Novel retinoic acid compound, pharmaceutical composition including thereof and use thereof

Abstract

This invention provides a compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, wherein the compound comprises retinoic acid conjugated with a carbohydrate. Furthermore, the use of the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the manufacture of medicaments for inhibiting viral infection or replication or for treating cancer is also provided.

Description

Novel Retinoic Acid Compounds, Pharmaceutical Compositions Containing the Same, and Their Uses The present invention relates to a novel retinoic acid compound, a pharmaceutical composition containing the same, and its use in the manufacture of a drug for inhibiting viral infection or replication or for treating cancer. Coronaviruses are a group of positive, single-stranded RNA viruses belonging to the Coronaviridae family, which include seven species / strains that infect humans, namely Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Human Coronavirus 229E (HcoV-229E), Human Coronavirus OC43 (HCoV-OC43), Human Coronavirus NL63 (HCoV-NL63), and Human Coronavirus HKU (HCoV-HKU1). Notably, SARS-CoV-2 has been identified as the virus strain that caused the 2019 coronavirus disease (COVID-19) pandemic. The genomes of SARS-CoV-2 and SARS-CoV have a high degree of sequence identity. Both SARS-CoV-2 and SARS-CoV are highly dependent on the activities of two viral proteases, namely 3C-like protease (3CLpro, also known as main protease (Mpro) or non-structural protein 5 (nsp5)) and papain-like protease (PLpro, which is the protease domain of non-structural protein 3 (nsp3)), to achieve the viral growth cycle and viral transmission. It has been reported that all-trans retinoic acid (ATRA, also known as retinoic acid or tretinoin) can be considered a potential therapeutic agent against SARS-CoV-2 by inhibiting the activity of 3CLpro. In addition to 3CLpro, PLpro is also a potential target as this enzyme plays an essential role in the cleavage and maturation of viral polyproteins, the assembly of the replicase-transcriptase complex, and the disruption of host responses. Although the main function of Mpro and PLpro is to process viral polyproteins in a cooperative manner, PLpro also has additional functions of stripping ubiquitin from host cell proteins and interfering with interferon-stimulatory gene factor 15 (ISG15) to enable coronaviruses to evade the host innate immune response. That is to say, PLpro is not only related to viral replication but also to the dysregulation of the signaling cascade in infected cells, leading to increased cell death in surrounding uninfected cells. Therefore, drugs designed to inhibit the function of PLpro also have the potential to combat SARS-CoV-2. Recently, in addition to ATRA, some researchers reported that its derivative 13-cis retinoic acid (also known as isotretinoin) is a potential PLpro inhibitor and can be used to treat COVID-19 caused by SARS-CoV-2. In addition, retinoic acids (including ATRA and 13-cis retinoic acid) have become promising compounds for the treatment of various cancers due to their specific effects on cell proliferation, differentiation, and apoptosis and low toxicity. Retinoic acid receptors in the human cell nucleus have been found by biochemists and are not mutated in cancer cells, so retinoic acid may exert its anti-cancer effects in many malignancies. For example, it was found that in children with high-risk neuroblastoma, treatment with 13-cis retinoic acid can reduce the risk of cancer recurrence after high-dose chemotherapy and stem cell transplantation. ATRA has been combined with other drugs in the study of various cancers and precancerous lesions. Currently, multiple clinical trials are underway with ATRA as part of combination therapies. For example, ATRA combined with different interferons (IFNs) has been shown to enhance the effects of the two drugs and lead to growth inhibition and cell death of tumor cell lines. Nevertheless, to unleash the therapeutic potential of retinoic acid, many studies have emphasized the need to better understand the mechanisms that block retinoic acid signaling and retinoic acid-regulated gene expression in cancers such as acute myeloid leukemia (AML). Apparently, combination therapies targeting multiple gene silencing mechanisms may be the most effective strategy to reactivate ATRA-sensitive gene expression and AML cell differentiation and mediate the general anti-cancer activity of ATRA. Currently, the identification of protein classes that control gene expression via histone and DNA modifications can drive the development of novel therapeutic agents, namely epigenetic drugs that alter chromatin structure. However, these epigenetic modification drugs have been shown to be only partially effective for different cancers when used alone. For the above reasons, the present invention provides a novel retinoic acid compound and a pharmaceutical composition containing the same, which can effectively inhibit virus infection or replication, or treat cancer. In one aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises retinoic acid conjugated with a carbohydrate. Preferably, the compound is represented by formula (I): (I), wherein R 1 is a substituted or unsubstituted functional group of the carbohydrate. Preferably, the carbohydrate is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Preferably, the oligosaccharide is a homo-oligosaccharide or a hetero-oligosaccharide; and the polysaccharide is a homo-polysaccharide or a hetero-polysaccharide. Preferably, the carbohydrate includes glucose, fructose, galactose, mannose, sucrose, lactose, maltose, β-1,3 / 1,6-glucan oligosaccharide, raffinose, stachyose, verbascose, fructooligosaccharide, starch, glycogen, cellulose, or any combination thereof. Preferably, the compound or its pharmaceutically acceptable salt is coated with liposomes. In another aspect of the present invention, there is provided a pharmaceutical composition, which comprises the above-mentioned compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier includes liposomes, and the compound or its pharmaceutically acceptable salt is coated with liposomes. Preferably, the pharmaceutical composition further includes metal ions. Preferably, the metal ions include monovalent ions, divalent ions, or a combination thereof. More preferably, the monovalent ions include K + 、Na + or a combination thereof; and the divalent ions include Zn 2+ 、Mg 2+ 、Cu 2+ 、Mn 2+ 、Ca 2+ 、Fe 2+ or any combination thereof. Preferably, the pharmaceutically acceptable carrier includes liposomes, and the metal ions are coated with liposomes. Preferably, the compound or its pharmaceutically acceptable salt and metal ion are encapsulated by liposomes either alone or simultaneously. In yet another aspect, the present invention provides the use of the compound or its pharmaceutically acceptable salt or the pharmaceutical composition in the manufacture of a drug for inhibiting viral infection or replication. In a further aspect, the present invention provides the use of the compound or its pharmaceutically acceptable salt or the pharmaceutical composition in the manufacture of a drug for treating cancer. Therefore, the present invention provides at least the following advantages: 1. Compared with retinoic acid alone, the compound and its pharmaceutical composition claimed in this case can enhance the ability to inhibit viral infection and / or replication, wherein the compound is a retinoic acid conjugated with a carbohydrate. 2. The compound and its pharmaceutical composition claimed in this case can be used as potential drugs against coronaviruses (especially SARS-CoV-2 that causes COVID-19). 