CN111773240A - Application of marine organism-derived natural sulfated polysaccharide as anti-coronavirus and anti-coronavirus-induced disease medicine - Google Patents
Application of marine organism-derived natural sulfated polysaccharide as anti-coronavirus and anti-coronavirus-induced disease medicine Download PDFInfo
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Abstract
The invention belongs to the field of biological medicines, and particularly relates to application of natural sulfated polysaccharide from marine organisms as a medicine for resisting coronavirus and diseases caused by coronavirus. Application of natural sulfated polysaccharide and pharmaceutically acceptable salt derived from marine organisms in preparation of medicines combined with Spike protein (Spike), inhibitor of main protease (Mpro), or papain-like (PLpro) inhibitor. The marine organism-derived natural sulfated polysaccharide provided by the invention has an obvious effect of inhibiting the multiplication of coronavirus, can inhibit the combination of Spike protein (Spike) on the surface of the coronavirus and host cells, and can inhibit the activities of main protease (Mpro) and papain-like (PLpro), thereby effectively blocking the coronavirus from infecting the host cells.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to application of natural sulfated polysaccharide from marine organisms as a medicine for resisting coronavirus and diseases caused by coronavirus.
Background
The world health organization names the disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) as new coronary pneumonia (COVID-19), and announces the disease as an international emergent public health event in 1-30.2020. COVID-19 spreads rapidly worldwide, and poses a great threat to human health and social public health safety. However, no specific medicine for the virus exists at present, the clinical application mainly aims at supporting the symptomatic treatment for treating and improving symptoms, and the research and development of the anti-SARS-CoV-2 medicine are not slow. A large number of drug screening experiments have been conducted on new coronaviruses on a global scale, but no drug having a good therapeutic effect has yet been found.
SARS-CoV-2 is an RNA virus with an envelope structure. Spike glycoprotein on the lipid membrane of virions, responsible for adhesion to host receptors. Viral genomic RNA within the lipid membrane may encode replicase polyproteins which are cleaved by 3C-like protease (3CLpro, also known as the main protease Mpro) and papain-like protease (PLpro) to produce functional polypeptides such as RNA-dependent RNA polymerase (RdRp) and helicase (Hel) which are involved in viral RNA transcription and replication. Therefore, the spike glycoprotein related to SARS-CoV-2 infection of host cells, the main protease related to SARS-CoV-2 transcription replication and papain-like protease are important targets for the development of anti-SARS-CoV-2 drugs.
The natural sulfated polysaccharides from marine organisms, such as fucoidan sulfate with a complex structure from brown algae, have the effect of resisting various influenza viruses (publication No. CN 103880975A; patent No. ZL201432101608. x), the main chain structure of the natural sulfated polysaccharides comprises α -1, 2-mannose (Man) and β -1, 4-glucuronic acid (GlcA), and the C3 position of mannose contains a branched chain α -1, 3-linked-sulfated rockFucose residues (Jiandong Wu, J Carbohy Chem, 34: 303-317; Wei Wang, Sci. Rep.2017,7:40760), and recently, it was reported that fucoidan (RPI-27 and RPI-128) having similar structure and different molecular weights (100kD and 12kD) have activity of inhibiting CoVID-COV-2 coronavirus Spike protein, which contains α -1, 2-mannose (Man) and β -1, 4-glucuronic acid (GlcA) backbones, containing branched chains at mannose C3 position α -1,2/1, 3-linked-sulfated-sugar residues (Pauls. Kwon, Cell Discovey, 2020, 6:50), fucoidan (Hayashi, K, int.munocorma.2008, 2) having activity against fucoidan (H.11, HSV) and further, it was found that further, the fucoidan (Hv-11, 13, 11-11, 11-12-150) has activity against Streptococcus mangium viruses, and further that further, the further, the further, the further
Drugs, 2015,13, 697-712), but no activity against new coronaviruses was found.
Disclosure of Invention
The invention aims to provide an application of marine organism-derived natural sulfated polysaccharide in preparing anti-coronavirus and anti-disease drugs, which is prepared by taking specific marine plants and marine animals as raw materials, extracting and separating to obtain a series of marine-derived natural sulfated polysaccharides, screening the marine-derived natural sulfated polysaccharides to inhibit the activity of coronavirus, particularly novel coronavirus (SARS-COV-2), and providing an effective drug for treating coronavirus, particularly novel coronavirus pneumonia (COVID-19) and a composition thereof.
