Methods for treating infective diseases

Abstract

The present invention provides a method of treating an infectious disease. The method comprises the step of administering to a subject in need thereof an effective amount of (i) a polymer-flavonoid conjugate, (ii) a flavonoid oligomer, or (iii) a micelle having a shell formed from one or more polymer-flavonoid conjugates or one or more flavonoid oligomers, or a combination thereof and having an agent encapsulated within the shell. The methods of the present invention can effectively treat viral infections, such as, for example; severe acute respiratory syndrome coronavirus (SARS-CoV), enterovirus, HIV, hepatitis B virus, MERS-CoV, influenza virus, dengue fever virus, respiratory syncytial virus, hepatitis C virus, monkey pox virus, human papilloma virus, methicillin-resistant staphylococcus aureus, pseudomonas, tuberculosis, bacillus anthracis, tetanus, streptococcus pneumoniae, meningococcus, escherichia coli, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, bacillus subtilis, , Legionella genus, Neisseria gonorrhoeae, Neisseria meningitidis, and Salmonella genus.

Description

Technical Field

[0001] The present invention provides a method for treating infectious diseases (such as bacterial infections and viral infections). The method comprises the step of administering to a subject in need thereof an effective amount of the following substances: (i) a polymer-flavonoid conjugate, (ii) a flavonoid oligomer, or (iii) a micelle having a shell formed of one or more polymer-flavonoid conjugates or one or more flavonoid oligomers or a combination thereof and having an active agent encapsulated within the shell. Background Art

[0002] Infectious diseases

[0003] An infectious disease is a disorder caused by a pathogenic organism (such as a bacterium, a virus, a fungus or a parasite). An infectious disease is the invasion of body tissues by a pathogen, its multiplication, and the reaction of host tissues to the infecting agent and the toxins it produces.

[0004] Bacterial infections and viral infections constitute most infectious diseases. The host can utilize its own immune system to combat the infection. The mammalian host's response to infection is an innate response, which typically involves inflammation, followed by an adaptive response. The typical signs and symptoms of infection are signs of the host inflammatory response caused by these pathogens, such as fatigue, loss of appetite, weight loss, fever, night sweats, chills, pain, rash, cough or runny nose.

[0005] Bacterial infections

[0006] A bacterial infection is the multiplication of harmful bacterial strains on or within the body. A bacterial infection occurs when bacteria enter the body, increase in number and cause a reaction within the body. Bacteria can enter the body through openings in the skin, through the airways, the digestive system, and cause an infection. Bacteria can infect any area of the body. Pneumonia, meningitis and food poisoning are just a few of the diseases that can be caused by harmful bacteria. Bacteria have three basic shapes: rod-shaped (bacilli), spherical (cocci) or spiral-shaped (spirilla). Bacteria can also be classified as Gram-positive or Gram-negative. Gram-positive bacteria have thick cell walls, while Gram-negative bacteria do not. Gram staining, bacterial culture and antibiotic susceptibility testing, as well as other tests (such as genetic analysis) are used to identify bacterial strains and help determine an appropriate treatment regimen.

[0007] Bacteria cause disease by secreting or excreting toxins (such as in botulism), by producing toxins internally (released when the bacteria disintegrate (such as in typhoid)), or by inducing sensitivity to their antigenic properties (such as in tuberculosis).

[0008] Some serious bacterial diseases include cholera, diphtheria, bacterial meningitis, tetanus, Lyme disease, gonorrhea, syphilis, tuberculosis, anthrax, tetanus, leptospirosis, pneumonia, botulism, Pseudomonas infections, MRSA infections, E. coli infections, and bubonic plague.

[0009] Viral infections

[0010] Viral diseases (or viral infections) occur when an organism is invaded by a pathogenic virus and the infectious viral particles (virions) attach to and enter susceptible cells. These viruses include, but are not limited to, adenovirus, Coxsackievirus, cytomegalovirus, Epstein - Barr virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex virus type 1, herpes simplex virus type 2, HIV, human coronavirus 229E (HCoV - 229E), human coronavirus HKU1 (HCoV - HKU1), human coronavirus NL63 (HCoV - NL63), human coronavirus OC43 (HCoV - OC43), human herpesvirus, human papillomavirus, influenza virus, measles virus, Middle East respiratory syndrome - related coronavirus (MERS - CoV), mumps virus, parainfluenza virus, poliovirus, rabies virus, respiratory syncytial virus, rubella virus, severe acute respiratory syndrome coronavirus (SARS - CoV), severe acute respiratory syndrome coronavirus 2 (SARS - CoV - 2), varicella - zoster virus.

[0011] Viral infection is the multiplication of harmful viruses within a host. Viruses cannot replicate without the help of a host. Viruses infect a host by introducing their genetic material into cells and using the cell's internal mechanisms to produce more viral particles.

[0012] Antibiotic therapy

[0013] Bacterial infections have been treated with antibiotics. However, the pipeline of new drugs is drying up. For example, nearly 40 years have passed between the introduction of the two most recent molecular classes of antibiotics: fluoroquinolones (such as Cipro) in 1962 to oxazolidinones (such as Zyvox) in 2000. Large pharmaceutical companies have limited interest in investing resources in the antibiotic market because these short - term drugs are less profitable than drugs for treating chronic and lifestyle - related diseases (such as hypertension or high cholesterol). Research and development of antibiotics is equally expensive, risky, and time - consuming. Given that resistance to antibiotics develops over time, ultimately reducing their effectiveness, the return on this investment may be unpredictable.

[0014] Flavonoids

[0015] Flavonoids have a general structural formula with a 15-carbon skeleton, which consists of two benzene rings (A and B) and a heterocyclic ring (C, which contains an embedded oxygen).

[0016]

[0017] This carbon structure can be abbreviated as C6-C3-C6. According to IUPAC nomenclature, flavonoids can be classified as:

[0018] Flavonoids or bioflavonoids

[0019] Isoflavonoids, which are derived from the 3-phenylchromen-4-one (3-phenyl-1,4-benzopyranone) structure; Neoflavonoids, which are derived from the 4-phenylcoumarin (4-phenyl-1,2-benzopyranone) structure Description of the Drawings

[0020] Figure 1 Shows an embodiment of a MINC (Multi-channel Immunomodulatory Nanocomplex Combination Therapy)-drug, which is a micelle having a polymer-flavonoid conjugate (e.g., PEG-EGCG conjugate) in the shell and an encapsulated drug.

[0021] Figure 2 Shows another embodiment of a MINC-agent, which is a micelle comprising a polymer-flavonoid conjugate (e.g., PEG-EGCG conjugate) in the outer shell, a flavonoid oligomer (e.g., oligomeric EGCG (OEGCG)) in the inner shell, and an encapsulated drug.

[0022] Figure 3 Shows that OEGCG reduces the colony formation of methicillin-resistant Staphylococcus aureus (MRSA).

[0023] Figure 4 Shows that OEGCG reduces the colony formation of Pseudomonas aeruginosa.

[0024] Figure 5 Shows that OEGCG and PEG-EGCG inhibit SARS-CoV-2 infection.

[0025] Figure 6 Shows that OEGCG inhibits EV D68 infection.

[0026] Figure 7 Shows that different polymer-flavonoid conjugates and different flavonoid oligomers have all successfully generated MINC-anti-HER2 micelles with a particle size of approximately 100 nm.

[0027] Figure 8It is demonstrated that different polymers in the polymer-flavonoid conjugates successfully generate MINC-BSA.

[0028] Figure 9 It is shown that MINC-IFN-α is successfully formulated.

[0029] Figure 10 It is shown that MINC-IFN-γ is successfully formulated.

[0030] Figure 11 It is shown that MINC-IL-12 is successfully formulated.

[0031] Figure 12 It is shown that MINC-IL-2 is successfully formulated.

[0032] Figure 13 It is shown that MINC-IL-6 is successfully formulated.

[0033] Figure 14 It is shown that MINC-IL-15 is successfully formulated.

[0034] Figure 15 It is shown that MINC-IL-21 is successfully formulated. Detailed Description

[0035] Definitions

[0036] The term "epigallocatechin gallate" refers to an ester of epigallocatechin and gallic acid and can be used interchangeably with "epigallocatechin-3-gallate" or "EGCG".

[0037] The term "oligomeric EGCG" (OEGCG) refers to 3 to 20 covalently linked EGCG monomers. OEGCG preferably contains 4 to 12 EGCG monomers.

[0038] The term "polyethylene glycol-epigallocatechin gallate conjugate" or "PEG-EGCG" refers to polyethylene glycol (PEG) conjugated to one or two EGCG molecules. The term "PEG-EGCG" refers to both PEG-mEGCG conjugates (monomeric EGCG) and PEG-dEGCG (dimeric EGCG) conjugates.

[0039] The term "nucleoside analog" refers to a nucleoside in which the natural base (A, T, G, C, or U) or the natural ribose / deoxyribose is modified. Nucleoside analogs can be used to prevent virus replication in infected cells.

[0040] The term "nucleotide analogue" refers to a nucleotide in which a natural base (A, T, G, C or U), natural ribose / deoxyribose, or phosphate is modified. Nucleotide analogues can be used to prevent virus replication in infected cells. For example, remdesivir is a nucleotide analogue.

[0041] The present invention provides a method for treating an infectious disease. The method comprises the step of administering to a subject in need thereof an effective amount of (i) a polymer-flavonoid conjugate, (ii) a flavonoid oligomer, or (iii) a micelle having a shell formed of one or more polymer-flavonoid conjugates or one or more flavonoid oligomers or a combination thereof and having an agent encapsulated within the shell.

[0042] Flavonoids

[0043] Flavonoids suitable for the present invention have a general structural formula of Formula I:

[0044]

[0045] Wherein:

[0046] R 1 is H or phenyl;

[0047] R 2 is H, OH, gallate or phenyl; wherein the phenyl is optionally substituted with one or more (e.g., 2 to 3) hydroxyl groups;

[0048] R 3 is H, OH or ═O (oxo group); or

[0049] R 1 and R 2 together form a closed loop structure; or

[0050] R 2 and R 3 together form a closed loop structure.

[0051] The 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position of Formula I can be linked to a group containing hydrocarbon, halogen, oxygen, nitrogen, sulfur, phosphorus, boron or metal.

[0052] Examples of flavonoids of Formula I include:

[0053]

[0054] Preferred flavonoid compounds of Formula I include:

[0055] EGCG (CAS#989-51-5), EC (CAS#490-46-0), EGC (CAS#970-74-1) or ECG (CAS#1257-08-5)

[0056]

[0057] Polymer-flavonoid conjugates

[0058] As used throughout this application, a polymer-flavonoid conjugate refers to a conjugate of a hydrophilic polymer and a flavonoid compound of formula I.

[0059] A hydrophilic polymer refers to a polymer that is soluble in polar solvents and can form hydrogen bonds. Hydrophilic polymers suitable for the polymer-flavonoid conjugates of the present invention include, but are not limited to: poly(ethylene glycol) (PEG), aldehyde-derived hyaluronic acid, hyaluronic acid, dextran, diethyl acetal conjugates (such as diethyl acetal PEG), D-α-tocopheryl polyethylene glycol succinate, aldehyde-derived hyaluronic acid-tyramine, hyaluronic acid-aminoacetaldehyde diethyl acetal conjugate-tyramine, cyclotriphosphazene core phenoxymethyl(methylhydrazino) dendrimer or thiophosphoryl core phenoxymethyl(methylhydrazino) dendrimer, acrylamide, oxazoline, imine, acrylic acid, methacrylate, diol, ethylene oxide, alcohol, amine, acid anhydride, ester, lactone, terephthalate, amide and ether, polyacrylamide, poloxamer, poly(N-isopropylacrylamide), poly(oxazoline), polyethyleneimine, poly(acrylic acid), polymethacrylate, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), polyether, poly(allylamine), polyanhydride, poly(β-amino ester), poly(butylene succinate), polycaprolactone, polycarbonate, polydioxanone, poly(glycerol), polyglycolic acid, poly(3-hydroxypropionic acid), poly(2-hydroxyethyl methacrylate), poly(N-(2-hydroxypropyl)methacrylamide), polylactic acid, poly(lactic-co-glycolic acid), poly(orthoester), poly(2-oxazoline), poly(sebacic acid), poly(terephthalate-co-phosphate), povidone and copolymers.