3. The compound and its pharmaceutical composition claimed in this case can also enhance the ability to inhibit cancer cells, thereby effectively treating various cancers, such as lung cancer, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer and liver cancer. Although the present invention is susceptible to various modifications and alternative forms, specific embodiments are shown by way of example in the drawings and are described in detail herein. However, it should be understood that this description is not intended to limit the present invention to the specific embodiments, but on the contrary, the present invention will cover all modifications, equivalents and alternative forms falling within the spirit and scope of the present invention. Definitions Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein. The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the embodiments of the present invention. Unless the context clearly indicates otherwise, the singular forms "a", "an" and "the" used herein are also intended to include the plural forms. It will be further understood that the terms "comprising", "comprises", "including" and / or "includes", when used herein, specify the presence of the stated features, integers, steps, operations, elements, parts and / or combinations thereof, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, parts and / or combinations thereof. As used herein, the term "subject" refers to a mammal in need of diagnosis, prognosis, or treatment. Generally, the mammal is a human. In certain embodiments, the mammal may refer to non-human mammals, such as non-human primates, cows, horses, goats, sheep, dogs, cats, rabbits, pigs, mice, or rats, used for, for example, screening, characterizing, and evaluating drugs and therapies. As used herein, the term "administer" or "administered" means introducing, providing, or delivering a predetermined active ingredient to a subject by any applicable route for its intended function. As used herein, the term "cancer" refers to leukemia, lymphoma, carcinoma, sarcoma, and other malignant tumors that may grow without limitation, which can spread locally by invasion and systemically by metastasis. Examples of cancers include (but are not limited to) ovarian cancer, adrenal cancer, bone cancer, brain cancer, breast cancer, bronchial cancer, colorectal cancer, and / or rectal cancer, gallbladder cancer, head and neck cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, cancer of the nervous tissue, pancreatic cancer, prostate cancer, parathyroid cancer, skin cancer, gastric cancer, and thyroid cancer. Some other examples of cancers include cholangiocarcinoma, acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical epithelial dysplasia and carcinoma in situ, Ewing's sarcoma, epidermoid carcinoma, giant cell tumor, glioblastoma multiforma, hairy cell tumor, small intestinal ganglioneuroma, proliferative corneal neuroma, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, malignant carcinoid, malignant melanoma, malignant hypercalcemia, marfanoid habitus tumor, medullary carcinoma, metastatic skin cancer, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteosarcoma, pheochromocytoma, polycythermia vera, primary brain tumor, small cell lung tumor, ulcerative and papillary squamous cell carcinoma, cell proliferation, seminoma, soft tissue sarcoma, retinoblastoma, rhabdomyosarcoma, renal cell carcinoma, local skin lesions, reticulum cell sarcoma, and Wilm's tumor. As used herein, the term "oligosaccharide" refers to a carbohydrate composed of a small number of monosaccharides, usually about three to ten monosaccharide units. Among them, an oligosaccharide having one type of monosaccharide sub-unit is called a monooligosaccharide; an oligosaccharide having more than one type of monosaccharide sub-unit is called a hetero-oligosaccharide. As used herein, the term "polysaccharide" refers to a carbohydrate composed of a large number of monosaccharide units. Among them, a polysaccharide having one monosaccharide sub-unit is called a homopolysaccharide; a polysaccharide having more than one monosaccharide sub-unit is called a heteropolysaccharide. As used herein, the term "liposome" refers to a particle characterized by having an aqueous internal space separated from the external medium by a membrane of one or more bilayers forming vesicles. The main types of liposomes are multilamellar vesicles (MLV, having several lamellar phase lipid bilayers), small unilamellar vesicles (SUV, having a single lipid bilayer), and large unilamellar vesicles (LUV, having a single lipid bilayer). The bilayer membrane of the unilamellar or multilamellar vesicles is typically formed of lipids (i.e., amphiphilic molecules of synthetic or natural origin including spatially separated hydrophobic and hydrophilic domains). Example Descriptions Hereinafter, exemplary embodiments of the present invention will be described in more detail with reference to the accompanying drawings. In one embodiment, there is provided a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound (hereinafter referred to as the "first" pharmaceutical composition), wherein the compound comprises retinoic acid conjugated with a carbohydrate. In an exemplary embodiment, the compound is represented by formula (I): , wherein R 1 is a substituted or unsubstituted functional group of the carbohydrate. In certain embodiments, the concentration of the compound comprising retinoic acid conjugated with a carbohydrate can be (but is not limited to) 0.1 μM to 10 mM, 0.1 μM to 1 mM, 0.1 μM to 500 μM, 0.1 μM to 250 μM, 0.1 μM to 100 μM, 0.1 μM to 50 μM, 1 μM to 10 mM, 1 μM to 1 mM, 1 μM to 500 μM, 1 μM to 250 μM, 1 μM to 100 μM, 1 μM to 50 μM, 10 μM to 10 mM, 10 μM to 1 mM, 10 μM to 500 μM, 10 μM to 250 μM, 10 μM to 100 μM, or 10 μM to 50 μM. In another embodiment, there is provided a pharmaceutical composition comprising retinoic acid and a carbohydrate (hereinafter referred to as the "second" pharmaceutical composition). In certain embodiments, the retinoic acid is 13-cis retinoic acid (also known as isotretinoin). In certain embodiments, the concentration of retinoic acid can be (but is not limited to) 1 μM to 10 mM, 1 μM to 1 mM, 1 μM to 500 μM, 1 μM to 250 μM, 1 μM to 100 μM, 1 μM to 50 μM, 10 μM to 10 mM, 10 μM to 1 mM, 10 μM to 500 μM, 10 μM to 250 μM, 10 μM to 100 μM, or 10 μM to 50 μM. In certain embodiments, the carbohydrate can be a monosaccharide, disaccharide, oligosaccharide or polysaccharide. The oligosaccharide can be a homo-oligosaccharide or a hetero-oligosaccharide. The polysaccharide can be a homo-polysaccharide or a hetero-polysaccharide. The monosaccharide can be selected from (but not limited to) glucose, fructose, galactose and mannose. The disaccharide can be selected from (but not limited to) sucrose, lactose and maltose. The oligosaccharide can be selected from (but not limited to) β-1,3 / 1,6-glucan oligosaccharide, raffinose, stachyose, verbascose and fructooligosaccharide. The polysaccharide can be selected from (but not limited to) starch, glycogen and cellulose. In certain embodiments, the concentration of the carbohydrate can be (but not limited to) 0.1 μM to 200 mM, 0.1 μM to 150 mM, 0.1 μM to 100 mM, 0.1 μM to 10 mM, 0.1 μM to 1 mM, 0.1 μM to 500 μM, 0.1 μM to 250 μM, 0.1 μM to 100 μM, 0.1 μM to 50 μM, 1 μM to 200 mM, 1 μM to 150 mM, 1 μM to 100 mM, 1 μM to 10 mM, 1 μM to 1 mM, 1 μM to 500 μM, 1 μM to 250 μM, 1 μM to 100 μM, 1 μM to 50 μM, 10 μM to 200 mM, 10 μM to 150 mM, 10 μM to 100 mM, 10 μM to 10 mM, 10 μM to 1 mM, 10 μM to 500 μM, 10 μM to 250 μM, 10 μM to 100 μM or 10 μM to 50 μM. In certain embodiments, the molar ratio of retinoic acid to carbohydrate in the second pharmaceutical composition can be about 1:10 -3 ~100, 1:10 -3 ~20, 1:1~20 or 1:1~10. In certain embodiments, the first pharmaceutical composition and the second pharmaceutical composition can each optionally further comprise a metal ion. Preferably, the metal ion comprises a monovalent ion, a divalent ion or a combination thereof. In certain embodiments, the monovalent ion comprises K + 、Na + or a combination thereof; and the divalent ion comprises Zn 2+ 、Mg 2+ 、Cu 2+ 、Mn 2+ 、Ca 2+ 、Fe 2+ or any combination thereof. In certain embodiments, the concentration of the metal ion can be from 1 μM to 300 mM, from 1 μM to 250 mM, from 1 μM to 200 mM, from 1 μM to 150 mM, from 1 μM to 100 mM, from 1 μM to 10 mM, from 1 μM to 1 mM, from 1 μM to 500 μM, from 1 μM to 250 μM, from 1 μM to 100 μM, from 1 μM to 50 μM, from 10 μM to 300 mM, from 10 μM to 250 mM, from 10 μM to 200 mM, from 10 μM to 150 mM, from 10 μM to 100 mM, from 10 μM to 10 mM, from 10 μM to 1 mM, from 10 μM to 500 μM, from 10 μM to 250 μM, from 10 μM to 100 μM, or from 10 μM to 50 μM. In certain embodiments, the molar ratio of the compound to the metal ion in the first