The technical scheme of the invention is as follows:
the application of marine organism-derived natural sulfated polysaccharide in preparing a medicament combined with Spike protein (Spike), preparing an inhibitor of main protease (Mpro) or preparing a papain-like (PLpro) inhibitor is characterized in that the marine organism-derived natural sulfated polysaccharide has any one of the following structural characteristics, has a molecular weight range of 3-600 kDa and comprises the following steps:
(1) fucoidan (also called fucoidan) has one of the following structural features: (a) the I-type structure fucoidin comprises a main chain which is composed of alpha-1, 3-connected sulfated fucose; (b) the fucoidin with the type II structure comprises a main chain of sulfated fucose alternately connected with alpha-1, 3 and alpha-1, 4; (c) the fucoidan with III-type structure comprises a main chain consisting of beta-1, 4-glucuronic acid and alpha-1, 2-mannose, and a branch structure consisting of alpha-1, 3-sulfated fucooligosaccharide; (d) other types of fucoidan, the backbone of which consists of sulfated fucose in α -1,2 and α -1,3 and/or α -1, 4-linkages;
(2) fucosylated chondroitin sulfate, its structural features are as follows: a chondroitin sulfate disaccharide repeating unit with a main chain formed by alternate connection of glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc) through beta-1, 3 and beta-1, 4 glycosidic bonds, wherein C4, C6 or C4 of the GalNAc and hydroxyl at the C6 position contain sulfate groups, and a sulfated fucooligosaccharide branch is connected at the C3 position of the GlcA through an alpha-1, 3 glycosidic bond;
(3) the sulfated galactan has the following structural characteristics: galactose (Gal) consisting of β -1, 3-linked and α -1, 4-linked galactose or β -1, 3-linked and α -1, 4-linked-3, 6-lacto galactose (AnG), and galactose containing different sulfate groups at the C2, C4 or C6 positions;
(4) and (3) rhamnosan sulfate: the structure is characterized as follows: is formed by connecting rhamnose (Rha) and glucuronic acid alternately through alpha-1, 4 and beta-1, 4 glycosidic bonds; or Rha and iduronic acid are alternately connected through alpha-1, 4 glycosidic bonds; or rhamnose (Rha) and xylose (Xyl) are alternately connected through alpha-1, 4 and beta-1, 4 glycosidic bonds; or alternatively connected by alpha-1, 2 and alpha-1, 3-rhamnose; and the C2 and/or C3 position of the structure Rha contains a sulfate group.
The I-type structure fucoidin also has other sugar residue branched structures; the fucoidan with type II structure also has other sugar residue branched structure.
The coronavirus is one or more selected from SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS-CoV.
The natural sulfated polysaccharide is derived from marine plants or marine animals.
The natural sulfated polysaccharide can be combined with the Spike protein (Spike) of the coronavirus to be used as an inhibitor for inhibiting the coronavirus from infecting cells, and can inhibit the replication and amplification of the virus by inhibiting the activity of main protease (Mpro) and/or papain-like protease (PLpro) of the coronavirus.
The natural sulfated polysaccharide and the pharmaceutically acceptable salt are applied to the preparation of the coronavirus inhibitor.
The natural sulfated polysaccharide and the pharmaceutically acceptable salt are applied to the preparation of the drugs for preventing and/or treating coronavirus infection or preventing and/or treating diseases or symptoms related to coronavirus infection.
The natural sulfated polysaccharide, the pharmaceutically acceptable salt and Spike protein (Spike) combined kit or reagent, the kit or reagent for preparing the main protease (Mpro) inhibitor, or the kit or reagent for preparing the papain-like protease (PLpro) inhibitor.
The natural sulfated polysaccharide, the pharmaceutically acceptable salt and one or more than two other active agents for preventing and/or treating the coronavirus infection are mixed to prepare the pharmaceutical composition for preventing and/or treating the coronavirus infection.
The design idea of the invention is as follows:
the marine organism-derived natural sulfated polysaccharide provided by the invention can inhibit the combination of Spike protein (Spike) on the surface of coronavirus and host cells, thereby effectively blocking the coronavirus from infecting the host cells, and also can inhibit the activities of main protease (Mpro) and papain-like (PLpro) of coronavirus, thereby inhibiting the replication and amplification processes of the virus. Therefore, the marine natural sulfated polysaccharide provided by the invention has great potential for being developed into anti-coronavirus and disease-caused medicines.