[0060] Preferred hydrophilic polymers include poly(ethylene glycol), hyaluronic acid, dextran, polyethyleneimine, poloxamer, povidone, D-α-tocopherol and polyethylene glycol succinate. The molecular weight of the hydrophilic polymer in the polymer-flavonoid conjugate is generally 1K-100K daltons, preferably 2K-40K daltons, 2K-50K daltons, 2K-80K daltons, 3K-80K daltons or 5K-40K daltons.

[0061] In one embodiment, the polymer contains an aldehyde group conjugated to the 5-position, 6-position, 7-position, or 8-position (preferably the 6-position or 8-position) of the A-ring of a flavonoid compound. In another embodiment, the polymer contains a thiol group conjugated to R 1 or R 2 when R 1 or R 2 is -OH).

[0062] In one embodiment, the polymer-flavonoid conjugate is PEG-EGCG, which is PEG conjugated to one or two molecules of epigallocatechin gallate (EGCG). For example, PEG-EGCG can be prepared by conjugating aldehyde-capped PEG to EGCG via the reaction of a free aldehyde group with the 5-position, 6-position, 7-position, or 8-position (preferably the 6-position or 8-position) of Formula I through the linkage of PEG. See WO2006 / 124000 and WO2009 / 054813. PEG-EGCG can also be prepared by conjugating thio-capped PEG to EGCG via the reaction of a free thio group with R1 or R2 of Formula I (wherein R1 or R2 is phenyl) through the linkage of PEG. See WO2015 / 171079.

[0063] Flavonoid oligomers

[0064] A flavonoid oligomer is a conjugate of one flavonoid with one or more flavonoids. Flavonoid oligomers can contain the same flavonoid (homologous oligomers) or different flavonoids (heterologous oligomers). The flavonoid oligomers useful in the present invention generally have 2 to 50 or 2 to 20, preferably 4 to 12, of one type or a mixed type of flavonoids.

[0065] In some embodiments, the flavonoid oligomer is oligomeric EGC (OEGCG), oligomeric EC (OEC), oligomeric EGC (OEGC), or oligomeric ECG (OECG). OEGCG refers to 3 to 20 covalently linked EGCG monomers. For example, OEGCG can be synthesized at the 5-position, 6-position, 7-position, or 8-position (preferably the 6-position or 8-position) of the A-ring according to WO2006 / 124000.

[0066] Since the A-ring is present in all flavonoids according to Formula 1, other oligomeric flavonoids can be prepared similarly according to WO2006 / 124000. For example, OEC, OEGC, and OECG can also be prepared according to WO2006 / 124000.

[0067] MINC-drugs

[0068] MINC (Multi-channel Immunomodulatory Nanocomplex Combination Therapy) is a platform technology that utilizes the biological activity of polymer-flavonoid conjugates or flavonoid oligomers that form micelles in solution. The MINC platform can encapsulate additional agents (such as drugs) to form nanoparticle compositions for combination therapy.

[0069] MINC-drugs are micelles having a shell formed by one or more polymer-flavonoid conjugates or one or more flavonoid oligomers or a combination thereof and having a drug encapsulated within the shell. As used herein, a drug refers to a molecule having therapeutic activity against bacterial or viral infections, including but not limited to anti-inflammatory agents, nucleotide / nucleoside analogs, and agents that enhance the host immune defense response. Host immune defense agents are mainly anti-inflammatory cytokines, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IL-18, IFN-α, IFN-β, IFN-γ, TNF-α, G-CSF, GM-CSF, or M-CSF.

[0070] In one embodiment, the MINC-drug is a micelle that contains a polymer-flavonoid conjugate (e.g., a PEG-EGCG conjugate) in the shell and has an encapsulated agent (see Figure 1 ).

[0071] In another embodiment, the MINC-drug is a micelle that contains a polymer-flavonoid conjugate (e.g., a PEG-EGCG conjugate) in the outer core, a flavonoid oligomer (e.g., oligomeric EGCG (OEGCG)) in the inner core, and an encapsulated agent (see Figure 2 ).

[0072] "Polymer-flavonoid conjugates" or "flavonoid oligomers" can be used to treat infectious diseases, including viral or bacterial infections, by mechanisms including but not limited to: inhibiting viral or bacterial replication; killing viruses or bacteria; preventing viruses or bacteria from entering / infecting their target cells / tissues / organs; preserving the function / activity of infected cells / tissues / organs; modulating host immunity to kill infectious microorganisms.

[0073] MINC-drug compositions contain two or more therapeutically active components that are functionally complementary to form a multi-targeted combination therapy through their backbone components (polymer-flavonoid conjugates or flavonoid oligomers) and the encapsulated drugs (agents). MINC-drugs are stable in hydrophilic environments such as blood circulation.

[0074] In one embodiment, the agent is a cytokine, including but not limited to IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IL-18, IFN-α, IFN-β, IFN-γ, TNF-α, G-CSF, GM-CSF or M-CSF. These cytokines are used for treatment across disease types; the aim is to induce a host immune response against infectious microorganisms, not limited to a specific type of infectious disease. These cytokines are suitable for the treatment of viral infections, including adenovirus, coxsackievirus, cytomegalovirus, enterovirus, Epstein-Barr virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex virus type 1, herpes simplex virus type 2, HIV, human coronavirus 229E (HCoV-229E), human coronavirus HKU1 (HCoV-HKU1), human coronavirus NL63 (HCoV-NL63), human coronavirus OC43 (HCoV-OC43), human herpesvirus, human papillomavirus, influenza virus, measles virus, Middle East respiratory syndrome-related coronavirus (MERS-CoV), mumps virus, parainfluenza virus, poliovirus, rabies virus, respiratory syncytial virus, rubella virus, rotavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or varicella-zoster virus. These cytokines are suitable for the treatment of bacterial infections, including but not limited to Mycobacterium tuberculosis, Clostridium tetani, Salmonella Typhi, Corynebacterium diphtheria, Treponema pallidum, Mycobacterium lepromatosis or methicillin-resistant Staphylococcus aureus.

[0075] In one embodiment, the agent is an antiviral antibody for the treatment of SARS-CoV-2 infection that causes COVID-19, including but not limited to anti-SARS-CoV-2-RBD, anti-SARS-CoV-2-SP, anti-SARS-CoV-2-SD1 / SD2, anti-SARS-COV-2-S2, bamlanivimab, etesevimab, casirivimab, imdevimab, cilgavimab, tixagevimab, sotrovimab or radezlimab.

[0076] In one embodiment, the agent is an antiviral antibody for treating HIV (human immunodeficiency virus) infection that causes AIDS, including but not limited to anti-HIV-gp120, VRC01, 10-1074, anti-HIV-Env, 3BNC117, anti-HIV-gp41, 4E10, 2F5, 2G12, anti-CCR5, PRO 140, anti-CD4, ibalizumab, or leronlimab.

[0077] In one embodiment, the agent is an antiviral antibody for treating HPV (human papillomavirus) infection that causes cervical cancer, including but not limited to anti-HPV-E6 or anti-HPV-E7.

[0078] In one embodiment, the agent is an antiviral antibody for treating CMV (cytomegalovirus) infection, including but not limited to anti-CMV-gB, CSJ148, TCN-202, anti-CMV-gH, LPJ539, anti-CMV-gH / gH, MCMV5322A, cidofovir, or MCMV3068A.

[0079] In one embodiment, the agent is an antiviral antibody for treating influenza virus infection, including but not limited to anti-influenza A hemagglutinin, MHAA4549A, VIS410, CR6261, CR8020, or TCN-032.

[0080] In one embodiment, the agent is an antiviral antibody for treating RSV (respiratory syncytial virus) infection, including but not limited to anti-RSV-glycoprotein F, palivizumab, REGN2222, motavizumab, MEDI8897, ALX-0171, or nirsevimab.

[0081] In one embodiment, the agent is an antiviral antibody for treating Ebola virus, including but not limited to ZMapp, atoltivimab, maftivimab, or olaratumab.

[0082] In one embodiment, the agent is an antiviral antibody for treating rabies virus infection, including but not limited to CR57, CR4098, CL184, or RAB-1.

[0083] In one embodiment, the agent is an antiviral nucleoside analog for treating SARS-CoV-2 infection, including but not limited to ribavirin, favipiravir, lopinavir, ritonavir, or nafamostat.

[0084] In one embodiment, the agent is an antibacterial antibody for treating Staphylococcus aureus infection, including but not limited to AR301, MEDI4893, 514G3, or ARN-100.

[0085] In one embodiment, the agent is an antibacterial antibody for treating Pseudomonas aeruginosa infection, including but not limited to MEDI3902 or AR101.

[0086] In one embodiment, the agent is an antibacterial antibody for treating Clostridium difficile infection, including but not limited to PolyCAb or Cd-ISTAb.

[0087] In one embodiment, the agent is an antibacterial antibody for treating Acinetobacter baumannii infection, including but not limited to AR401-mAb or VXD-003.

[0088] In one embodiment, the agent is an antibacterial antibody for treating Escherichia coli (ST131) infection, including but not limited to ASN-4.

[0089] In one embodiment, the agent is an antibacterial antibody for treating Klebsiella pneumoniae infection, including but not limited to ASN-5.

[0090] In one embodiment, the agent is an antiviral nucleotide analogue for treating SARS-CoV-2 infection, including but not limited to remdesivir.

[0091] In one embodiment, the agent is an antiviral nucleoside analogue for treating HIV (human immunodeficiency virus) infection, including but not limited to abacavir, didanosine, emtricitabine, stavudine or zidovudine.

[0092] In one embodiment, the agent is an antiviral nucleotide analogue for treating HIV (human immunodeficiency virus) infection, including but not limited to tenofovir, tenofovir diphosphate, d4TMP, d4TTP, AzTMP or AzTTP.

[0093] In one embodiment, the agent is an antiviral nucleoside analogue for treating HSV (herpes simplex virus) infection, such as acyclovir, famciclovir or valacyclovir.

[0094] In one embodiment, the agent is an antiviral nucleoside analogue for treating HBV (hepatitis B virus) infection, such as adefovir, emtricitabine, entecavir, lamivudine, telbivudine, tenofovir or ribavirin.

[0095] In one embodiment, the agent is an antiviral nucleotide analogue for treating HBV (hepatitis B virus) infection, such as 3TCMP, 3TCTP, acyclovir monophosphate, acyclovir triphosphate, telbivudine monophosphate or telbivudine triphosphate.

[0096] In one embodiment, the agent is an antiviral nucleoside analogue for treating HCV (hepatitis C virus) infection, such as sofosbuvir or ribavirin.

[0097] In one embodiment, the agent is an antiviral nucleotide analogue for treating HCV (hepatitis C virus) infection, such as ribavirin monophosphate or ribavirin triphosphate.

[0098] In one embodiment, the agent is an antiviral nucleoside analogue for treating CMV (cytomegalovirus) infection, such as cidofovir, ganciclovir or valganciclovir.

[0099] In one embodiment, the agent is an antiviral nucleoside analogue for treating VZV (varicella-zoster virus) infection, such as famciclovir or valacyclovir.

[0100] In one embodiment, the agent is an antiviral nucleotide analogue for treating VZV (varicella-zoster virus) infection, such as acyclovir monophosphate or acyclovir triphosphate.

[0101] In one embodiment, the agent is an antiviral nucleoside analogue for treating influenza virus infection, such as ribavirin, 5-azacytidine and 5-fluorouracil, zanamivir, oseltamivir, peramivir or baloxavir.

[0102] In one embodiment, the agent is an antiviral nucleotide analogue for treating influenza virus infection, such as ribavirin monophosphate or ribavirin triphosphate.

[0103] In one embodiment, the agent is IFN-α for treating viral or bacterial infection. For example, the MINC-drug is IFN-α encapsulated in micelles formed by the polymer-flavonoid conjugate PEG-EGCG and the flavonoid oligomer OEGCG. For the structure and preparation method, see WO2009 / 054813.