pharmaceutical composition can be about 1:10 -3 ~10 3 , 1:0.1~20, 1:0.1~10, or 1:1~10. In certain embodiments, the molar ratio of retinoic acid, carbohydrate, and metal ion in the second pharmaceutical composition can be about 1:10 -4 ~20:10 -4 ~10 3 , 1:10 -4 ~20:10 -3 ~10 3 , 1:10 -4 ~20:10 -3 ~20, 1:10 -4 ~20:0.1~20, 1:10 -4 ~20:1~10, 1:0.1~20:10 -4 ~10 3 , 1:0.1~20:10 -3 ~10 3 、1:0.1 to 20:10 -3 ~20, 1:0.1 to 20:0.1 to 20, 1:0.1 to 20:1 to 20, 1:0.1 to 20:1 to 10, 1:0.1 to 1:10 -4 ~10 3 、1:0.1 to 1:10 -3 ~10 3 、1:0.1 to 1:10 -3 ~20, 1:0.1 to 1:0.1 to 20, 1:0.1 to 1:1 to 20 or 1:0.1 to 1:1 to 10. In certain embodiments, the first pharmaceutical composition and the second pharmaceutical composition each optionally further comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is widely used in the field of drug manufacturing. Examples of pharmaceutically acceptable carriers can include (but are not limited to) liposomes, excipients, adjuvants, solvents, buffers, emulsifiers, suspending agents, disintegrants, disintegrating agents, dispersants, binders, stabilizers, chelating agents, diluents, gelling agents, preservatives, wetting agents, lubricants, absorption delaying agents, and the like. The selection and amount of the pharmaceutically acceptable carrier are within the professional knowledge scope of those having ordinary knowledge in the art. In certain embodiments, the pharmaceutically acceptable carrier is a liposome. The compound or its pharmaceutically acceptable salt is encapsulated by the liposome. The compound or its pharmaceutically acceptable salt and metal ions in the first pharmaceutical composition can be encapsulated by the liposome alone or simultaneously. The retinoic acid and carbohydrates in the second pharmaceutical composition can be encapsulated by the liposome alone or simultaneously. All or at least two of the retinoic acid, carbohydrates, and metal ions in the second pharmaceutical composition can be encapsulated by the liposome alone or simultaneously. Exemplary liposomes can be neutral, positively charged, or negatively charged liposomes. Generally, lipids commonly used in liposomes typically include dialiphatic chain lipids, such as phospholipids, diglycerides, and dialiphatic glycolipids; single lipids, such as sphingomyelin and glycosphingolipid; steroids, such as cholesterol and its derivatives, and combinations thereof. Examples of phospholipids include (but are not limited to) phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylcholine (PC), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine (PSPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), hydrogenated soy phosphatidylcholine (HSPC), 1,2-dimyristoyl-sn-glycero-3-phosphate-(1'-rac-glycerol)(sodium salt) (DMPG), 1,2-dipalmitoyl-sn-glycero-3-phosphate(1'-rac-glycerol)(sodium salt) (DPPG), 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphate-(1'-rac-glycerol)(sodium salt) (PSPG), 1,2-distearoyl-sn-glycero-3-phosphate-(1'-rac-glycerol)(sodium salt) (DSPG), 1,2-dioleoyl-sn-glycero-3-phosphate-(1'-rac-glycerol) (DOPG), 1,2-dimyristoyl-sn-glycero-3-phosphate-L-serine (sodium salt) (DMPS), 1,2-dipalmitoyl-sn-glycero-3-phosphate-L-serine (sodium salt) (DPPS), 1,2-distearoyl-sn-glycero-3-phosphate-L-serine (sodium salt) (DSPS), 1,2-dioleoyl-sn-glycero-3-phosphate-L-serine (DOPS), 1,2-dimyristoyl-sn-glycero-3-phosphate (sodium salt) (DMPA), 1,2-dipalmitoyl-sn-glycero-3-phosphate (sodium salt) (DPPA), 1,2-distearoyl-sn-glycero-3-phosphate (sodium salt) (DSPA), 1,2-Dioleoyl-sn-glycero-3-phosphate (sodium salt) (DOPA), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-myo-inositol) (ammonium salt) (DPPI), 1,2-distearoyl-sn-glycero-3-phosphoinositol (ammonium salt) (DSPI), 1,2-dioleoyl-sn-glycero-3-phospho-(1-myo-inositol) (ammonium salt) (DOPI), cardiolipin, L-α-phosphatidylcholine (EPC), 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (18:1 EPC), L-α-phosphatidylethanolamine (EPE), dimethyldioctadecylammonium (DDAB), 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), and 3β-[N-(N',N'-dimethylaminoethane)carbamoyl]cholesterol hydrochloride., The lipid(s) used can be a lipid mixture of one or more of the aforementioned lipids, or a mixture of one or more of the aforementioned lipids with one or more other lipids, membrane stabilizers or antioxidants not listed previously. The molar percentage of the lipid in the bilayer membrane can be equal to or less than about 50, 45, 40, 35, 30, 25, 20, 15, 10, 5 or any value or range between them (e.g., about 5-50%, about 5-45%, about 5-40%, about 5-35%, about 5-30%, about 5-25%, about 5-20%, about 5-15% or about 5-10%). The lipids of the bilayer membrane can be a mixture of a first phospholipid and a second phospholipid. The first phospholipid can be selected from the group consisting essentially of: PC, HSPC, DOPC, POPC, DSPC, DPPC, DMPC, PSPC, and combinations thereof, and the second phospholipid is selected from the group consisting essentially of: PE, PG, DOPE, PEG-DSPE, DPPG, DOPG, DOTAP, DOTMA, DDAB, and combinations thereof. In other embodiments, the molar percentage of the first phospholipid in the bilayer membrane is about 50, 45, 40, 35, 30, 25, 20, 15, 10, or any value or range of values between them (e.g., about 5-50%, about 5-45%, about 5-40%, about 5-35%, about 5-30%, about 5-25%, about 5-20%, about 5-15%, or about 5-10%), and the molar percentage of the second phospholipid in the bilayer membrane is between 0.1 and about 15, 14, 13, 12, 11, 10, 9, 8, 7, or any value or range of values between them (e.g., about 0.1-15%, about 0.1-10%, about 0.5-15%, about 0.5-10%, or about 0.5-7%). In an exemplary embodiment, the molar ratio of the first phospholipid (DSPC) to the second phospholipid (DOPE, DOPG, or DDAB) can be from 4:1 to 6:1. In an exemplary embodiment, the bilayer membrane of the liposome comprises less than about 55 molar percentage of sterol, preferably cholesterol. The molar percentage of sterol (such as cholesterol) in the bilayer membrane can be about 15-55%, about 20-55%, about 25-55%, about 15-50%, about 20-50%, about 25-50%, about 15-45%, about 20-45%, about 25-45%, about 15-40%, about 20-40%, or about 25-40%. The molar percentage of phospholipid and cholesterol in the bilayer membrane can be about 25-50%, 15-55%, 25-50%, 20-55%, or 25-50%, 15-50%. The molar ratio of phospholipid to cholesterol can be from 1:1 to 3:1. The molar percentage of the first phospholipid, the second phospholipid, and cholesterol in the bilayer membrane can be about 25-50%, 0.1-15%, 15-55%, 5-50%, 0.1-15%, 10-40%, or 25-50%, 0.5-10%, 5-20%. Liposomes encapsulating the capture agent can be prepared by any technique known currently or developed subsequently. For example, MLV liposomes can be formed directly by hydrating a lipid film, spray-dried powder, or lyophilized cake of the selected lipid composition with the capture agent; SUV liposomes and LUV liposomes can be sized from MLV liposomes by sonication, homogenization, microfluidization, or extrusion. In yet another embodiment, the compound comprising retinoic acid conjugated to a carbohydrate or a pharmaceutically acceptable salt thereof, and the first pharmaceutical composition and the second pharmaceutical composition can be used to inhibit viral infection or replication. The virus can be an RNA virus. The RNA virus can include a coronavirus, human immunodeficiency virus (HIV), hepatitis C virus (HCV), influenza virus, or any combination thereof. The coronavirus can include severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus 229E (HcoV-229E), human coronavirus OC43 (HCoV-OC43), human coronavirus NL63 (HCoV-NL63), human coronavirus HKU (HCoV-HKU1), or any combination thereof. In an exemplary embodiment, the coronavirus is SARS-CoV-2 that causes COVID-19. In yet a further embodiment, the compound comprising retinoic acid conjugated to a carbohydrate, a pharmaceutically acceptable salt thereof, and the first pharmaceutical composition and the second pharmaceutical composition can be used to treat cancer. The cancer can include leukemia, lymphoma, carcinoma, or sarcoma. In an exemplary embodiment, the cancer can be lung cancer, ovarian cancer, breast cancer, liver cancer, pancreatic cancer, or cholangiocarcinoma. In certain embodiments, the compound and the metal ion