The invention has the advantages and beneficial effects that:
(1) the marine organism-derived natural sulfated polysaccharide provided by the invention can inhibit the combination of Spike protein (Spike) on the surface of coronavirus and host cells, and the inhibition activity level of the marine organism-derived natural sulfated polysaccharide is superior to that of clinical drugs heparin and low molecular heparin.
(2) The marine organism-derived natural sulfated polysaccharide provided by the invention has the activity of inhibiting main protease (Mpro) and papain-like protease (PLpro), and the inhibition activity level of the marine organism-derived natural sulfated polysaccharide is superior to that of heparin.
(3) In a whole, the natural sulfated polysaccharide from marine organisms provided by the invention has the anti-coronavirus activity superior to that of clinical drugs heparin and low molecular heparin, and can be used in the fields of preparation and application of anti-coronavirus and disease-related drugs.
Drawings
FIG. 1 fucoidan, galactan sulfate, fucosylated chondroitin sulfate, rhamsan sulfate and heparin have inhibitory activity against SARS-CoV-2 spike protein. In the graph, the abscissa Log Dose represents the logarithm of the concentration of the compound (. mu.M), and the ordinate Relative Luminescence represents the Relative Luminescence intensity (%).
FIG. 2 is a graph showing the inhibitory effect of galactan sulfate, fucoidan sulfate, fucosylated chondroitin sulfate on SARS-CoV-2 major protease. In the figure, the abscissa Time represents Time(s), the ordinate Intensity represents fluorescence Intensity, Blank represents Blank, Iota-carrageenan represents Iota-carrageenan, FCS represents fucosylated chondroitin sulfate, and Fucoidan represents Fucoidan sulfate.
FIG. 3 fucoidan sulfate inhibits SARS-CoV-2 major protease IC50The curve was measured. In the figure, the concentration on the abscissa Log represents the logarithm of the concentration (nM), IC50Represents the median inhibitory concentration.
Detailed Description
In the specific implementation process, the invention relates to application of natural sulfated polysaccharide and pharmaceutically acceptable salt of marine origin in preparation of coronavirus inhibition inhibitors, wherein the natural sulfated polysaccharide has any one of the following structures:
(1) fucoidan (also called fucoidan), which comprises: (a) the I type fucoidan has a main chain composed of alpha-1, 3-linked sulfated fucose and can also have other sugar residue branched structures; (b) the main chain of the type II fucoidan consists of sulfated fucose which is alternately connected with alpha-1, 3 and alpha-1, 4, and can also have other sugar residue branched structures; (c) type III fucoidan, the main chain is composed of beta-1, 4-glucuronic acid and alpha-1, 2-mannose, and the branch structure is composed of alpha-1, 3-sulfated fucooligosaccharide; (d) other types of fucoidan have a backbone consisting of sulfated fucose with alpha-1, 2 and alpha-1, 3 and/or alpha-1, 4 linkages.
(2) Fucosylated chondroitin sulfate, its structural features are as follows: the main chain is a chondroitin sulfate disaccharide repeating unit formed by alternate connection of glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc) through beta-1, 3 and beta-1, 4 glycosidic bonds, and the sulfated fucooligosaccharide branch is connected at C3 position of the GlcA through alpha-1, 3 glycosidic bonds.
(3) The sulfated galactan has the following structural characteristics: consists of a β -1, 3-linked and α -1, 4-linked galactose (Gal), or a β -1, 3-linked and α -1, 4-linked-3, 6-lacto galactose (AnG), and the galactose contains different sulfate groups at the C2, C4 or C6 positions.
(4) The rhamnosulfate has the following structural characteristics: is formed by connecting rhamnose (Rha) and glucuronic acid alternately through alpha-1, 4 and beta-1, 4 glycosidic bonds; or Rha and iduronic acid are alternately connected through alpha-1, 4 glycosidic bonds; or rhamnose (Rha) and xylose (Xyl) are alternately connected through alpha-1, 4 and beta-1, 4 glycosidic bonds; or alternatively connected by alpha-1, 2 and alpha-1, 3-rhamnose; and the C2 and/or C3 position of the structure Rha contains a sulfate group.