[0104] In one embodiment, the agent is not an antibiotic.

[0105] Drug compositions

[0106] The present invention uses a pharmaceutical composition, which comprises a polymer-flavonoid conjugate, a flavonoid oligomer or a MINC-pharmaceutical composition as described in the present application, and optionally comprises one or more pharmaceutically acceptable carriers. For tablets, powders or parenteral preparations, the nanoparticle composition in the pharmaceutical composition is generally about 1% to 90%, preferably 20% to 90% or 30% to 80%. For capsule preparations, the polymer-flavonoid conjugate, flavonoid oligomer or MINC-pharmaceutical composition in the pharmaceutical composition is generally 1% to 100%, preferably 20% to 100%, 50% to 100% or 70% to 100%. For liquid suspension preparations, the nanoparticle composition in the pharmaceutical composition is generally 1% to 50%, 5% to 50% or 10% to 40%.

[0107] In one embodiment, the pharmaceutical composition can be in dosage forms such as tablets, capsules, granules, fine granules, powders, suspensions, patches, parenterals, injectables, etc. The above pharmaceutical composition can be prepared by conventional methods.

[0108] A pharmaceutically acceptable carrier is an inactive ingredient that can be selected by those skilled in the art using conventional standards. A pharmaceutically acceptable carrier can contain a variety of components, including but not limited to saline and aqueous electrolyte solutions; ionic and non-ionic osmotic agents such as sodium chloride, potassium chloride, glycerol, and glucose; pH regulators and buffers such as salts of hydroxides, phosphates, citrates, acetates, borates, and triethanolamine; antioxidants such as salts, acids, and / or bases of bisulfite, sulfite, metabisulfite, thiosulfite, ascorbic acid, acetylcysteine, cysteine, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, and ascorbyl palmitate; surfactants such as lecithin and phospholipids, including but not limited to phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol; poloxamer and poloxamine; polysorbates such as polysorbate 80, polysorbate 60, and polysorbate 20; polyethers such as polyethylene glycol and polypropylene glycol; polyethylenes such as polyvinyl alcohol and polyvinylpyrrolidone (PVP, povidone); cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose and their salts; petroleum derivatives such as mineral oil and white petrolatum; fats such as lanolin, peanut oil, palm oil, soybean oil; monoglycerides, diglycerides, and triglycerides; polysaccharides such as dextran; and glycosaminoglycans such as sodium hyaluronate. Such pharmaceutically acceptable carriers can be preserved with well-known preservatives to prevent bacterial contamination, including but not limited to benzalkonium chloride, ethylenediaminetetraacetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, or can be formulated as a non-preserved preparation for single or multiple use.

[0109] For example, tablets, capsules, or parenteral formulations of an active compound can contain other excipients that are not biologically active and do not react with the active compound. Excipients for tablets or capsules can include fillers, binders, lubricants and glidants, disintegrants, wetting agents, and release rate regulators. Examples of excipients for tablets or capsules include but are not limited to carboxymethylcellulose, cellulose, ethylcellulose, hydroxypropylmethylcellulose, methylcellulose, karaya gum, starch, tragacanth, gelatin, magnesium stearate, titanium dioxide, poly(acrylic acid), and polyvinylpyrrolidone.

[0110] For example, tablet formulations can contain inactive ingredients such as colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide. Capsule formulations can contain inactive ingredients such as gelatin, magnesium stearate, and titanium dioxide. Powder oral formulations can contain inactive ingredients such as silica gel, sodium benzoate, sodium citrate, sucrose, and xanthan gum.

[0111] The pharmaceutical composition can be administered by partial administration and systemic administration. Partial administration includes topical administration. Systemic administration includes oral administration, parenteral administration (such as intravenous administration, intramuscular administration, subcutaneous administration or rectal administration) and other systemic administration routes. In systemic administration, the active compound first reaches the plasma and then distributes into the target tissue. Parenteral administration (such as intravenous bolus injection or intravenous infusion) and oral administration are preferred administration routes.

[0112] Therapeutic methods

[0113] The present invention relates to a method for treating infectious diseases, including viral infections and bacterial infections. The infections are caused by DNA viruses, RNA viruses, Gram-positive bacteria or Gram-negative bacteria.

[0114] Suitable viral infectious diseases to be treated by the present invention include, but are not limited to, viral infections caused by the following viruses: adenovirus, coxsackievirus, cytomegalovirus, Epstein-Barr virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex virus type 1, herpes simplex virus type 2, HIV, human coronavirus 229E (HCoV-229E), human coronavirus HKU1 (HCoV-HKU1), human coronavirus NL63 (HCoV-NL63), human coronavirus OC43 (HCoV-OC43), human herpesvirus, human papillomavirus, influenza virus, measles virus, Middle East respiratory syndrome-related coronavirus (MERS-CoV), mumps virus, parainfluenza virus, poliovirus, rabies virus, respiratory syncytial virus, rubella virus, severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or varicella-zoster virus.

[0115] Suitable bacterial infectious diseases to be treated by the present invention include, but are not limited to, the following bacterial infections: tuberculosis caused by bacilli, cocci or spirilla, anthrax, tetanus, leptospirosis, pneumonia, cholera, botulism, Pseudomonas infection, MRSA infection, Escherichia coli infection, meningitis, gonorrhea, bubonic plague or syphilis.

[0116] Polymer-flavonoids

[0117] In a first aspect of the present invention, the method comprises the step of administering an effective amount of a polymer-flavonoid conjugate to a subject in need thereof. As used in this application, "effective amount" is an amount that can effectively treat a disease by improving the pathological condition or alleviating the symptoms of the disease.

[0118] The polymer-flavonoid conjugates of the present invention have immunomodulatory, antiviral, and antibacterial activities against infectious diseases.

[0119] In one embodiment, the flavonoid is EGCG, EC, EGC, or ECG.

[0120] In one embodiment, the polymer is a hydrophilic polymer having a molecular weight of 1,000 to 100,000 daltons and is selected from the group consisting of PEG, hyaluronic acid, dextran, polyethyleneimine, poloxamer, polyvinylpyrrolidone, D-α-tocopherol, and polyethylene glycol succinate.

[0121] A preferred polymer-flavonoid conjugate is PEG-EGCG.

[0122] In one embodiment, the infection is caused by a DNA virus selected from the group consisting of hepatitis B virus, human herpesvirus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, monkeypox virus, and varicella-zoster virus.

[0123] In one embodiment, the infection is caused by an RNA virus selected from the group consisting of SARS-CoV-2, enterovirus, HIV, MERS-CoV, hepatitis C virus, hepatitis A virus, rotavirus, norovirus, influenza virus, parainfluenza virus, dengue virus, respiratory syncytial virus, and SARS-CoV.

[0124] In one embodiment, the infection is caused by a Gram-positive bacterium selected from the group consisting of methicillin-resistant Staphylococcus aureus, tuberculosis, Bacillus anthracis, Clostridium tetani, Streptococcus pneumoniae, Clostridium botulinum, Clostridia, Mycobacterium tuberculosis, Clostridium tetani, Corynebacterium diphtheria, and Mycobacterium leprae.

[0125] In one embodiment, the infection is caused by a Gram-negative bacterium selected from the group consisting of Pseudomonas, Meningococcus, Leptospira, Neisseria gonorrhoeae, Neisseria meningitidis, Yersinia pestis, Treponema pallidum, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Mycobacterium tuberculosis, Legionella, and Salmonella.

[0126] The administration of the injectable polymer-flavonoid (e.g., PEG-EGGC) is typically from 0.1 mg / kg to 10000 mg / kg, from 0.6 mg / kg to 1200 mg / kg (total weight of polymer-flavonoid / subject body weight), or from 1 mg / kg to 1000 mg / kg.

[0127] Flavonoid oligomers

[0128] In a second aspect of the invention, the method comprises the step of administering an effective amount of a flavonoid oligomer to a subject in need thereof. The flavonoid oligomers of the present invention have immunomodulatory, antiviral, and antibacterial activities against infectious diseases.

[0129] In one embodiment, the flavonoid is EGCG, EC, EGC, or ECG.

[0130] In one embodiment, the flavonoid oligomer comprises 4 to 12 flavonoids of EGCG, EC, EGC, or ECG.

[0131] The preferred flavonoid oligomer is an oligomer of EGCG.

[0132] In one embodiment, the infection is caused by a DNA virus selected from the group consisting of hepatitis B virus, human herpesvirus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, monkeypox virus, and varicella-zoster virus.

[0133] In one embodiment, the infection is caused by an RNA virus selected from the group consisting of SARS-CoV-2, enterovirus, HIV, MERS-CoV, hepatitis C virus, hepatitis A virus, rotavirus, norovirus, influenza virus, parainfluenza virus, dengue virus, respiratory syncytial virus, and SARS-CoV.

[0134] In one embodiment, the infection is caused by a Gram-positive bacterium selected from the group consisting of methicillin-resistant Staphylococcus aureus, tuberculosis, Bacillus anthracis, Clostridium tetani, Streptococcus pneumoniae, Clostridium botulinum, Clostridium spp., Mycobacterium tuberculosis, Clostridium tetani, Corynebacterium diphtheriae, and Mycobacterium leprae.

[0135] In one embodiment, the infection is caused by a Gram-negative bacterium selected from the group consisting of Pseudomonas spp., Neisseria meningitidis, Leptospira spp., Neisseria gonorrhoeae, Neisseria meningitidis, Yersinia pestis, Treponema pallidum, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Mycobacterium tuberculosis, Legionella spp., and Salmonella spp.

[0136] The administration of injectable flavonoid oligomers (e.g., OEGCG) is typically 0.1 mg / kg to 1000 mg / kg, 0.1 mg / kg to 100 mg / kg (total weight of flavonoid oligomer / subject body weight), or 1 mg / kg to 100 mg / kg.

[0137] MINC-drugs

[0138] In a third aspect of the invention, the method comprises the step of administering to a subject in need thereof an effective amount of micelles for treating a bacterial or viral infection, said micelles having an outer shell comprising one or more polymer-flavonoid conjugates and optionally an inner shell comprising one or more flavonoid oligomers, and a drug encapsulated within said shells. In one embodiment, the shell is formed by one or more polymer-flavonoid conjugates. In one embodiment, the outer shell is formed by one or more polymer-flavonoid conjugates and the inner shell is formed by one or more flavonoid oligomers. The polymer-flavonoid conjugate or flavonoid oligomer provides its own therapeutic effect and further delivers the agent for treating infectious diseases.

[0139] In one embodiment, the polymer is a hydrophilic polymer having a molecular weight of 1,000 daltons to 100,000 daltons and is selected from the group consisting of poly(ethylene glycol) (PEG), hyaluronic acid, dextran, polyethyleneimine, poloxamer, polyvinylpyrrolidone, D-α-tocopherol, and polyethylene glycol succinate.

[0140] In one embodiment, the flavonoid oligomer comprises 2 to 20 flavonoids of EGCG, EC, EGC, or ECG.

[0141] In one embodiment, the shell is formed by PEG-EGCG.

[0142] In one embodiment, the shell is formed by PEG-EGCG and OEGCG.

[0143] In one embodiment, the drug in the MINC-drug is not an antibiotic.

[0144] In one embodiment, the infection is caused by methicillin-resistant Staphylococcus aureus, and the drug is IFN-α, IFN-γ, IFN-β, an IL-13 topoisomerase inhibitor, an FtsZ inhibitor, a β-lactamase inhibitor, a ribosome inhibitor, a dihydropteroate synthase inhibitor, a dihydropteroate synthase inhibitor, anti-AR301, anti-MEDI4893, anti-514G3, or anti-ARN-100.

[0145] In one embodiment, the infection is caused by Pseudomonas, and the drug is IFN-α, an OprF vaccine, anti-LPS, anti-alginate, anti-PcrV, anti-OPK, anti-DNABII, a β-lactamase inhibitor, LptD, LpxD, a lytic agent, an iron mimetic, a biofilm matrix disruptor, a T3SS inhibitor, anti-MEDI3902, or anti-AR101.