in the first pharmaceutical composition can be administered separately, simultaneously, or sequentially. The retinoic acid and the carbohydrate in the second pharmaceutical composition can be administered separately, simultaneously, or sequentially. All or at least two of the retinoic acid, the carbohydrate, and the metal ion in the second pharmaceutical composition can be administered separately, simultaneously, or sequentially. In an exemplary embodiment, the metal ion and the carbohydrate are administered simultaneously, followed by the administration of retinoic acid. In an exemplary embodiment, the time interval between sequential administrations can be 1 to 30 minutes, 30 to 60 minutes, 60 to 90 minutes, 90 to 120 minutes, 2 to 3 hours, 3 to 12 hours, or 12 to 24 hours. In certain embodiments, the compound comprising retinoic acid conjugated to a carbohydrate, a pharmaceutically acceptable salt thereof, and the first pharmaceutical composition and the second pharmaceutical composition can each be prepared in dimethyl sulfoxide (DMSO), ethanol, buffer, or water for administration. The dosage and frequency of administration can vary depending on the following factors: the severity of the viral infection (e.g., coronavirus infection) or the disease to be treated (e.g., cancer) and the weight, age, physical condition, and response of the individual to be treated. The daily dosage of the above therapeutic agent can be administered as a single dose or multiple doses. In certain embodiments, the compounds comprising retinoic acid conjugated to a carbohydrate, their pharmaceutically acceptable salts, and the first and second pharmaceutical compositions are each administered by an oral, intravenous, intramuscular, subcutaneous, intraperitoneal, intranasal, or topical route. Example The present invention will be further illustrated by the following examples. However, it should be understood that the following examples are for illustrative purposes only and should not be construed as limiting the present invention in its implementation. Materials and Methods A , Prepare a novel retinoic acid compound represented by formula ( Ia ) according to the following synthetic flowchart, namely galactose-modified isotretinoic acid: I. General experimental methods All reagents were commercially available and used without further purification. Yields refer to compounds that were purified and spectroscopically identified as being of high purity. Thin layer chromatography (TLC) was performed using Merck TLC aluminum sheets silica gel 60 F 254 plates and visualized by fluorescence quenching under ultraviolet light. Flash chromatography was carried out using silica gel (Chromatorex, MB 70-40 / 75, 40~75 μm) purchased from Fuji Silysia Chemicals. NMR spectra were recorded on a Varian-400MR, which was operated at 400 MHz for analysis 1 of H. Chemical shifts were reported in ppm and the solvent resonance was used as an internal standard. Data were reported as follows: s = singlet, br = broad peak, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet; coupling constants were in Hz; integration was performed. Purity was recorded on a Waters e2695 separation module / 2998 PDA detector HPLC system (column: XBridge C18, 5 μm, 4.6 mm (ID) x 150 mm (L), eluent: a mixture of mobile phase A and B, mobile phase A: 100% acetonitrile; mobile phase B: pure water containing 0.1% formic acid and 10 mM NH 4 OAc, flow rate: 0.5 mL / min. Detection: UV, 254 nm). II. Compound (2R,3S,4S,5R,6R)-2-( acetoxymethyl )-6-(3- Bromopropoxy ) Tetrahydro -2H- Pyran -3,4,5- Triyl triacetate ( (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(3-bromopropoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate ) ( 2 ) Synthesis of At 0 °C, boron trifluoride-diethyl etherate (8.04 mL, 64.0 mmol) was added to a solution of pentaacetylgalactose (compound ( 1 ), 5.0 g, 13 mmol), 3-bromo-1-propanol (1.73 mL, 19.0 mmol) and freshly dried molecular sieves in anhydrous dichloromethane (50 mL). The resulting mixture was stirred overnight at room temperature. The solution was neutralized with triethylamine, the molecular sieves were removed by passing through diatomaceous earth, and the reaction mixture was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product was purified by silica gel column chromatography (EtOAc:hexane = 1:2) to give the desired product ( 2 ) (0.625 g, 10%), which was a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) : δ 5.40 (dd, J = 3.4, 1.2 Hz, 1H), 5.22 - 5.16 (m, 1H), 5.04 - 5.01 (m, 1H), 4.48 (d, J = 8 Hz, 1H), 4.21 - 4.11 (m, 2H), 4.03 - 3.98 (m, 1H), 3.92 (td, J = 5.8, 0.8 Hz, 1H), 3.72 - 3.66 (m, 1H), 3.50 - 3.47 (m, 2H), 2.25 - 1.99 (m, 14H); LCMS (ESI) m / z calculated for C 17 H 25 BrO 10 469.28; found 491.04 [M + Na] + 。 III. Compound (2R,3S,4S,5R,6R)-2 - ( acetoxymethyl ) - 6 - (3 - azidopropoxy ) tetrahydro - 2H - pyran 3,4,5 - triyl triacetate ( (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(3-azidopropoxy)tetrahydro-2H-pyran 3,4,5-triyl triacetate ) ( 3 ) Synthesis Sodium azide (0.43 g, 6.6 mmol) was added to a solution of compound ( 2 ) (0.62 g, 1.3 mmol) in DMF (4 mL). The resulting mixture was stirred at 100 °C for 2 h. The solution was concentrated to dryness. The crude product was purified by silica gel column chromatography (EtOAc:hexane = 1:2) to afford the desired product ( 3 ) (458 mg, 80%), which was a colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ 5.39 (dd, J = 3.4, 0.8 Hz, 1H), 5.22 - 5.18 (m, 1H), 5.03 - 5.00 (m, 1H), 4.48 (d, J = 8 Hz, 1H), 4.21 - 4.10 (m, 2H), 3.99 - 3.89 (m, 1H), 3.63 - 3.58 (m, 1H), 3.39 - 3.35 (m, 2H), 2.15 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.92 - 1.77 (m, 2H); LCMS (ESI) m / z calculated for C 17 H 25 N 3 O 10 431.40; found 454.2 [M + Na] + 。 IV. Compound ( (2R,3R,4S,5R,6R)-2-(3- azidopropoxy )-6-( hydroxymethyl ) tetrahydro -2H- pyran -3,4,5- triol ( (2R,3R,4S,5R,6R)-2-(3-azidopropoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol ) ( 4 ) Synthesis Sodium methoxide (28 mg, 0.5 mmol) was added to a solution containing compound ( 3 ) in a solution of dichloromethane (1.0 mL) and methanol (4.0 mL) of (0.45 g, 1 mmol). The resulting mixture was stirred at room temperature for 10 h. The solution was neutralized with Dowex 50WX8 and evaporated to dryness to obtain the desired product ( 4), which was used in the next step without further purification. LCMS (ESI) m / z calculated for C 9 H 17 N 3 O 6 263.25; found 286.1 [M + Na] + . V. Compound ( (2R,3R,4S,5R,6R)-2-(3- aminopropoxy )-6-( hydroxymethyl ) tetrahydro -2H- pyran -3,4,5- triol ( (2R,3R,4S,5R,6R)-2-(3-aminopropoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol ) ( 5 ) Synthesis The crude compound ( 2 4 ) in methanol (10.5 mL) was treated with Pd / C (11 mg) and acetic acid (6.3 mg) under H environment. The solution was filtered through a Celite pad, and then the filtrate was concentrated under reduced pressure to obtain (2 R,3 R,4S,5 R,6 R)-2-(3-aminopropoxy)-6-(hydroxymethyl)tetrahydro-2 H-Pyran-3,4,5-triol ( 5), which can be used in the next step without further purification. LCMS (ESI) m / z calculated for C 9 H 19 NO 6 237.25; found 237.8 [M] + . VI. Compound perfluorophenyl (2Z,4E,6E,8E)-3,7- dimethyl -9-(2,6,6- trimethylcyclohex -1- ene -1- yl ) nona -2,4,6,8- tetraenoate ( perfluorophenyl (2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoatee )( 6 ) Synthesis At 0 °C, pentafluorophenyl trifluoroacetate (compound ( 8), 0.081 mL, 0.47 mmol) was added to a solution of retinoic acid (compound ( 7 )), 0.10 g, 0.33 mmol) and triethylamine (0.093 mL, 0.67 mmol) in anhydrous DMF (1.0 mL). The solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed with 0.1 N aqueous HCl, followed by NaHCO 3Aqueous solution and brine washing. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness to obtain the desired product. ( 6 ), without further purification. VII. Target compound (2Z,4E,6E,8E)-3,7- Dimethyl -N-(3-(((2R,3R,4S,5R,6R)-3,4,5- Trihydroxy -6-( Hydroxymethyl ) Tetrahydro -2H- Pyran -2- yl ) Oxy ) Propyl )-9-(2,6,6- Trimethylcyclohex -1- En -1- yl ) Nona -2,4,6,8- Tetraenamide ( (2Z,4E,6E,8E)-3,7-dimethyl-N-(3-(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)propyl)-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamide ) ( Ia ) Synthesis of Triethylamine (0.049 mL, 0.33 mmol) was added to a solution containing the crude compound ( 5 ) (30 mg, 0.13 mmol) and the active ester ( 6 ) (150 mg, 0.33 mmol) in DMF (1.0 mL). The resulting mixture was stirred overnight. The solution was concentrated to dryness. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 1:9). LCMS (ESI) m / z calculated for C 29 H 45 NO 7 519.68; found 520.5 [M+H] + . See Figure 1. B , SARS-CoV-2 PLPro Preparation To determine whether the claimed compounds and pharmaceutical compositions can inhibit SARS-CoV-2, their in vitro inhibitory effects on the activity of SARS-CoV-2 papain-like protease (PLpro) were first evaluated. The codon-optimized gene sequence encoding wild-type SARS-CoV-2 PLpro was synthesized by Biotools Co., Ltd. (New Taipei City, Taiwan) and subcloned into the pET-21a (Novagen) vector using NdeI and XhoI restriction enzyme sites, while the His-tag coding region (-LEHHHHHH-) was retained at the C-terminus. The vector inserted with the SARS-CoV-2 PLPro gene was transformed into Escherichia coli BL21(DE3) strain (Yeastern Biotech Co., Ltd., New Taipei City, Taiwan) for overexpression of PLPro therein. The culture was carried out in LB medium (containing 1% tryptone, 0.5% yeast extract and 1% NaCl) supplemented with ampicillin (100 μg / mL) as an antibiotic marker. The resulting culture was initially cultured at 37 °C with shaking at a speed of 200 rpm. At 600 nm (OD 600)At an optical density between 0.6 and 0.8, isopropyl β-D-1-thiogalactopyranoside (IPTG) was added to a final concentration of 0.4 mM to induce the expression of PLpro. Incubation was continued at 18 °C and 200 rpm for 20 h. Cells were harvested by centrifugation (5,000 x g) and lysed by sonication in a lysis buffer containing 50 mM sodium phosphate (pH 7.4), 1.0 mM DTT, 5% glycerol and 100 mM NaCl. Subsequently, the cell debris was removed by centrifugation at 20,000 x g for 50 min. The supernatant was loaded onto a 5 mL His-Trap HP column (GE Healthcare Life Sciences), and the proteins therein were eluted using a gradient of 50 mM sodium phosphate (pH 7.4) and 100 mM NaCl containing 0 - 500 mM imidazole. Fractions containing His-tagged SARS-CoV-2 PLpro were pooled and concentrated using a Centricon membrane (10 K cutoff, GE Healthcare Life Sciences). His-tagged SARS-CoV-2 PLpro was further purified by gel filtration chromatography using a Superdex 75 gel filtration column (GE Healthcare Life Sciences) in 50 mM sodium phosphate buffer (pH 7.4). The concentration of SARS-CoV-2 PLpro was determined by measuring the ultraviolet absorbance at 280 nm (using the extinction coefficient (ε280) of 45270 M -1 cm -1 ). C , SARS-CoV-2 PLPro Activity assay The enzymatic activity of the SARS-CoV-2 PLpro obtained above was measured by a colorimetry-based peptide cleavage assay using a peptide substrate of 6 monomer units (6-mer), namely FRLKGG-p-nitroaniline (FG6-pNA) (HPLC purity 97%; GL Biochem Ltd., Shanghai, China). In the cleavage assay, the 6-mer peptide substrate is cleaved at the Gly-pNA bond to release free pNA, which changes the color of the solution to yellow. The absorbance at 405 nm (A 405 ) was continuously monitored at 30 °C using a 96-well microplate spectrophotometer (Epoch™ 2, Biotek) to determine the enzymatic activity. Specifically, the cleavage assay was carried out in a 96-well microplate. Each well of the microplate contained 50 mM phosphate buffer (pH 7.4), and FG6-pNA was added to each well to prepare substrate solutions with various FG6-pNA concentrations (0.1875 mM, 0.375 mM, 0.75 mM, 1.5 mM, 3.0 mM, 6.0 mM). The test mixture (180 μL per well) was pre-incubated for 10 minutes to precisely control the temperature, and the reaction was initiated by adding 20 μL of the SARS-CoV-2 PLpro solution (1.75 μM) to the test mixture. The SARS-CoV-2 PLpro solution was prepared by mixing the above-obtained SARS-CoV-2 PLpro with 50 mM sodium phosphate buffer (pH 7.4). By measuring A 405 , and using the extinction coefficient (ε405) of 9800 M -1 cm -1 (at 1 mM, A 405 = 9.8), the concentration of pNA released by proteolysis was calculated. Using OriginPro8.0 software (OriginLab Corporation, USA), steady-state enzyme kinetic parameters were obtained by fitting the initial velocity (V 0 ) data based on the Michaelis-Menten equation. All measurements were performed in triplicate. The data obtained were expressed as mean ± standard deviation. Results: K M and k cat The values are 2.50 ± 0.03 mM and 0.85 ± 0.01 s, respectively. -1 . Therefore, it was verified that according to the above manufacturing method, SARS-CoV-2 PLPro with protease activity was successfully prepared, which can be used for subsequent SARS-CoV-2 PLPro inhibition tests. D. SARS-CoV-2 Establishment of an animal model Golden Syrian hamsters (5 - 6 weeks old, with an average body weight of about 100 g) were obtained from the National Laboratory Animal Center of the National Research Institutes (Taipei, Taiwan). The hamsters were housed in an animal room under specific pathogen-free (SPF) conditions commonly used in the art. In addition, water and feed were provided ad libitum for all hamsters. All experiments involving hamsters were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the Academia Sinica (Taiwan). The hamsters were inoculated nasally with 1x10 4 plaque-forming units (PFU) and infected at 12:00 PM with phosphate-buffered saline (PBS) containing SARS-CoV-2 (obtained from the P3 laboratory of the Genomic Research Center of the Academia Sinica; wild-type Wuhan strain) in order to establish a SARS-CoV-2 animal model. The established SARS-CoV-2 animal model was confirmed (data not shown). Examples 1 For in vitro evaluation of a novel retinoic acid compound (galactose-modified isotretinoic acid) against SARS-CoV-2 antiviral effect SARS-CoV-2 PLPro inhibition test An enzyme inhibition test was performed in a 96-well microplate. Each well of the microplate contained 50 mM phosphate buffer (pH 7.4). The SARS-CoV-2 PLPro (0.9 μM) obtained above was added to each well to form an enzyme solution. The enzyme solution in each well was divided into a control group (abbreviated as "control"), a comparison group (abbreviated as "comparative example_1"), and an experimental group (abbreviated as "experimental example_1"). The following table The corresponding inhibitor shown in Figure 1 was added to each group of enzyme solutions to form a test mixture (total volume of 180 μL). A pre-incubation was carried out for 30 minutes. Table 1 20 μL of the above FG6-pNA (1.2 mM) was added to each group of test mixtures to initiate the enzyme reaction. The enzyme reaction was allowed to proceed at 30 °C for 300 seconds. By using a 96-well microplate spectrophotometer (Epoch™ 2, Biotek), the absorbance at 405 nm (A 405 ) was continuously monitored to determine the enzyme activity. The reaction rate was calculated accordingly, where the reaction rate was the slope of the absorbance A 405 changing with time (seconds), and the total reaction time was 300 seconds. The data are presented in Figure 2. The inhibition percentage was calculated using the following formula: A = [1-(B / C)]x100 ( I ) where A = Inhibition percentage B = Reaction rate of each group C = The data obtained for the reaction rate of the control group were all expressed as mean ± standard deviation. Results: The inhibition percentages of different treatment groups were as follows Table 2 shows. Table 2 As Figure 2 and Table 2 show, the inhibition rate of Example_1 was significantly higher than that of Comparative Example_1, which indicates that galactose-modified isotretinoic acid is more effective than isotretinoic acid alone in inhibiting the activity of PLpro enzyme. This result shows that galactose-modified isotretinoic acid has a better inhibitory effect on the activity of papain-like protease. In addition, it provides important insights into the biochemical properties of the coronavirus PLpro family and paves the way for promising treatment strategies against SARS-CoV-2. Example 2 Novel retinoic acid compound (galactose-modified isotretinoic acid) in SARS-CoV-2 animal model for SARS-CoV-2 in vivo evaluation of antiviral effect Since the novel retinoic acid compound galactose-modified isotretinoic acid has been proven to have an in vitro inhibitory effect on