The invention also provides application of marine organism-derived natural sulfated polysaccharide and pharmaceutically acceptable salts in preparing a medicament combined with Spike protein (Spike), preparing a main protease (Mpro) inhibitor or preparing a papain-like protease (PLpro) inhibitor, wherein the marine organism-derived sulfated polysaccharide has any one of the following structures:
(1) fucoidan (also called fucoidan), which comprises: (a) the I-type structure fucoidin comprises a main chain which is composed of alpha-1, 3-connected sulfated fucose and can also have other sugar residue branched structures; (b) the main chain of the fucoidin with the type II structure consists of sulfated fucose which is alternately connected with alpha-1, 3 and alpha-1, 4, and can also have other sugar residue branched structures; (c) the fucoidan with type III structure comprises a main chain consisting of beta-1, 4-glucuronic acid and alpha-1, 2-mannose, and a branch structure consisting of alpha-1, 3-sulfated fucooligosaccharide; (d) other types of fucoidan have a backbone consisting of sulfated fucose with alpha-1, 2 and alpha-1, 3 and/or alpha-1, 4 linkages.
(2) Fucosylated chondroitin sulfate, its structural features are as follows: the main chain is a chondroitin sulfate disaccharide repeating unit formed by alternate connection of glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc) through beta-1, 3 and beta-1, 4 glycosidic bonds, and the sulfated fucose branch is connected at C3 position of the GlcA through alpha-1, 3 glycosidic bonds.
(3) The sulfated galactan has the following structural characteristics: consists of a β -1, 3-linked and α -1, 4-linked galactose (Gal), or a β -1, 3-linked and α -1, 4-linked-3, 6-lacto galactose (AnG), and the galactose contains different sulfate groups at the C2, C4 or C6 positions.
(4) And (3) rhamnosan sulfate: the structure is characterized as follows: is formed by connecting rhamnose (Rha) and glucuronic acid alternately through alpha-1, 4 and beta-1, 4 glycosidic bonds; or Rha and iduronic acid (IdoA) are alternately connected through alpha-1, 4 glycosidic bonds; or rhamnose (Rha) and xylose (Xyl) are alternately connected through alpha-1, 4 and beta-1, 4 glycosidic bonds; or alternatively connected by alpha-1, 2 and alpha-1, 3-rhamnose; and the C2 and/or C3 position of the structure Rha contains a sulfate group.
The above-mentioned applications are preferably one or more of Spike protein (Spike), major protease (Mpro), and papain-like protease (PLpro) in coronavirus; more preferably, the coronavirus is one or more selected from the group consisting of COVID-19(SARS-CoV-2), HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS-CoV.
The invention also provides application of the marine organism-derived natural sulfated polysaccharide and pharmaceutically acceptable salt in preparation of coronavirus inhibitors.
The invention also provides application of the natural sulfated polysaccharide and the pharmaceutically acceptable salt of the marine organism in preparing a medicament for preventing and/or treating coronavirus infection or preventing and/or treating diseases or symptoms related to coronavirus infection.
As used herein above, preferably, the coronavirus is selected from the group consisting of COVID-19(SARS-CoV-2), HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, and MERS-CoV.
The invention also provides application of the marine organism-derived natural sulfated polysaccharide and the pharmaceutically acceptable salt in preparation of a kit or a reagent combined with Spike protein (Spike), a kit or a reagent for preparing a main protease (Mpro) inhibitor or a kit or a reagent for preparing a papain-like protease (PLpro) inhibitor.
The invention also provides a pharmaceutical composition for preventing and/or treating coronavirus infection, which comprises the natural sulfated polysaccharide from marine organisms, pharmaceutically acceptable salts and one or more than two active agents for preventing and/or treating coronavirus infection.
Preferably, the molecular weight range of the marine organism-derived natural sulfated polysaccharide is 3-600 kDa.
The invention shows through experimental screening research that the series of marine organism-derived natural sulfated polysaccharides have better inhibiting effect on coronavirus, especially Spike protein (Spike), main protease (Mpro or 3CL pro) and PLpro of novel coronavirus (SARS-CoV-2). The invention provides the application potential of natural sulfated polysaccharide from marine organisms in resisting coronavirus, especially SARS-CoV-2, and proves that the natural sulfated polysaccharide has good clinical development and application prospects.