[0146] In one embodiment, the infection is caused by tuberculosis, and the drug is IFN-α, anti-TNF-α, IFN-γ, GM-CSF, TGF-β, anti-VEGF, IL-2, IL-4, IL-7, IL-10, IL-12, IL-15, IL-23, IL-24, IL-37, anti-IL4 prostaglandin E, a phosphodiesterase inhibitor, an ATP synthase inhibitor, a ribosome inhibitor, a DprE1 inhibitor, a gyrase inhibitor, an MmpL3 inhibitor, a Leu tRNA synthase inhibitor, a Murl inhibitor, an InhA inhibitor, an NDH-2 inhibitor, a QcrB inhibitor, a MenG inhibitor, an FtsZ inhibitor, an EthR inhibitor, or a LepB inhibitor.

[0147] In one embodiment, the infection is caused by Bacillus anthracis, and the drug is IFN-α, anti-PA63, enoyl-ACP reductase, ribonucleotide reductase, nucleoside hydrolase, replicative DNA helicase, acetohydroxy acid synthase, NAD synthase, nicotinate mononucleotide adenylyltransferase, lumazine synthase, the cytoskeletal protein FtsZ, dihydropteroate synthase, or dihydrofolate reductase.

[0148] In one embodiment, the infection is caused by Clostridium tetani, and the drug is IFN-α, anti-tetanus immunoglobulin, tetanus toxoid, benzodiazepine drugs, magnesium sulfate, intrathecal baclofen, dantrolene, ketamine, propofol, botulinum toxin, human anti-tetanus immunoglobulin, or a tetanus toxoid vaccine.

[0149] In one embodiment, the infection is caused by Streptococcus pneumoniae, and the drugs are IFN-α, IL-26, HMGB1, anti-IL-6, anti-TNFα, anti-IL-1β, anti-CXCL8, CD4, IL-4, CD8A, IL-10, anti-PTPRC, JAK inhibitor, anti-manL, anti-cps4L, anti-recU, anti-SP_0645, anti-ezrA, anti-prsA, anti-tarJ, anti-SP_1280, anti-SP_1617, anti-ptsG, anti-DltD, anti-hprK, anti-pepF, anti-coiA, anti-fib, anti-acpS, anti-manA, anti-mvaK2, anti-mtlD, anti-mtlF or TPCA-1.

[0150] In one embodiment, the infection is caused by Neisseria meningitidis, and the drugs are IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, CGRP, anti-PARP, TACE, EGFR, EGF, anti-ATM, ESR-1, anti-CASP8, NGF, anti-sdhA, anti-ribH, anti-ruvA, anti-ruvX, anti-ponA, anti-rr03, anti-fabH, anti-fabZ, anti-metE, anti-recJ, anti-rpsP, anti-plsY, anti-ftsK, anti-dnaE, anti-holB, anti-rsmI, anti-mtf, anti-dnaG, anti-rpoD, anti-pta, anti-rplU, anti-hup, anti-ptsI, anti-rsmG, anti-lgt, anti-greA, anti-secA1, anti-queF, anti-nusG, anti-ackA, anti-dapH, anti-ilvD or anti-dnaC.

[0151] In one embodiment, the infection is caused by Severe Acute Respiratory Syndrome Coronavirus 2, and the drugs are IFN-α, IFN-β, IL-6, IL-12, IL-21, anti-IL-6, anti-IL-6R, spike protein vaccine, RBD vaccine, ACE2 antagonist, anti-TMPRSS2, anti-CD147, anti-VEGFA, anti-GM-CSF, dexamethasone, chloroquine, Nsp12-RdRp inhibitor, hydroxychloroquine, anti-3CLpro, interferon-α, AAK-1 inhibitor or JAK inhibitor.

[0152] In one embodiment, the infection is caused by enterovirus, and the drugs are IFN-α, IFN-β, capsid binder, 3Cpro inhibitor, 3Dpol inhibitor, 2CATPase inhibitor, 2APro inhibitor, anti-HSP90, anti-PI4KB, anti-OSBP, anti-RdRP, SP40, SP45, SP55, SP81, LVLQTM, VAD or AAPV.

[0153] In one embodiment, the infection is caused by HIV, and the drugs are IFN-α, anti-tetanus immunoglobulin, tetanus toxoid, benzodiazepine drugs, magnesium sulfate, intrathecal baclofen, dantrolene, ketamine, propofol, botulinum toxin, human anti-tetanus immunoglobulin or tetanus toxoid vaccine.

[0154] In one embodiment, the infection is caused by hepatitis B virus, and the drugs are IFN-α, IFN-γ, IL-12, IL-6, IL-21, DNA polymerase reverse transcriptase activity inhibitor, pre-S1 peptide, CRISPR / Cas9, ZFN, capsid assembly modulator, E-neg and E-pos RNAi, lamivudine, adefovir, entecavir, tenofovir, TLR agonist, STING agonist or cyclophilin inhibitor.

[0155] In one embodiment, the infection is caused by MERS-CoV, and the drugs are IFN-α, IFN-β, IFN-γ, anti-DPP4, Poly IC, anti-ACE2 antagonist, RdRp inhibitor, chlorpromazine hydrochloride, chloroquine, peptide, endosomal protease inhibitor, TMPRSS2 inhibitor, furin protease inhibitor, anti-clathrin endocytosis, MERS-CoV SDNA or RBD subunit vaccine.

[0156] In one embodiment, the infection is caused by influenza virus, and the drugs are IFN-α, IFN-β, IFN-γ, IL-12, IL-6, IL-15, IL-21, neuraminidase inhibitor, cap-dependent endonuclease inhibitor, M2 ion channel blocker, nucleoprotein inhibitor, anti-NS1-1, anti-CPSF30, anti-PABII, anti-eIF4G1, anti-PABP1, anti-p85, anti-PKR, anti-PACT, anti-NXF1, anti-p15, anti-importin, anti-crk, anti-crkL, anti-RIG-1, anti-nucleolin, anti-TRIM25, anti-Gas8, anti-Akt, anti-p53, anti-PARP10, anti-RIL, anti-Hsp90, anti-PDZ, anti-NOLC1, anti-RAP55, anti-IKK, anti-hPAF1C or anti-hGBP1.

[0157] In one embodiment, the infection is caused by dengue virus, and the drugs are anti-TNF-α, anti-IL-6, anti-RANTES, chloroquine, prednisolone, NS5 nucleoside inhibitor, ER-related α, glucosidase inhibitor, lovastatin, capsid inhibitor, envelope inhibitor, anti-NS4B, anti-NS2B / 3, anti-NS1 or NS1 vaccine.

[0158] In one embodiment, the infection is caused by respiratory syncytial virus, and the drugs are IL-15, anti-TNF-α, benzimidazole derivatives, disulfonated stilbene, imidazoisoindolinone derivatives, triphenol compounds, anti-envelope glycoprotein, sulfated sialic acid lipids, anti-NS1, anti-F glycoprotein, siRNA inhibiting P protein, NS1 protein or N protein gene.

[0159] In one embodiment, the infection is caused by SARS-CoV, and the drugs are IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, anti-VEGFA, anti-GM-CSF, spike protein vaccine, RBD vaccine, ACE2 antagonist, anti-TMPRSS2, anti-CD147, dexamethasone, chloroquine, Nsp12-RdRp inhibitor, hydroxychloroquine, anti-3CLpro, interferon-α, AAK-1 inhibitor, JAK inhibitor, anti-ATM, anti-SIRT1, anti-GSK3B or anti-Torin-2.

[0160] In one embodiment, the infection is caused by Escherichia coli, and the drugs are IFN-α, anti-IL-1β, anti-TNFα, anti-IL-6, anti-bamD, anti-cydX, anti-dnaT, anti-fabA, anti-ftsB, anti-ftsL, anti-ftsQ, anti-hemD, anti-higA, anti-hipB, anti-holD, anti-iraM, anti-lolA, anti-lolB, anti-lptA, anti-lptD, anti-lptE, anti-mreD, anti-mukB, anti-mukE, anti-mukF, anti-pheM, anti-priB, anti-safA, anti-secE, anti-trpL, anti-tusE, anti-wzyE, anti-ycaR, anti-yciS, anti-ydfO, anti-ydhL, anti-ygfZ, anti-yqeL, anti-yrfF or anti-zipA.

[0161] In one embodiment, the infection is caused by Legionella, and the drugs are IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, anti-Hsp60, anti-MOMP, anti-Mip, anti-Les, anti-Lsp, anti-CpxTRA, anti-PilEL, anti-Lvh, anti-IcM, anti-UDP, anti-FtsL, anti-MrdA, anti-RpoH, anti-multidrug resistance protein, anti-amino acid permease, anti-TolB, anti-Kup1, anti-MviN, anti-Tig, anti-MurE, anti-SCD, anti-TTF, anti-UMF1, anti-HMP, anti-HslU, anti-htrB, anti-Kdo, anti-OGT or anti-RpoH.

[0162] In one embodiment, the infection is caused by Neisseria gonorrhoeae, and the drugs are IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, CDP-4-dehydro-6-deoxyglucose reductase, anti-LpxC, anti-SSADH, anti-RNR, anti-DacC, anti-PBP, anti-PIB, anti-dsbA, anti-NarX, anti-Zur, anti-PTS, anti-Hpr, anti-PPP, anti-YgfZ, anti-HP, anti-RimM, anti-BspRI, anti-rluF, anti-FAD, anti-EF-P, anti-dnaN, anti-tilS or anti-RluD.

[0163] In one embodiment, the infection is caused by Neisseria meningitidis, and the drugs are IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, anti-TerC, anti-MscS, anti-OPT, anti-MFS, anti-MscS, anti-NaCT, anti-ABC, anti-TauE / SafE, anti-CBS, anti-NRAMP, anti-OATP, anti-YggX, anti-SstT, anti-PMT, anti-YjgP, anti-yhhQ, anti-TerC, anti-MAPEG, anti-MSG, anti-PilW, anti-PilX, anti-RlpA, anti-Rrf2, anti-IclR or anti-Rim.

[0164] In one embodiment, the infection is caused by Salmonella, and the drugs are IFN-α, anti-IL-1β, anti-TNFα, anti-IL-6, anti-bamD, anti-cydX, anti-dnaT, anti-fabA, anti-ftsB, anti-ftsL, anti-ftsQ, anti-hemD, anti-higA, anti-hipB, anti-holD, anti-iraM, anti-lolA, anti-lolB, anti-lptA, anti-lptD, anti-lptE, anti-mreD, anti-mukB, anti-mukE, anti-mukF, anti-pheM, anti-priB, anti-safA, anti-secE, anti-trpL, anti-tusE, anti-wzyE, anti-ycaR, anti-yciS, anti-ydfO, anti-ydhL, anti-ygfZ, anti-yqeL, anti-yrfF or anti-zipA.

[0165] In one embodiment, the infection is caused by hepatitis C virus, and the drugs are IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, anti-EGFR, anti-NS2, anti-NS3, anti-NS4A, anti-NS5A, anti-NS5B, anti-helicase, anti-TLR-9, anti-HCV E2, anti-E1, anti-E2, anti-p7, anti-CD81, anti-SRB1, anti-CLDN1, anti-EphA2, anti-TfR1, anti-NPC1L1, cyclosporine A, anti-α-glucosidase, anti-DGAT-1, anti-VLDL, anti-CD81, anti-CLDN1 or anti-SR-Bl.

[0166] In one embodiment, the infection is caused by monkeypox virus, and the drugs are IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, rosmarinic acid, myricetin, quercitrin, ofloxacin, anti-VP37, anti-F13L, anti-E9L, anti-A24R, anti-A48R, anti-H5R, anti-B1R, anti-F10L, anti-E8L, anti-A6R, anti-SPGF, anti-B8R, anti-A50R, anti-I7L, anti-D13L, anti-Top1 or anti-TMPK.

[0167] In one embodiment, the infection is caused by human papillomavirus, and the drugs are IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, anti-EGFR, anti-c-Met, anti-IGF-1R, anti-PI3K, anti-Akt, anti-mTOR, anti-Ras, anti-Raf, anti-MAPK, anti-VEGF, anti-VEGFR, anti-HIF-1α, anti-PD-L1, anti-CD38, anti-PD1, anti-RNR, anti-FGFR, anti-PDGFR, anti-Kit or anti-Ret.