SARS-CoV-2, the antiviral effect of the novel retinoic acid compound on SARS-CoV-2 was further evaluated in in vivo animal tests. The infected hamsters obtained above were divided into the following four groups (n = 5 for each group): a control group (abbreviated as "control"), two comparison groups (abbreviated as "comparative example_1" and "comparative example_2" respectively), and an experimental group (abbreviated as "experimental example_1"). The therapeutic agents used for these groups are listed in Table 3. Table 3 Specifically, for each hamster in experimental example_1, the novel retinoic acid compound was administered intranasally at a dose of 0.35 mg / kg at 8:00 AM on the day of infection (i.e., 4 hours before SARS-CoV-2 infection, day 1) and at a dose of 0.35 mg / kg at 8:00 PM on the day of infection. On the next two days (day 2 and day 3), the novel retinoic acid compound was administered intranasally twice a day at 8:00 AM and 8:00 PM at a dose of 0.35 mg / kg each. For each hamster in the comparison group, isotretinoic acid in Comparative Example_1 or liposome-encapsulated isotretinoic acid in Comparative Example_2 was administered intranasally at a dose of 0.35 mg / kg at 8:00 AM on the day of infection (i.e., 4 hours before SARS-CoV-2 infection) and at a dose of 0.35 mg / kg at 8:00 PM on the day of infection. On the two days following the day of infection, isotretinoic acid in Comparative Example_1 or liposome-encapsulated isotretinoic acid in Comparative Example_2 was administered intranasally twice a day at a dose of 0.35 mg / kg at 8:00 AM and 8:00 PM. The liposome-encapsulated isotretinoic acid in Comparative Example_2 was prepared by Taipei Medical University (Taiwan) using techniques commonly used in the art and was described in detail above. Since the main technical feature of the present invention is the galactose-modified isotretinoic acid of the novel retinoic acid compound, for the sake of brevity, the details of the liposome are omitted here. For each hamster in the control group, buffer was administered intranasally in a volume of 100 μL at 8:00 AM on the day of infection (i.e., 4 hours before SARS-CoV-2 infection) and in a volume of 100 μL at 8:00 PM on the day of infection. On the two days following the day of infection, buffer was administered intranasally twice a day in a volume of 100 μL at 8:00 AM and 8:00 PM. After 3 days of treatment, the hamsters were sacrificed and their lungs were collected for use in 50 testing to measure the live virus load in Vero E6 cells. Using the Reed-Muench method, the virus titer was determined based on the 50% tissue culture infective dose (TCID 50 ). All experiments with SARS-CoV-2 were conducted in a biosafety level 3 (BSL-3) laboratory and were approved by the Academia Sinica (Taipei, Taiwan). The experimental data were analyzed using Tukey's test to evaluate the differences between groups. Statistical significance was indicated by p < 0.05. Results: See Figure 3. The TCID 50 of Experimental Example_1 was significantly lower than the TCID 50 of Comparative Example_1 and Comparative Example_2, indicating that the galactose-modified isotretinoic acid of the novel retinoic acid compound has higher in vivo efficacy against SARS-CoV-2 compared to isotretinoic acid alone or liposome-encapsulated isotretinoic acid alone. Example 3 Novel retinoic acid compound Evaluation of the in vitro cytotoxic effects of galactose-modified 2 all-trans retinoic acid on different cancer cell lines In this example, seven cell lines were used, namely AsPC-1, MDA-MB-231, HCT-116, Huh-7, SKOV-3, A549 and H460 cancer cell lines. Each cell line was cultured in a designated growth medium containing 10% FBS and incubated in a humidified incubator at 37 °C containing 5% CO 4 2. One day before treatment, cells in the logarithmic growth phase were harvested, counted and seeded in 96-well plates at a density of 1x10 cells / 100 μL / well. After overnight incubation, the medium in each well was gently removed and then fresh medium (200 μL / well) was added. The test article (TA) was a novel retinoic acid compound (abbreviated as "novel compound" in this example), which was freshly prepared as a 96 mM stock solution in 100% DMSO on the day of treatment. All-trans retinoic acid was serially diluted 2-fold with 100% DMSO to obtain different concentrations of all-trans retinoic acid ranging from 7.5 mM to 96 mM. Cells were treated by adding 2.02 μL of the specified concentration of all-trans retinoic acid to each well to obtain a final concentration range of all-trans retinoic acid from 7.5 μM to 960 μM, and all wells were maintained to contain 1% DMSO, including the DMSO control. All components were gently mixed and incubated for 24 hours. Cells were treated by adding 2.02 μL of the specified concentration of the novel compound or DMSO to each well, then gently mixed and incubated for 24 hours. On the day of measuring cell viability, the medium in each well was replaced with freshly prepared Alamar blue dye (10% v / v) and incubated at 37 °C for 2 to 3 hours. The spectrophotometric absorbance was recorded at wavelengths of 570 nm and 600 nm. The percentage of cell viability was calculated using the following formula: % Viability = (TA of [A 570 / A 600 ratio ] / DMSO of [A 570 / A 600 ratio ]) * 100% where TA = the article to be tested A 570 = 570 nm absorbance at A 600 = 600 nm absorbance at Result: See Figure 4 to Figure 10, which show that the novel compound can significantly reduce the cell viability of all seven cancer cell lines, indicating that the galactose-modified isotretinoic acid of the novel retinoic acid compound can be a potential anti-cancer drug for the effective treatment of various cancers (such as lung cancer, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer and liver cancer). Table 4 shows IC 50 . Table 4 Example 4 for in vitro evaluation of the second pharmaceutical composition against SARS-CoV-2 antiviral effect of SARS-CoV-2 PLPro inhibition test The enzyme inhibition test was carried out in a 96-well microplate. Each well of the microplate contained 50 mM phosphate buffer (pH 7.4). The SARS-CoV-2 PLPro obtained above was added to each well to form an enzyme solution with a final concentration of 0.9 μM. The enzyme solution in each well was divided into a control group (abbreviated as "control"), four comparison groups (abbreviated as "comparative example_1", "comparative example_2", "comparative example_3" and "comparative example_4") and two experimental groups (abbreviated as "experimental example_1" and "experimental example_2"). The following Table 5 shows the corresponding inhibitors added to each group of enzyme solutions to form a test mixture (total volume of 180 μL). Pre-incubation was carried out for 30 minutes. Table 5 Add 20 μL of the above FG6-pNA (1.2 mM) to each group of test mixtures to initiate the enzymatic reaction. Allow the enzymatic reaction to proceed at 30 °C for 300 seconds. Continuously monitor the absorbance at 405 nm (A 405 ) using a 96-well microplate spectrophotometer (Epoch™ 2, Biotek) to determine the enzyme activity. Calculate the reaction rate accordingly, where the reaction rate is the slope of the absorbance A 405 changing over time (seconds), and the total reaction time is 300 seconds. The data are presented in Figure 11. The percentage of inhibition is calculated as described in Example 3. Results: The percentage of inhibition for different treatment groups is as follows Table 6. Table 6 As Figure 11 and Table 6 show, the inhibitory effect of each group in the experimental group is significantly higher than that of each group in the comparison group, which indicates that the two experimental groups: (1) isotretinoic acid and oligosaccharide, and (2) isotretinoic acid, oligosaccharide, Zn 2+ and Mg 2+ , are more effective than the individual components of only isotretinoic acid, oligosaccharide, Zn 2+ or Mg 2+ . These results suggest that isotretinoic acid, oligosaccharide, and divalent metal ions have a synergistic inhibitory effect on papain-like protease activity. In addition, it provides important insights into the biochemical properties of the coronavirus PLpro family and paves the way for promising therapeutic strategies against SARS-CoV-2. Example 5 Evaluation of the in