The marine organism-derived natural sulfated polysaccharide provided by the invention is preferably characterized by the following structural characteristics:
(1) fucoidan (also called fucoidan), which comprises: (a) the I-type structure fucoidin comprises a main chain which is composed of alpha-1, 3-connected sulfated fucose and can also have other sugar residue branched structures; (b) the main chain of the fucoidin with the type II structure consists of sulfated fucose which is alternately connected with alpha-1, 3 and alpha-1, 4, and can also have other sugar residue branched structures; (c) the fucoidan with type III structure comprises a main chain consisting of beta-1, 4-glucuronic acid and alpha-1, 2-mannose, and a branch structure consisting of alpha-1, 3-sulfated fucooligosaccharide; (d) other types of fucoidan have a backbone consisting of sulfated fucose with alpha-1, 2 and alpha-1, 3 and/or alpha-1, 4 linkages.
(2) Fucosylated chondroitin sulfate, its structural features are as follows: the main chain is a chondroitin sulfate disaccharide repeating unit formed by alternate connection of glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc) through beta-1, 3 and beta-1, 4 glycosidic bonds, and the sulfated fucose branch is connected at C3 position of the GlcA through alpha-1, 3 glycosidic bonds.
(3) The sulfated galactan has the following structural characteristics: consists of beta-1, 3-linked and alpha-1, 4-linked galactose (Gal), or of beta-1, 3-linked galactose and alpha-1, 4-linked-3, 6-lactonic galactose (AnG), and the C2, C4 or C6 position of galactose contains different sulfate groups.
(4) And (3) rhamnosan sulfate: the structure is characterized as follows: is formed by connecting rhamnose (Rha) and glucuronic acid alternately through alpha-1, 4 and beta-1, 4 glycosidic bonds; or Rha and iduronic acid are alternately connected through alpha-1, 4 glycosidic bonds; or rhamnose (Rha) and xylose (Xyl) are alternately connected through alpha-1, 4 and beta-1, 4 glycosidic bonds; or alternatively connected by alpha-1, 2 and alpha-1, 3-rhamnose; and the C2 and/or C3 position of the structure Rha contains a sulfate group.
The marine organism-derived sulfated polysaccharides of the invention have the function of inhibiting coronavirus, especially novel coronavirus (SARS-CoV-2). The experimental results show that the sulfated polysaccharides from various marine organisms provided by the invention have obvious effects of resisting novel coronavirus and inhibiting IC of Spike50IC with value of 0.01-30 μ M for inhibiting Mpro50IC of value between 1nM and 100nM, inhibition of papain-like protease (PLpro)50The value is 0.001 to 30 μ M. IC for inhibiting Mpro like fucoidan sulfate50IC for inhibition of Spike protein at 5.68nM50IC at 0.06. mu.M inhibiting papain-like protease (PLpro)507.65nM, and the effect is obvious and goodIn heparin.
Preferably, the above-described uses include, but are not limited to, novel coronavirus (COVID-19), HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV (causing severe acute respiratory syndrome), and MERS-CoV (causing middle east respiratory syndrome).
The marine organism-derived natural sulfated polysaccharide provided by the invention can be used for preparing a spray, an injection, a capsule, an ointment, a cream, a gel, a liniment and a liniment.
A therapeutically effective amount of the marine organism-derived natural sulfated polysaccharide, pharmaceutically acceptable salt or stereoisomer of the invention is preferably administered to a patient in need of such treatment, formulated according to the usual route of administration and according to methods known in the art in conventional pharmaceutical compositions (which comprise an effective amount of the active ingredient and a suitable pharmaceutical carrier) and dosage forms.
By "therapeutically effective amount" is meant an amount which, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the disease in question. The specific dose of the compound administered according to the invention will be determined by the specific circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations. In particular, a "therapeutically effective amount of a compound" refers to an amount of the compound sufficient to prevent or to some extent ameliorate one or more coronavirus infection.
Individual doses as well as daily doses will vary further depending on the type and severity of the coronavirus infection to be treated and the response of the particular patient to drug treatment. Thus, the exact individual doses will be determined according to standard medical principles under the direction of a physician.
An effective daily dosage for humans using the marine organism-derived natural sulfated polysaccharides, pharmaceutically acceptable salts of the invention in the treatment of diseases caused by coronaviruses is an oral dosage form of injection or other active agent of from 1mg to about 500mg, from about 5mg to about 1000mg, or from about 10mg to about 2000 mg.
The marine organism-derived natural sulfated polysaccharides and pharmaceutically acceptable salts of the present invention may be used alone or in combination therapy with other therapeutic agents.