[0168] The administration of the MINC-drug is based on the known dose of the drug for treating a specific disease and the condition of the subject. The dose can be the dose approved by the US Food and Drug Administration (FDA) or the dose used in clinical trials.

[0169] In the MINC-drug, generally, the dose of PEG-EGCG combined with OEGCG ranges from 10 μg / kg to 100 mg / kg.

[0170] The concentration of the encapsulated pharmaceutical agent can be as low as 0.01 μg / kg (e.g., for cytokine drugs, IFN-α) and as high as 500 mg / kg (e.g., for antibody drugs, ativerab).

[0171] For example, for the treatment of SARS-CoV-2, HIV, HPV, or other viral infections in adults, IFN-α is administered once to three times a week at a dose of 0.01 μg / kg to 500 μg / kg IV (or 0.01 mIU to 500 mIU). The same effective dose of MINC-IFN-α can be used to treat other viral infections.

[0172] For example, for the treatment of Mycobacterium tuberculosis, Clostridium tetani, Salmonella typhi, Corynebacterium diphtheriae, Treponema pallidum, Mycobacterium leprae, methicillin-resistant Staphylococcus aureus, or other bacterial infections in adults, IFN-α is administered once to three times a week at a dose of 0.01 μg / kg to 500 μg / kg IV (or 0.01 mIU to 500 mIU). The same effective dose of MINC-IFN-α can be used to treat other bacterial infections.

[0173] For example, for the treatment of SARS-CoV-2, HIV, HPV, or other viral infections in adults, IFN-β is administered once to three times a week at a dose of 0.01 μg / kg to 500 μg / kg IV (or 0.01 mIU to 500 mIU). The same effective dose of MINC-IFN-β can be used to treat other viral infections.

[0174] For example, for the treatment of Mycobacterium tuberculosis, Clostridium tetani, Salmonella typhi, Corynebacterium diphtheriae, Treponema pallidum, Mycobacterium leprae, methicillin-resistant Staphylococcus aureus, or other bacterial infections in adults, IFN-β is administered once to three times a week at a dose of 0.01 μg / kg to 500 μg / kg IV (or 0.01 mIU to 500 mIU). The same effective dose of MINC-IFN-β can be used to treat other bacterial infections.

[0175] Generally, when the MINC-drug is a cytokine such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IL-18, IFN-α, IFN-β, TNF-α, G-CSF, GM-CSF, or M-CSF for the treatment of viral and bacterial infections, the cytokine can be administered once to three times a week at a dose in the range of 0.01 μg / kg to 500 μg / kg IV (or 0.01 mIU to 500 mIU).

[0176] For example, for the treatment of SARS-CoV-2 in adults, 10 mg to 2000 mg of baricitinib is administered IV once. The effective dose of MINC-baricitinib within the same dose range can be used to treat SARS-CoV-2.

[0177] For example, for the treatment of HIV in adults, ibalizumab is administered IV once every two weeks at a dose of 10 mg to 6000 mg. The effective dose of MINC-ibalizumab within the same dose range can be used to treat HIV.

[0178] For example, when the MINC-drug has a drug as an antibody for the treatment of viral infections, where the antibody includes but is not limited to f-CoV-2-RBD, anti-SARS-CoV-2-SP, anti-SARS-CoV-2-SD1 / SD2, anti-SARS-COV-2-S2, bamlanivimab, etesevimab, casirivimab, imdevimab, cilgavimab, tixagevimab, sotrovimab, remdesivir, anti-HIV-gp120, VRC01, 10-1074, anti-HIV-Env, 3BNC117, anti-HIV-gp41, 4E10, 2F5, 2G12, anti-CCR5, PRO 140, anti-CD4, ibalizumab, leridistimab, anti-HPV-E6, anti-HPV-E7, anti-CMV-gB, CSJ148, TCN-202, anti-CMV-gH, LPJ539, anti-CMV-gH / gH, MCMV5322A, svelimab, MCMV3068A, anti-influenza A hemagglutinin, MHAA4549A, VIS410, CR6261, CR8020, TCN-032, anti-RSV-glycoprotein F, palivizumab, REGN2222, motavizumab, MEDI8897, ALX-0171, nirsevimab, ZMapp, atetevimab, matetevimab, oseltamivir, CR57, CR4098 or CL184, RAB-1, the agent can be administered IV once daily to once every three weeks at a dose in the range of 0.1 mg / kg to 500 mg / kg.

[0179] For example, when the MINC-drug has a drug as an antibody for the treatment of bacterial infections, where the antibody includes but is not limited to AR301, MEDI4893, 514G3, ARN-100, MEDI3902, AR101, PolyCAb, Cd-ISTAb, AR401-mAb, VXD-003, ASN-4 or ASN-5, the drug can be administered IV once daily to once every three weeks at a dose in the range of 0.1 mg / kg to 500 mg / kg.

[0180] For example, for the treatment of SARS-CoV-2 in adults, remdesivir is administered IV once daily to once every other day at a dose of 10 mg to 1000 mg. The effective dose of MINC-remdesivir within the same dose range can be used to treat SARS-CoV-2 or other viral infections.

[0181] For example, for the treatment of SARS-CoV-2, HBV, HCV, influenza virus or other viral infections in adults, ribavirin is administered IV at a dose of 50 mg to 10,000 mg once daily to once every three days. The effective dose of MINC-ribavirin within the same dose range can be used to treat SARS-CoV-2 or SARS-CoV-2, HBV, HCV, influenza virus or other viral infections.

[0182] For example, when the MINC-drug is a drug that is a nucleoside or nucleotide analog for the treatment of viral infections, where the nucleoside or nucleotide analog includes but is not limited to favipiravir, lopinavir, ritonavir, acyclovir, famciclovir, valacyclovir, abacavir, didanosine, emtricitabine, stavudine, tenofovir, zidovudine, adefovir, emtricitabine, entecavir, lamivudine, telbivudine, cidofovir, ganciclovir, valganciclovir, famciclovir, valacyclovir, 5-azacytidine and 5-fluorouracil, zanamivir, oseltamivir, peramivir or baloxavir, the drug can be administered IV once to three times a week at a dose in the range of 0.5 mg to 25,000 mg.

[0183] The present invention can be used to treat humans and non-human animals. For example, the present invention can be used to treat mammalian subjects such as humans, horses, pigs, cats and dogs.

[0184] The following examples further illustrate the present invention. These examples are only intended to illustrate the present invention and should not be construed as restrictive.

[0185] Examples

[0186] Active ingredients of all examples

[0187] OEGCG :

[0188] OEGCG is oligomerized EGCG. OEGCG is prepared according to WO2006 / 124000.

[0189] PEG-EGCG :

[0190] PEG-EGCG is PEG conjugated with one or two EGCG. PEG-EGCG is prepared according to WO2006 / 124000, WO2009 / 054813 or WO2015 / 171079.

[0191] MINC-drugs :

[0192] The MINC-drug is prepared in the same manner as MINC-doxorubicin according to WO2011 / 112156 or WO2015 / 171079. Alternatively, the MINC-drug can be prepared by encapsulating a pharmaceutical agent within micelles formed from PEG-EGCG and OEGCG according to the methods in WO2006 / 124000 or WO2009 / 054813.

[0193] Example 1: OEGCG has antibacterial activity against MRSA

[0194] Materials

[0195] OEGCG is oligomerized EGCG. OEGCG is prepared according to WO2006 / 124000.

[0196] Methods

[0197] To understand the efficacy of the MINC platform in antibacterial therapy, OEGCG was used to treat methicillin-resistant Staphylococcus aureus (MRSA). OEGCG was prepared at 100 μg / mL. The concentration of the bacterial suspension was approximately 1.0×10 8 CFU / mL to 1.0×10 9 CFU / mL. After adding 0.1 mL of MRSA to 10 mL of the tested OEGCG and control sterile saline, the incubation procedure was performed in accordance with "ASTM E2315-16, Standard Guide for Assessment of Antimicrobial Activity Using a Time-Kill Procedure". Each group was inoculated on the culture medium, and growth was observed and colony counts were recorded. The data are expressed as the decline rate = 100×(1 - 10 LR ); LR = Log(control) – Log(OEGCG).

[0198] Results

[0199] Figure 3 It is shown that OEGCG reduces the colony formation of methicillin-resistant Staphylococcus aureus (MRSA), demonstrating its efficacy in inhibiting the growth of MRSA. Staphylococcus belongs to Gram-positive bacteria, and the results prove the efficacy in treating this group of bacteria.

[0200] Example 2: OEGCG has antibacterial activity against Pseudomonas aeruginosa

[0201] Materials

[0202] Methods

[0203] To understand the efficacy of the MINC platform in antimicrobial therapy, OEGCG was used to treat Pseudomonas aeruginosa. OEGCG was prepared at 100 μg / mL. The concentration of the bacterial suspension was approximately 1.0×10 8 CFU / mL to 1.0×10 9 CFU / mL. After adding 0.1 mL of Pseudomonas aeruginosa to 10 mL of the tested OEGCG and control sterile saline, the incubation procedure was carried out according to "ASTM E2315-16, Standard Guide for Assessment of Antimicrobial Activity Using a Time-Kill Procedure". Each group was inoculated on the medium, and the growth was observed and the colony counts were recorded. The data was expressed as the decline rate = 100×(1 - 10LR); LR = Log(control) – Log(OEGCG).

[0204] Results

[0205] Figure 4 It was shown that OEGCG reduced the colony formation of Pseudomonas aeruginosa, indicating its efficacy in inhibiting the growth of Pseudomonas aeruginosa. Pseudomonas belongs to Gram-negative bacteria, and the results demonstrated the efficacy in treating this group of bacteria.

[0206] Example 3: OEGCG and PEG-EGCG inhibit SARS-CoV-2 infection

[0207] Materials

[0208] The human coronavirus (nCoV-Luc-D614G), as a substitute for SARS-CoV-2, was obtained from the siRNA Center of the Chinese Academy of Sciences.

[0209] HEK293T-hACE2 cells were generated by transducing VSV-G pseudotyped lentivirus carrying the human ACE2 gene in HEK-293T / 17( CRL-11268TM).

[0210] Methods

[0211] HEK293T-hACE2 cells were seeded in 96-well plates at 1×10 4 cells / well using a Beckman Biomek i5 liquid handling system. On day 1: The cells were seeded and incubated in 5% CO 2Incubate for 16 to 18 hours in an incubator. The next day, add 100 μL of serially diluted OEGCG or PEG-EGCG to 4,000 TU of SARS-CoV-2 pseudovirus in 100 μL of medium. Incubate OEGCG and PEG-EGCG with the virus at 37 °C for 1 hour each. After incubation, take 50 μL of the mixture and add it to 50 μL of pre-seeded HEK293T-hACE2 cells, and incubate at 37 °C for 24 hours. After 24 hours, take out 80 μL of the medium, and add 50 μL of the medium (DMEM containing 10% FBS) to a 96-well plate. At 72 hours post-infection, add 50 μL of Bright-Glo-luciferase reagent to each well and mix well using a Beckman liquid handling system (Beckman program: white plate ace2 – day 5 - luciferase - 3 or 6 plates - deep well - SPL). Detect the relative light units (RLU) using a microplate reader Tecan Infinite F500 (program: Luminescence Nunc White96_100ms)

[0212] Results

[0213] The anti-SARS-CoV-2 potency of OEGCG was shown as ID50 value and ID90 value being 13.5 nM and 24.6 nM respectively( Figure 5 A). Measure the anti-SARS-CoV-2 activity of PEG-EGCG at concentrations of 5 μM and 20 μM, showing 18.4% and 28.3% inhibition( Figure 5 B). The results demonstrated that both OEGCG and PEG-EGCG have antiviral activity against SARS-CoV-2. [No, I don't agree with this conclusion]

[0214] Example 4: OEGCG inhibits enterovirus infection

[0215] Materials

[0216] Rhabdomyosarcoma (RD) cells were obtained from ATCC CCL-136TM

[0217] Methods

[0218] Evaluate the antiviral activity of OEGCG against EV71. Seed RD cells at 2×10 4Cells were seeded at a density of [X] cells / well in a 96-well plate and incubated at 37 °C for 16 to 18 hours. For virus infection, different concentrations of OEGCG were co-incubated with EV-D68 virus at a multiplicity of infection (MOI) of 0.1 in a 96-well plate containing RD cells at 33 °C or 37 °C for 1 hour. At 48 hours post-infection, cell viability was examined using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay (Sigma-Aldrich, USA). Absorbance (O.D.) was read at 570 nm using a microplate reader. The antiviral activity (%) was calculated as [(O.D. value of the sample treated with OEGCG) - (O.D. value of virus only)] / (O.D. value of virus only) × 100%

[0219] Results

[0220] The results demonstrated that OEGCG treatment inhibited EV-D68 infection ( Figure 6 ). The antiviral activity of OEGCG showed a dose-dependent increase, with corresponding percentages of 8.3%, 29.2%, and 53.1% at 50 μM, 75 μM, and 100 μM, respectively.

