrin is HPpCD at a concentration between 1-
11. The composition of claim 1 wherein the composition is atomized and administered to the airways of a subject.
12. A composition, comprising: a nanobody engineered to attach to a host cell membrane protein;
HPpCD at a concentration of 1-5%; quercetin at a concentration of 8 pg ml/1; zinc chloride at a concentration of 1 mg ml/1; and, benzalkonium at a concentration of 0.01%; wherein the solution is either citrate buffered at a pH of 2.5 or phosphate buffered at a pH of 7.5.
13. The composition of claim 11 wherein the composition is atomized and administered to the airways of a subject.
14. The composition of claim 13 wherein the administration occurs in two steps, wherein the nanobody and cyclodextrin is first administered and the quercetin and zinc is administered second.
15. The composition of claim 12 wherein the composition is suspended in an aqueous solution.
16. A method of treating a subject at risk of contracting a viral infection, caused by an enveloped virus, the method comprising the step of: administering to the subject a composition comprising a nanobody, a cyclodextrin, a zinc ionophore; a zinc-containing compound, and benzalkonium.
17. The method according to claim 16, wherein: the nanobody is engineered to attach to a viral protein.
18. The method according to claim 17, wherein: the viral protein is a viral spike protein.
The method according to claim 18, wherein: the viral spike protein is a coronavirus spike protein. The method according to claim 18, wherein: the zinc ionophore is quercetin.
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