vivo therapeutic effect of the combination of isotretinoic acid, oligosaccharide, or divalent metal ions against SARS-CoV-2 in an animal model SARS-CoV-2 The infected hamsters obtained in Part A of this experiment were divided into the following six groups (n = 5 for each group): one control group, two experimental groups (i.e., Experimental Example_1 and Experimental Example_2), and four comparison groups (i.e., Comparative Example_1, Comparative Example_2, Comparative Example_3, and Comparative Example_4). The therapeutic agents used for these groups are listed below Table 7. Table 7 The liposome-coated therapeutic agent was prepared by Taipei Medical University using techniques commonly used in the art and is described in detail above. Since the main technical feature of the present invention lies in the combination of retinoic acid with or without metal ions and oligosaccharides, for the sake of brevity, the details of the liposome are omitted here. Specifically, for each hamster in the experimental group, liposome-coated isotretinoic acid was administered intranasally at a dose of 0.35 mg / kg at 8:00 AM on the day of infection (i.e., 4 hours before SARS-CoV-2 infection, Day 1) and at a dose of 0.35 mg / kg at 8:00 PM on the day of infection. On the next two days (Day 2 and Day 3), liposome-coated isotretinoic acid was administered intranasally twice a day at 8:00 AM and 8:00 PM at a dose of 0.35 mg / kg each. In addition to administering liposome-coated isotretinoic acid intranasally twice a day at 8:00 AM and 8:00 PM at a dose of 0.35 mg / kg each, a 15 μL volume of liposome-coated oligosaccharide mixture (i.e., Experimental Example_1), or a combination of oligosaccharide mixture (15 μL) and Zn 2+ (100 μM), Mg 2+ (200 μM), and K + (200 μM) (15 μL), both encapsulated in liposomes with a total volume of 30 μL (i.e., Experimental Example_2), were administered intranasally once a day at 7:30 PM to 8:00 PM on the day of infection (i.e., 0.5 hour to 1 hour before administering liposome-coated isotretinoic acid in the evening), and 15 μL volume of Experimental Example_1 or 30 μL volume of Experimental Example_2 was administered on the next two days. For each hamster in the control group, isotretinoin in Comparative Example_1 or liposome-encapsulated isotretinoin in Comparative Example_2 was administered intranasally at a dose of 0.35 mg / kg at 8:00 AM on the day of infection (i.e., 4 hours before SARS-CoV-2 infection) and at a dose of 0.35 mg / kg at 8:00 PM on the day of infection. On the next two days after the day of infection, isotretinoin in Comparative Example_1 or liposome-encapsulated isotretinoin in Comparative Example_2 was administered intranasally twice a day at a dose of 0.35 mg / kg at 8:00 AM and 8:00 PM. For each hamster, liposome-encapsulated Zn in Comparative Example_3 was administered nasally once a day from 7:30 PM to 8:00 PM on the day of infection 2+ (100 μM), Mg 2+ (200 μM), and K + (200 μM) combination and liposome-encapsulated oligosaccharide mixture in Comparative Example_4, and on the next two days, a volume of 15 μL each was administered. For each hamster in the control group, buffer was administered intranasally at a volume of 100 μL at 8:00 AM on the day of infection (i.e., 4 hours before SARS-CoV-2 infection) and at a volume of 100 μL at 8:00 PM on the day of infection. On the two days after the day of infection, buffer was administered intranasally twice a day at a volume of 100 μL at 8:00 AM and 8:00 PM. After 3 days of treatment, the hamsters were sacrificed and their lungs were collected for measuring the live virus load in Vero E6 cells by TCID 50 assay. Using the Reed-Muench method, the virus titer was determined based on the 50% tissue culture infective dose (TCID 50 ). All experiments on SARS-CoV-2 were conducted in a Biosafety Level 3 (BSL-3) laboratory and approved by the Academia Sinica (Taipei, Taiwan). Tukey's test was used to analyze the experimental data to evaluate the differences between groups. Statistical significance was indicated by p < 0.05. Results: See Figure 12. The TCID of each of Experimental Example_1 and Experimental Example_2 50 was significantly lower than the TCID of each of Comparative Example_1, Comparative Example_2, Comparative Example_3, and Comparative Example_4 50 Low, this shows that the combination of isotretinoic acid with or without metal ions and oligosaccharides has higher in vivo efficacy against SARS-CoV-2 compared to having only isotretinoic acid, only metal ions, or only oligosaccharides. Conclusion In view of the results of Examples 1 to 5, it is verified that the claimed novel retinoic acid compound or its pharmaceutically acceptable salt, or the claimed pharmaceutical composition comprising the compound (i.e., the first pharmaceutical composition), or the claimed pharmaceutical composition comprising retinoic acid and carbohydrates with or without metal ions (i.e., the second pharmaceutical composition) can provide improvement and / or synergistic effects in inhibiting the infection and replication of SARS-CoV-2 and treating diseases related to SARS-CoV-2 infection or cancer. Therefore, the compound comprising retinoic acid conjugated with carbohydrates, its pharmaceutically acceptable salt, and the first and second pharmaceutical compositions described in the present invention can indeed be used as drug-repurposing agents. The present invention has been described extensively and throughout this text. Each narrower form and subgroup falling within the scope of the overall disclosure also forms part of the present invention. Additionally, where the features or aspects of the present invention are described in accordance with a Markush group, those of ordinary skill in the art will understand that the present invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. None Figure 1 illustrates the liquid chromatography-mass spectrometry (LC-MS) analysis results of the compound (Ia) according to an embodiment of the present invention. Figure 2 illustrates a graph showing the change in absorbance over time in the SARS-CoV-2 PLPro inhibition test of the novel retinoic acid compound according to an embodiment of the present invention. Figure 3 illustrates 50 a graph that shows the antiviral effect of the novel retinoic acid compound according to an embodiment of the present invention in a SARS-CoV-2 animal model. Figure 4 illustrates a graph of cell viability that shows the cytotoxic effect of the novel retinoic acid compound according to an embodiment of the present invention on the AsPC-1 cancer cell line. Figure 5 illustrates a graph of cell viability that shows the cytotoxic effect of the novel retinoic acid compound according to an embodiment of the present invention on the MDA-MB-231 cancer cell line. Figure Figure 6 illustrates a graph of cell viability, which shows the cytotoxic effect of the novel retinoic acid compound according to an embodiment of the present invention on the HCT-116 cancer cell line. Figure 7 illustrates a graph of cell viability, which shows the cytotoxic effect of the novel retinoic acid compound according to an embodiment of the present invention on the Huh-7 cancer cell line. Figure 8 illustrates a graph of cell viability, which shows the cytotoxic effect of the novel retinoic acid compound according to an embodiment of the present invention on the SKOV-3 cancer cell line. Figure 9 illustrates a graph of cell viability, which shows the cytotoxic effect of the novel retinoic acid compound according to an embodiment of the present invention on the A549 cancer cell line. Figure 10 illustrates a graph of cell viability, which shows the cytotoxic effect of the novel retinoic acid compound according to an embodiment of the present invention on the H460 cancer cell line. Figure 11 illustrates a graph showing the change in absorbance over time in the SARS-CoV-2 PLPro inhibition assay of the second pharmaceutical composition according to an embodiment of the present invention. Figure 12 illustrates 50 a figure showing the antiviral effect of the second pharmaceutical composition according to an embodiment of the present invention in a SARS-CoV-2 animal model.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is a metaretinic acid conjugated to a carbohydrate via a linker -C3H6NH-.

2. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein the carbohydrate is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides and polysaccharides.

3. The compound as claimed in claim 2 or a pharmaceutically acceptable salt thereof, wherein the oligosaccharide is a mono-oligosaccharide or a hetero-oligosaccharide, and the polysaccharide is a mono-polysaccharide or a hetero-polysaccharide.

4. The compound as claimed in claim 2 or a pharmaceutically acceptable salt thereof, wherein the carbohydrate is glucose, fructose, galactose, mannose, sucrose, lactose, maltose, β-1,3 / 1,6-glucan oligosaccharide, raffinose, stachyose, verbascose, fructooligosaccharide, starch, glycogen, cellulose, or any combination thereof.

5. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein the carbohydrate is galactose.

6. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula (Ia): (Ia).

7. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

8. The pharmaceutical composition as claimed in claim 7, wherein the concentration of the compound or a pharmaceutically acceptable salt thereof is from 0.1 μM to 10 mM.

9. The pharmaceutical composition as described in claim 7, further comprising metal ions.

10. The pharmaceutical composition as claimed in claim 9, wherein the metal ion is a monovalent ion, a divalent ion, or a combination thereof.

11. The pharmaceutical composition as claimed in claim 10, wherein the monovalent ion is K+, Na+ or a combination thereof, and the divalent ion is Zn2+, Mg2+, Cu2+, Mn2+, Ca2+, Fe2+ or any combination thereof.

12. The pharmaceutical composition as described in any one of claims 9 to 11, wherein the concentration of the metal ion is from 1 μM to 300 mM.

13. The pharmaceutical composition as claimed in claim 12, wherein the molar ratio of the compound or a pharmaceutically acceptable salt thereof to the metal ion is 1:10-3 to 1:

103.

14. A pharmaceutical composition as described in any one of claims 9 to 11, wherein the pharmaceutically acceptable carrier is a liposome, adjuvant, solvent, buffer, emulsifier, suspending agent, disintegrant, disintegrant, dispersant, binder, stabilizer, chelating agent, diluent, gelling agent, preservative, wetting agent, lubricant, absorption delay agent, or any combination thereof.

15. The pharmaceutical composition as described in claim 14, wherein the pharmaceutically acceptable carrier is a liposome.

16. The pharmaceutical composition as claimed in claim 15, wherein the liposome is a dilipoprotein lipid, a single lipid, a steroid, or any combination thereof.

17. The pharmaceutical composition as claimed in claim 15, wherein the compound or a pharmaceutically acceptable salt thereof is encapsulated by the liposome.

18. A pharmaceutical composition as described in any one of claims 9 to 11, wherein the pharmaceutically acceptable carrier is a liposome, and the metal ion is encapsulated by the liposome.

19. The pharmaceutical composition as claimed in claim 18, wherein the compound or a pharmaceutically acceptable salt thereof and the metal ion are encapsulated by the liposome.

20. Use of a pharmaceutical composition as described in any one of claims 9 to 19 in the manufacture of a medicament for inhibiting viral infection or replication.

21. The use as described in claim 20, wherein the virus is an RNA virus.

22. The use as described in claim 21, wherein the RNA virus is a coronavirus, human immunodeficiency virus (HIV), hepatitis C virus (HCV), influenza virus, or any combination thereof.

23. The use as described in claim 20, wherein the compound or a pharmaceutically acceptable salt thereof is administered simultaneously with the metal ion.

24. The use as described in claim 20, wherein the pharmaceutical composition is administered by oral, intravenous, intramuscular, subcutaneous, intraperitoneal, intranasal, or local route.

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