[0221] Examples 5 to 6 show different flavonoid oligomers and polymer-flavonoid conjugates formed by MINC-drugs

[0222] Example 5: Methods for preparing MINC-anti-HER2 using different flavonoids in flavonoid oligomers and polymer-flavonoid conjugates Materials

[0223] Methods

[0224] Anti-HER2 is trastuzumab obtained from Eirgenix.

[0225] Figure 7

[0226] MINC anti-HER2 nanoparticles were prepared according to WO2009 / 054813. Briefly, anti-HER2 was incubated in PBS. Subsequently, different flavonoid oligomers including OEGCG or OECG were added to anti-HER2, followed by the addition of different polymer-flavonoids including PEG-EGCG, PEG-ECG, or PEG-EC. After incubating the mixture at room temperature, unreacted oligomer flavonoids and polymer-flavonoids were removed using a 10K MWCO centrifugal filter. Nanoparticle size was measured using DLS (Anton Paar Litesizer500), and the results are shown in Results as follows.

[0227] Figure 7

[0228] Figure 7It was shown that different polymer-flavonoid conjugates and different flavonoid oligomers were all successfully used to generate MINC-anti-HER2 micelles with a particle size of approximately 100 nm. The results demonstrated that homogeneous nanoparticles (micelles) with an expected size of approximately 100 nm were formed, which were different from unencapsulated anti-HER (approximately 5 nm to 10 nm).

[0229] In this example, the different flavonoid oligomers used were OEGCG( Figure 7 A, Figure 7 C, and Figure 7 D) and OECG( Figure 7 B); the different polymer-flavonoids used were PEG-EGCG( Figure 7 A and Figure 7 B), PEG-EC( Figure 7 C), and PEG-ECG( Figure 7 D).

[0230] These data supported that MINC nanoparticles could be formed from different flavonoid oligomers and different polymer-flavonoid conjugates.

[0231] Example 6: Methods for preparing MINC-BSA using different polymers and different polymer-flavonoid conjugates 。

[0232] Materials

[0233] BSA was purchased from Sigma-Aldrich.

[0234] Methods

[0235] MINC (multi-target immune nanocarrier combination)-BSA nanoparticles were prepared according to WO2009 / 054813. Briefly, BSA was incubated in PBS. Subsequently, OEGCG or OECG was added to BSA, and then different polymer-flavonoids, including PEG-EGCG, HA-EGCG, and dextran-EGCG, were added. After incubating the mixture at room temperature, unreacted OEGCG and polymer-flavonoids were removed using a 10K MWCO centrifugal filter. Nanoparticle size was measured using DLS (Anton Paar Litesizer 500).

[0236] Results

[0237] Figure 8 It was demonstrated that different polymers in the polymer-flavonoid conjugates could be used to successfully generate MINC-BSA. The results showed that homogeneous nanoparticles (micelles) were successfully formed, and no small peak of unencapsulated BSA (approximately 5 nm to 10 nm) was observed. These different polymers were PEG( Figure 8 A), HA(Figure 8 B) and dextran Figure 8 C). Collectively, these data support that MINC nanoparticles can be formed from different polymer-flavonoid conjugates.

[0238] Examples 7 to 13 show the successful formulation of MINC-IFN-α, MINC-IFN-γ, MINC-IL-12, MINC-IL-2, MINC-IL-6, MINC-IL-15, and MINC-IL-21.

[0239] OEGCG and PEG-EGCG used in Examples 8 to 13 were prepared by the same protocol as described in Example 7.

[0240] Example 7. MINC-IFNα formulation

[0241] Materials

[0242] IFN-α was purchased from PharmaEssentia.

[0243] Methods

[0244] MINC-IFN-α nanoparticles were prepared according to Example 5. The size of MINC-IFN-α nanoparticles was measured using DLS (Malvern Zetasizer Nano ZS).

[0245] Results

[0246] Figure 9 Show the successful formulation of MINC-IFN-α.

[0247] Example 8. MINC-IFN-γ formulation

[0248] Materials

[0249] IFN-γ was purchased from BioLegend.

[0250] Methods

[0251] MINC-IFN-γ nanoparticles were prepared according to Example 5. The size of MINC-anti-IFN-γ nanoparticles was measured using DLS (Anton Paar Litesizer 500).

[0252] Results

[0253] Figure 10 Show the successful formulation of MINC-IFN-γ.

[0254] Example 9. MINC-IL-12 formulation

[0255] Materials

[0256] IL-12 was purchased from BioLegend.

[0257] Methods

[0258] Prepare MINC-IL-12 nanoparticles according to Example 5. Measure the size of MINC-anti-IL-12 nanoparticles using DLS (Anton Paar Litesizer 500).

[0259] Results

[0260] Figure 11 It shows that MINC-IL-12 was successfully formulated.

[0261] Example 10. MINC-IL-2 formulation

[0262] Materials

[0263] IL-2 was purchased from BioLegend.

[0264] Methods

[0265] Prepare MINC-IL-2 nanoparticles according to Example 5. Measure the size of MINC-anti-IL-2 nanoparticles using DLS (Anton Paar Litesizer 500).

[0266] Results

[0267] Figure 12 It shows that MINC-IL-2 was successfully formulated.

[0268] Example 11. MINC-IL-6 formulation

[0269] Materials

[0270] IL-6 was purchased from BioLegend.

[0271] Methods

[0272] Prepare MINC-IL-6 nanoparticles according to Example 5. Measure the size of MINC-anti-IL-6 nanoparticles using DLS (Anton Paar Litesizer 500).

[0273] Results

[0274] Figure 13 It is shown that MINC-IL-6 was successfully formulated.

[0275] Example 12. MINC-IL-15 formulation

[0276] Materials

[0277] IL-15 was purchased from BioLegend.

[0278] Methods

[0279] MINC-IL-15 nanoparticles were prepared according to Example 5. The size of MINC-anti-IL-15 nanoparticles was measured using DLS (Anton Paar Litesizer 500).

[0280] Results

[0281] Figure 14 It is shown that MINC-IL-15 was successfully formulated.

[0282] Example 13. MINC-IL-21 formulation

[0283] Materials

[0284] IL-21 was purchased from BioLegend.

[0285] Methods

[0286] MINC-IL-21 nanoparticles were prepared according to Example 5. The size of MINC-anti-IL-21 nanoparticles was measured using DLS (Anton Paar Litesizer 500).

[0287] Results

[0288] Figure 15 It is shown that MINC-IL-21 was successfully formulated.

[0289] Example 14. MINC-IFN-α inhibits SARS-CoV-2 replication (predictive example)

[0290] Materials

[0291] Vero E6 cells (American Type Culture Collection, Manassas, VA) were used.

[0292] SARS-CoV-2 (WH strain or BA.1) was used.

[0293] Methods

[0294] The antiviral activity of MINC-IFN-α was evaluated using the cytopathic effect endpoint assay. Briefly, 100 μL of serially 10-fold diluted MINC-IFNα or IFNα was incubated with 100 μL of Vero E6 cells to obtain a final cell count of 20,000 cells / well in a 96-well plate. The cells were incubated overnight at 37 °C and 5% CO 2 2. The plates were incubated for 3 days at 37 °C and 5% CO

[0295] Results

[0296] 2, and the cytopathic effect (CPE) was observed daily. The endpoint was the drug dilution that inhibited CPE by 100% in four parallel wells.

[0297] Example 15: MINC-IFN-α inhibits MRSA proliferation (predictive example)

[0298] Materials

[0299] In this study, MINC-IFN-α prevented Vero cell death (CPE) caused by SARS-CoV-2 infection. We expect that at the same IFN-α concentration, MINC-IFN-α will have a lower IC50 (50% inhibitory concentration) than IFN-α alone.

[0300] Methods

[0301] For the MRSA killing assay, 4 × 10 5 neutrophils were placed in RPMI medium with PBS, MINC-IFN-α or IFN-α (100 ng / ml) and incubated, followed by the addition of 50 μl of MRSA (1:1800 dilution, optical density (OD 600 ) = 0.25 at 600 nm) pre-incubated in 10% autologous serum. At the desired time point, saponin (22 μl of 1% solution, final concentration 0.1%) was added to each well or tube, the contents were mixed, and then the plate or tube was incubated on ice for 15 minutes. Subsequently, the MRSA was plated on LB agar through a 25-gauge blunt needle (to disperse cell clumps). The surviving bacteria were counted the next day. The percentage of survival was calculated by comparing the number of surviving bacteria at t with the number of surviving bacteria at t = 0, using the formula: (CFU+ at t / CFU- at t0) × 100.

[0302] Results

[0303] MINC-IFN-α promotes the phagocytic activity of neutrophils in clearing MRSA. Compared with the vehicle control (saline), MINC-IFN-α treatment is expected to reduce the number of MRSA colony formations. We expect that at the same IFN-α concentration, MINC-IFN-α reduces the number of colonies to a greater extent than IFN-α alone.

[0304] List of abbreviations

[0305] 2APro 2A protease

[0306] 2CATPase 2C-like ATPase

[0307] 3CLpro 3-chymotrypsin-like protease

[0308] 3Cpro 3C protease

[0309] 3Dpol poliovirus RNA-dependent RNA polymerase

[0310] AAK-1 AP2-associated protein kinase 1

[0311] ABC ATP-binding cassette

[0312] Akt protein kinase B (PKB)

[0313] ALB albumin

[0314] ATM ataxia-telangiectasia mutated

[0315] CASP8 caspase 8

[0316] CBS cystathionine β-synthase

[0317] CD147 cluster of differentiation 147

[0318] CD38 cluster of differentiation 38

[0319] CD4 cluster of differentiation 4

[0320] CD81 cluster of differentiation 81

[0321] CGRP calcitonin gene-related peptide

[0322] CLDN1 claudin-1

[0323] c-Met hepatocyte growth factor receptor

[0324] CPSF30 cleavage and polyadenylation specificity factor subunit 30

[0325] CpxTRA impaired outer membrane protein transporter

[0326] crk proto-oncogene C-crk

[0327] crkL proto-oncogene C-crk-like

[0328] CXCL8 C-X-C motif chemokine ligand 8

[0329] DacC D-alanyl-D-alanine carboxypeptidase

[0330] DGAT-1 diacylglycerol O-acyltransferase 1

[0331] DNABII DNA-binding protein from starved cells

[0332] DprE1 decaprenylphosphoryl-β-D-ribose 2-epimerase 1

[0333] EGF epidermal growth factor

[0334] EGFR epidermal growth factor receptor

[0335] eIF4G1 eukaryotic translation initiation factor 4 gamma 1

[0336] EphA2 ephrin type-A receptor 2

[0337] ESR-1 estrogen receptor 1

[0338] EthR ethionamide resistance protein

[0339] F13L vaccinia virus protein F13L

[0340] FAD flavin adenine dinucleotide

[0341] FGFR fibroblast growth factor receptor

[0342] FtsL cell division protein FtsL

[0343] FtsZ cell division protein FtsZ

[0344] Gas8 growth arrest-specific 8

[0345] GSK3B glycogen synthase kinase 3 beta

[0346] hGBP1 human guanylate-binding protein 1

[0347] HIF-1alpha hypoxia-inducible factor 1 alpha

[0348] HMGB1 high-mobility group box 1 protein

[0349] HMP high-molecular weight penicillin-binding protein

[0350] HP haptoglobin

[0351] hPAF1C human PAF1 complex

[0352] Hpr histidine-containing phosphocarrier protein

[0353] HslU ATP-dependent protease HslU

[0354] HSP60 heat shock protein 60

[0355] HSP90 heat shock protein 90

[0356] IcM immunoglobulin mu chain

[0357] IFN-alpha interferon alpha

[0358] IGF-1R insulin-like growth factor 1 receptor

[0359] IKK I-kappa-B kinase

[0360] IL-1 interleukin-1

[0361] importin karyopherin alpha

[0362] InhA enoyl-[acyl-carrier protein] reductase [NADH]

[0363] JAK Janus kinase

[0364] Kit tyrosine-protein kinase KIT

[0365] Kup1 copper transporter Kup

[0366] LepB leptospiral outer membrane protein B

[0367] Les lactate efflux system protein

[0368] Leu leucine

[0369] LptD lipopolysaccharide transporter D

[0370] LpxD UDP-3-O-[3-hydroxymyristoyl] glucosamine N-acyltransferase

[0371] Lsp signal peptidase II

[0372] Lvh leptospiral virulence factor Lvh

[0373] LVLQTM uncharacterized protein LVLQTM

[0374] MAPEG Microsomal glutathione S-transferase

[0375] MAPK Mitogen-activated protein kinase

[0376] MEDI3902 Monoclonal antibody MEDI3902

[0377] MenG 1,4-Dihydroxy-2-naphthoic acid octaisoprenyltransferase

[0378] MFS Major facilitator superfamily

[0379] Mip Macrophage infectivity potentiator

[0380] MIP-2 Macrophage inflammatory protein-2

[0381] MMP Matrix metalloproteinase

[0382] MmpL3 Mycobacterial membrane large protein 3

[0383] MOMP Major outer membrane protein

[0384] MrdA Multidrug resistance and pH adaptation protein A

[0385] MSG Major surface glycoprotein

[0386] mTOR Mechanistic target of rapamycin

[0387] MurE UDP-N-acetylmuramoyl-L-alanine-D-glutamate ligase

[0388] Murl Muramoyl pentapeptide synthetase

[0389] MviN Lipid II flippase

[0390] NaCT Sodium-coupled citrate transporter

[0391] NarX Nitrate / nitrite response regulator NarX

[0392] NDH-2 NADH-quinone oxidoreductase subunit 2

[0393] NGF Nerve growth factor

[0394] NOLC1 Nucleolar and coiled-body phosphoprotein 1

[0395] NPC1L1 Niemann-Pick C1-like protein 1

[0396] NRAMP Natural resistance-associated macrophage protein

[0397] NS1 Nonstructural protein 1

[0398] Nsp12 RNA-dependent RNA polymerase

[0399] NXF1 Nuclear RNA export factor 1

[0400] OATP Organic anion transporting polypeptide

[0401] OGT O-linked N-acetylglucosamine transferase

[0402] OPK O-polysaccharide kinase

[0403] OprF Pseudomonas outer membrane porin F

[0404] OPT Oligopeptide transporter

[0405] OSBP Oxysterol-binding protein

[0406] p15 Cyclin-dependent kinase inhibitor 2B

[0407] p53 Tumor protein p53

[0408] p85 Phosphatidylinositol 3-kinase regulatory subunit alpha

[0409] PA63 Protective antigen

[0410] PABII Poly(A)-binding protein 2

[0411] PABP1 Poly(A)-binding protein 1

[0412] PACT Protein activator of interferon-induced protein kinase EIF2AK2

[0413] PARP Poly(ADP-ribose) polymerase

[0414] PARP10 Poly(ADP-ribose) polymerase family member 10

[0415] PBP Penicillin-binding protein

[0416] PcrV Pseudomonas aeruginosa type III secretion needle tip protein

[0417] PD1 Programmed cell death protein 1

[0418] PDGFR Platelet-derived growth factor receptor

[0419] PD-L1 Programmed death ligand 1

[0420] PDZ PSD-95 / discs large / ZO-1 homologous domain

[0421] PI3K Phosphatidylinositol 3-kinase

[0422] PI4KB phosphatidylinositol-4-kinase β

[0423] PIB peptidoglycan-associated lipoprotein

[0424] PilEL Pseudomonas aeruginosa type IV pilin-related protein

[0425] PilW Pseudomonas aeruginosa type IV pilus assembly protein

[0426] PKR protein kinase R

[0427] PMT peptide N-glycosidase and O-glycosidase

[0428] PPP protein phosphatase

[0429] PTPRC protein tyrosine phosphatase receptor type C

[0430] PTS phosphotransferase system

[0431] QcrB hydroquinone oxidase subunit B

[0432] Raf rapidly accelerated fibrosarcoma kinase

[0433] RAP55 RNA-binding protein 55

[0434] Ras rat sarcoma protein

[0435] RdRp RNA-dependent RNA polymerase

[0436] RdRP RNA-dependent RNA polymerase

[0437] Ret rearranged during transfection protein

[0438] RIG-1 retinoic acid-inducible gene I

[0439] RIL receptor-interacting protein-like

[0440] RNR ribonucleotide reductase

[0441] RpoH RNA polymerase σ-32 subunit

[0442] SCD stearoyl-CoA desaturase

[0443] SP40 simian virus 40

[0444] SP45 simian parvovirus 45

[0445] SP55 simian parvovirus 55

[0446] Simian parvovirus 81

[0447] Scavenger receptor class B type 1

[0448] Scavenger receptor class B type l

[0449] Succinic semialdehyde dehydrogenase

[0450] Stimulator of interferon genes

[0451] TNF-α converting enzyme

[0452] Transferrin receptor 1

[0453] Transforming growth factor-β

[0454] Trigger factor

[0455] Toll-like receptor

[0456] Toll-like receptor 9

[0457] Thymidine monophosphate kinase

[0458] Transmembrane protease, serine 2

[0459] Tumor necrosis factor α

[0460] Outer membrane protein TolB

[0461] 2-[(Aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide

[0462] Tripartite motif-containing protein 25

[0463] TATA-binding protein-associated factor

[0464] Uridine diphosphate

[0465] Ubiquitin-fold modifier 1

[0466] Vascular adhesion domain

[0467] Very low density lipoprotein

[0468] Viral protein 37

[0469] It should be understood that the foregoing describes preferred embodiments of the present invention and that modifications thereof can be made without departing from the scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as inventive, this specification concludes with the following claims.

Claims

1. A method for treating a bacterial or viral infection, the method comprising the step of administering to a subject in need thereof an effective amount of micelles, the micelles having an outer shell comprising one or more polymer-flavonoid conjugates, optionally having an inner shell comprising one or more flavonoid oligomers, and a drug encapsulated within the shell; wherein the polymer is a hydrophilic polymer having a molecular weight of 1,000 daltons to 100,000 daltons and is selected from the group consisting of poly(ethylene glycol) (PEG), hyaluronic acid, dextran, polyethyleneimine, poloxamer, polyvinylpyrrolidone, D-α-tocopherol, and polyethylene glycol succinate; the flavonoid is EGCG, EC, EGC, or ECG, as shown in the following structures: the flavonoid oligomer comprises 2 to 20 flavonoids of EGCG, EC, EGC, or ECG; the infection is caused by a bacterium or virus selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), enterovirus, HIV, hepatitis B virus, MERS-CoV, influenza virus, dengue virus, respiratory syncytial virus, hepatitis C virus, monkeypox virus, human papillomavirus, methicillin-resistant Staphylococcus aureus, Pseudomonas, Bacillus anthracis, Clostridium tetani, Streptococcus pneumoniae, Neisseria meningitidis, Escherichia coli, Legionella, Neisseria gonorrhoeae, Neisseria meningitidis, and Salmonella.

2. The method according to claim 1, wherein the micelles have an outer shell comprising PEG-EGCG and an inner shell comprising an EGCG oligomer.

3. The method according to claim 1 or 2, wherein the infection is caused by severe acute respiratory syndrome coronavirus 2, and the drug is IFN-α, IFN-β, IL-6, IL-12, IL-21, anti-IL-6, anti-IL-6R, spike protein vaccine, RBD vaccine, ACE2 antagonist, anti-TMPRSS2, anti-CD147, anti-VEGFA, anti-GM-CSF, dexamethasone, chloroquine, Nsp12-RdRp inhibitor, hydroxychloroquine, anti-3CLpro, interferon-α, AAK-1 inhibitor, or JAK inhibitor.

4. The method according to claim 1 or 2, wherein the infection is caused by an enterovirus, and the drug is IFN-α, IFN-β, capsid binder, 3Cpro inhibitor, 3Dpol inhibitor, 2CATPase inhibitor, 2APro inhibitor, anti-HSP90, anti-PI4KB, anti-OSBP, anti-RdRP, SP40, SP45, SP55, SP81, LVLQTM, VAD, or AAPV.

5. The method according to claim 1 or 2, wherein the infection is caused by HIV, and the drug is IFN-α, anti-tetanus immunoglobulin, tetanus toxoid, benzodiazepine drugs, magnesium sulfate, intrathecal baclofen, dantrolene, ketamine, propofol, botulinum toxin, human anti-tetanus immunoglobulin or tetanus toxoid vaccine.

6. The method according to claim 1 or 2, wherein the infection is caused by hepatitis B virus, and the drug is IFN-α, IFN-γ, IL-12, IL-6, IL-21, DNA polymerase reverse transcriptase activity inhibitor, pre-S1 peptide, CRISPR / Cas9, ZFN, capsid assembly modulator, E-neg and E-pos RNAi, lamivudine, adefovir, entecavir, tenofovir, TLR agonist, STING agonist or cyclophilin inhibitor.

7. The method according to claim 1 or 2, wherein the infection is caused by MERS-CoV, and the drug is IFN-α, IFN-β, IFN-γ, anti-DPP4, PolyIC, anti-ACE2 antagonist, RdRp inhibitor, chlorpromazine hydrochloride, chloroquine, peptide, endosomal protease inhibitor, TMPRSS2 inhibitor, furin protease inhibitor, anti-clathrin endocytosis, MERS-CoV SDNA or RBD subunit vaccine.

8. The method according to claim 1 or 2, wherein the infection is caused by influenza virus, and the drug is IFN-α, IFN-β, IFN-γ, IL-12, IL-6, IL-15, IL-21, neuraminidase inhibitor, cap-dependent endonuclease inhibitor, M2 ion channel blocker, nucleoprotein inhibitor, anti-NS1-1, anti-CPSF30, anti-PABII, anti-eIF4G1, anti-PABP1, anti-p85, anti-PKR, anti-PACT, anti-NXF1, anti-p15, anti-importin, anti-crk, anti-crkL, anti-RIG-1, anti-nucleolin, anti-TRIM25, anti-Gas8, anti-Akt, anti-p53, anti-PARP10, anti-RIL, anti-Hsp90, anti-PDZ, anti-NOLC1, anti-RAP55, anti-IKK, anti-hPAF1C or anti-hGBPl.

9. The method according to claim 1 or 2, wherein the infection is caused by dengue virus, and the drug is anti-TNF-α, anti-IL-6, anti-RANTES, chloroquine, prednisolone, NS5 nucleoside inhibitor, ER-related α, glucosidase inhibitor, lovastatin, capsid inhibitor, envelope inhibitor, anti-NS4B, anti-NS2B / 3, anti-NS1 or NS1 vaccine.

10. The method according to claim 1 or 2, wherein the infection is caused by respiratory syncytial virus, and the drug is IL-15, anti-TNF-α, benzimidazole derivative, disulfonated stilbene, imidazoisoindolinone derivative, triphenol compound, anti-envelope glycoprotein, sulfated sialic acid lipid, anti-NS1, anti-F glycoprotein, siRNA inhibiting P protein, NS1 protein or N protein gene.

11. The method according to claim 1 or 2, wherein the infection is caused by SARS-CoV, and the drug is IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, anti-VEGFA, anti-GM-CSF, spike protein vaccine, RBD vaccine, ACE2 antagonist, anti-TMPRSS2, anti-CD147, dexamethasone, chloroquine, Nsp12-RdRp inhibitor, hydroxychloroquine, anti-3CLpro, interferon-α, AAK-1 inhibitor, JAK inhibitor, anti-ATM, anti-SIRT1, anti-GSK3B or anti-Torin-2.

12. The method according to claim 1 or 2, wherein the infection is caused by hepatitis C virus, and the drug is IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, anti-EGFR, anti-NS2, anti-NS3, anti-NS4A, anti-NS5A, anti-NS5B, anti-helicase, anti-TLR-9, anti-HCV E2, anti-E1, anti-E2, anti-p7, anti-CD81, anti-SRB1, anti-CLDN1, anti-EphA2, anti-TfR1, anti-NPCIL1, cyclosporin A, anti-α-glucosidase, anti-DGAT-1, anti-VLDL, anti-CD81, anti-CLDN1 or anti-SR-Bl.

13. The method according to claim 1 or 2, wherein the infection is caused by monkeypox virus, and the drug is IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, rosmarinic acid, myricitrin, quercitrin, ofloxacin, anti-VP37, anti-F13L, anti-E9L, anti-A24R, anti-A48R, anti-H5R, anti-B1R, anti-F10L, anti-E8L, anti-A6R, anti-SPGF, anti-B8R, anti-A50R, anti-I7L, anti-D1 3L, anti-Top1 or anti-TMPK.

14. The method according to claim 1 or 2, wherein the infection is caused by human papillomavirus, and the drug is IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, anti-EGFR, anti-c-Met, anti-IGF-1R, anti-PI3K, anti-Akt, anti-mTOR, anti-Ras, anti-Raf, anti-MAPK, anti-VEGF, anti-VEGFR, anti-HIF-1α, anti-PD-L1, anti-CD38, anti-PD1, anti-RNR, anti-FGFR, anti-PDGFR, anti-Kit or anti-Ret.

15. The method according to claim 1 or 2, wherein the infection is caused by methicillin-resistant Staphylococcus aureus, and the drug is IFN-α, IFN-γ, IFN-β, IL-13 topoisomerase inhibitor, FtsZ inhibitor, β-lactamase inhibitor, ribosome inhibitor, dihydropteroate synthase inhibitor, dihydropteroate synthase inhibitor, anti-AR301, anti-MEDI4893, anti-514G3 or anti-ARN-100.

16. The method according to claim 1 or 2, wherein the infection is caused by Pseudomonas, and the drug is IFN-α, OprF vaccine, anti-LPS, anti-alginate, anti-PcrV, anti-OPK, anti-DNABII, β-lactamase inhibitor, LptD, LpxD, bacteriolytic agent, iron mimetic, biofilm matrix disruptor, T3SS inhibitor, anti-MEDI3902 or anti-AR101.

17. The method according to claim 1 or 2, wherein the infection is caused by tuberculosis, and the drug is IFN-α, anti-TNF-α, IFN-γ, GM-CSF, TGF-β, anti-VEGF, IL-2, IL-4, IL-7, IL-10, IL-12, IL-15, IL-23, IL-24, IL-37, anti-IL4 prostaglandin E, phosphodiesterase inhibitor, ATP synthase inhibitor, ribosome inhibitor, DprE1 inhibitor, gyrase inhibitor, MmpL3 inhibitor, Leu tRNA synthase inhibitor, Murl inhibitor, InhA inhibitor, NDH-2 inhibitor, QcrB inhibitor, MenG inhibitor, FtsZ inhibitor, EthR inhibitor or LepB inhibitor.

18. The method according to claim 1 or 2, wherein the infection is caused by Bacillus anthracis, and the drug is IFN-α, anti-PA63, enoyl-ACP reductase, ribonucleotide reductase, nucleoside hydrolase, replicative DNA helicase, acetohydroxy acid synthase, NAD synthase, nicotinic acid mononucleotide adenylyltransferase, Lumazine synthase, cytoskeletal protein FtsZ, dihydropteroate synthase or dihydrofolate reductase.

19. The method according to claim 1 or 2, wherein the infection is caused by Clostridium tetani, and the drug is IFN-α, anti-tetanus immunoglobulin, tetanus toxoid, benzodiazepine drugs, magnesium sulfate, intrathecal baclofen, dantrolene, ketamine, propofol, botulinum toxin, human anti-tetanus immunoglobulin or tetanus toxoid vaccine.

20. The method according to claim 1 or 2, wherein the infection is caused by Streptococcus pneumoniae, and the drug is IFN-α, IL-26, HMGB 1, anti-IL-6, anti-TNFα, anti-IL-1β, anti-CXCL8, CD4, IL-4, CD8A, IL-10, anti-PTPRC, JAK inhibitor, anti-manL, anti-cps4L, anti-recU, anti-SP_0645, anti-ezrA, anti-prsA, anti-tarJ, anti-SP_1280, anti-SP_1617, anti-ptsG, anti-DltD, anti-hprK, anti-pepF, anti-coiA, anti-fib, anti-acpS, anti-manA, anti-mvaK2, anti-mtlD, anti-mtlF or TPCA-1.

21. The method according to claim 1 or 2, wherein the infection is caused by Neisseria meningitidis, and the drug is IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, CGRP, anti-PARP, TACE, EGFR, EGF, anti-ATM, ESR-1, anti-CASP8, NGF, anti-sdhA, anti-ribH, anti-ruvA, anti-ruvX, anti-ponA, anti-rr03, anti-fabH, anti-fabZ, anti-metE, anti-recJ, anti-rpsP, anti-plsY, anti-ftsK, anti-dnaE, anti-holB, anti-rsmI, anti-mtf, anti-dnaG, anti-rpoD, anti-pta, anti-rplU, anti-hup, anti-ptsI, anti-rsmG, anti-lgt, anti-greA, anti-seca1, anti-queF, anti-nusG, anti-ackA, anti-dapH, anti-ilvD or anti-dnaC.

22. The method according to claim 1 or 2, wherein the infection is caused by Escherichia coli, and the drug is IFN-α, anti-IL-1β, anti-TNFα, anti-IL-6, anti-bamD, anti-cydX, anti-dnaT, anti-fabA, anti-ftsB, anti-ftsL, anti-ftsQ, anti-hemD, anti-higA, anti-hipB, anti-hold, anti-iraM, anti-lolA, anti-lolB, anti-lptA, anti-lptD, anti-lptE, anti-mreD, anti-mukB, anti-mukE, anti-mukF, anti-pheM, anti-priB, anti-safA, anti-secE, anti-trpL, anti-tusE, anti-wzyE, anti-ycaR, anti-yciS, anti-ydfO, anti-ydhL, anti-ygfZ, anti-yqeL, anti-yrfF or anti-zipA.

23. The method according to claim 1 or 2, wherein the infection is caused by Legionella, and the drug is IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, anti-Hsp60, anti-MOMP, anti-Mip, anti-Les, anti-Lsp, anti-CpxTRA, anti-PilEL, anti-Lvh, anti-IcM, anti-UDP, anti-FtsL, anti-MrdA, anti-RpoH, anti-multidrug resistance protein, anti-amino acid permease, anti-TolB, anti-Kup1, anti-MviN, anti-Tig, anti-MurE, anti-SCD, anti-TTF, anti-UMF1, anti-HMP, anti-HslU, anti-htrB, anti-Kdo, anti-OGT or anti-RpoH.

24. The method according to claim 1 or 2, wherein the infection is caused by Neisseria gonorrhoeae, and the drug is IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, CDP-4-dehydro-6-deoxyglucose reductase, anti-LpxC, anti-SSADH, anti-RNR, anti-DacC, anti-PBP, anti-PIB, anti-dsbA, anti-NarX, anti-Zur, anti-PTS, anti-Hpr, anti-PPP, anti-YgfZ, anti-HP, anti-RimM, anti-BspRI, anti-rluF, anti-FAD, anti-EF-P, anti-dnaN, anti-tilS or anti-RluD.

25. The method according to claim 1 or 2, wherein the infection is caused by Neisseria meningitidis, and the drug is IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, anti-TerC, anti-MscS, anti-OPT, anti-MFS, anti-MscS, anti-NaCT, anti-ABC, anti-TauE / SafE, anti-CBS, anti-NRAMP, anti-OATP, anti-YggX, anti-SstT, anti-PMT, anti-YjgP, anti-yhhQ, anti-TerC, anti-MAPEG, anti-MSG, anti-PilW, anti-PilX, anti-RlpA, anti-Rrf2, anti-IclR or anti-Rim.

26. The method according to claim 1 or 2, wherein the infection is caused by Salmonella, and the drug is IFN-α, anti-IL-1β, anti-TNFα, anti-IL-6, anti-bamD, anti-cydX, anti-dnaT, anti-fabA, anti-ftsB, anti-ftsL, anti-ftsQ, anti-hemD, anti-higA, anti-hipB, anti-holD, anti-iraM, anti-lolA, anti-lolB, anti-lptA, anti-lptD, anti-lptE, anti-mreD, anti-mukB, anti-mukE, anti-mukF, anti-pheM, anti-priB, anti-safA, anti-secE, anti-trpL, anti-tusE, anti-wzyE, anti-ycaR, anti-yciS, anti-ydfO, anti-ydhL, anti-ygfZ, anti-yqeL, anti-yrfF or anti-zipA.

27. A method of treating a bacterial or viral infection, the method comprising the step of administering to a subject in need thereof an effective amount of a polymer-flavonoid conjugate, wherein the polymer is a hydrophilic polymer having a molecular weight of 1,000 to 100,000 daltons and selected from the group consisting of: PEG, hyaluronic acid, dextran, polyethyleneimine, poloxamer, polyvinylpyrrolidone, D-α-tocopherol, and polyethylene glycol succinate; the flavonoid is EGCG, EC, EGC or ECG, as shown in the following structures: and the infection is caused by a DNA virus, an RNA virus, a Gram-positive bacterium or a Gram-negative bacterium.

28. The method according to claim 27, wherein the polymer-flavonoid conjugate is PEG-EGCG.

29. A method of treating a bacterial or viral infection, the method comprising the step of administering to a subject in need thereof an effective amount of a flavonoid oligomer, wherein the flavonoid is EGCG, EC, EGC or ECG, as shown in the following structures: the flavonoid oligomer comprises 4 to 12 flavonoids of EGCG, EC, EGC or ECG; the infection is caused by a DNA virus, an RNA virus, a Gram-positive bacterium or a Gram-negative bacterium.

30. The method according to claim 29, wherein the flavonoid oligomer is an oligomer of EGCG.

31. The method according to any one of claims 27 to 30, wherein the infection is caused by a DNA virus selected from the group consisting of hepatitis B virus, human herpes virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, monkeypox virus and varicella-zoster virus.

32. The method according to any one of claims 27 to 30, wherein the infection is caused by an RNA virus selected from the group consisting of SARS-CoV-2, enterovirus, HIV, MERS-CoV, hepatitis C virus, hepatitis A virus, rotavirus, norovirus, influenza virus, parainfluenza virus, dengue virus, respiratory syncytial virus and SARS-CoV.

33. The method according to any one of claims 27 to 30, wherein the infection is caused by a Gram-positive bacterium selected from the group consisting of methicillin-resistant Staphylococcus aureus, tuberculosis, Bacillus anthracis, Clostridium tetani, Streptococcus pneumoniae, Clostridium botulinum, Clostridium spp., Mycobacterium tuberculosis, Clostridium tetani, Corynebacterium diphtheriae and Mycobacterium leprae.

34. The method according to any one of claims 27 to 30, wherein the infection is caused by a Gram-negative bacterium selected from the group consisting of Pseudomonas spp., Neisseria meningitidis, Leptospira spp., Neisseria gonorrhoeae, Neisseria meningitidis, Yersinia pestis, Treponema pallidum, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Mycobacterium tuberculosis, Legionella spp. and Salmonella spp.

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