In one embodiment of the invention, the marine organism derived natural sulfated polysaccharides, pharmaceutically acceptable salts are for use in the prevention and/or treatment of coronavirus infection, wherein said prevention or treatment comprises administration as the sole active ingredient.
In another embodiment of the present invention, the above marine organism-derived natural sulfated polysaccharide, pharmaceutically acceptable salt, is for use in the prevention and/or treatment of coronavirus infection, wherein the prevention or treatment comprises use in combination therapy with a therapeutic agent selected from other therapeutic agents.
As will be apparent to the skilled person, the combination of the invention comprising the marine organism derived natural sulfated polysaccharide of the invention, a pharmaceutically acceptable salt and an additional therapeutic agent is not only effective when the active ingredients are used in a single composition, but also when used in two different compositions (administered simultaneously, sequentially or separately after a period of time). Furthermore, it will be appreciated by those skilled in the art that the marine-derived natural sulfated polysaccharides, pharmaceutically acceptable salts of the present invention may be formulated for use with other active ingredients in a combination therapy to prevent and/or treat coronavirus infection.
In a particular embodiment, the combination therapy comprises administering to the subject simultaneously, sequentially or separately the marine organism-derived natural sulfated polysaccharide of the invention, a pharmaceutically acceptable salt and an additional therapeutic agent. Alternatively, the combination therapy comprises administering to the subject the marine organism derived natural sulfated polysaccharide, the pharmaceutically acceptable salt or stereoisomer of the invention and the additional therapeutic agent in a single composition.
In one embodiment of the present invention, the marine organism-derived natural sulfated polysaccharide, pharmaceutically acceptable salt or stereoisomer of the present invention may be conveniently administered to a patient. Thus, the compounds for use according to the invention may be in the form of a pharmaceutical composition comprising an effective amount of the marine organism derived natural sulfated polysaccharides, pharmaceutically acceptable salts of the invention in combination with a pharmaceutically acceptable excipient or carrier. This aspect can also be expressed as a composition comprising an effective amount of the marine organism-derived natural sulfated polysaccharide, pharmaceutically acceptable salt of the present invention in combination with a pharmaceutically acceptable excipient or carrier for use in the prevention and/or treatment of coronavirus infection.
In one embodiment of the invention, the compounds used may be administered orally, by injection, subcutaneously, via the respiratory tract, transdermally, parenterally, rectally, topically, intravenously, intramuscularly or by other means in dosage unit formulations containing conventional pharmaceutical carriers. The pharmaceutical composition may be formulated in any pharmaceutical form, such as: tablet, granule, injection, gel, pill, capsule, suppository, implant, nanometer preparation, and powder for injection. Some dosage forms, such as tablets and capsules, can be subdivided into appropriate dosage unit forms containing appropriate quantities of the active component, such as an effective amount to achieve the desired purpose.
In another embodiment, the marine organism-derived natural sulfated polysaccharide, the pharmaceutically acceptable salt, or the like for use in the present invention is an injection preparation to be administered to a patient to be treated, and the injection preparation suitable for use in the present invention refers to a sterile or aseptic solution, emulsion, or suspension of the drug together with a suitable solvent or dispersion medium for injection into the human body, and a powder sterile preparation for formulation into a solution or suspension before use. The injection comprises injection (wherein the large-volume injection for intravenous drip is also called intravenous transfusion), sterile powder for injection and concentrated solution for injection.
Carriers include excipients and diluents, and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient to be treated. The carrier may be inert or it may itself have a pharmaceutical benefit.
Types of vectors include, but are not limited to: diluents such as fillers and bulking agents, binders, lubricants, anticaking agents, disintegrants, sweeteners, buffers, preservatives, solubilizers, isotonic agents, suspending and dispersing agents, wetting or emulsifying agents, flavoring and perfuming agents, thickening agents and vehicles.
Optional active agents may be included in the pharmaceutical composition which do not substantially affect the activity of the compounds of the invention.
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated. Unless otherwise indicated, reagents and materials used in the following examples are commercially available. The marine organism-derived natural sulfated polysaccharide has the following structure:
(1) fucoidan sulfate: the backbone consists of alpha-1, 3-linked sulfated fucose and has a molecular weight of 600 kDa.
(2) Iota-carrageenan: consists of repeated disaccharide units of beta-1, 3-linked galactose and alpha-1, 4-linked-3, 6-diether galactose, the C4 site of galactose residue and the C2 site of diether galactose residue are substituted by sulfate, and the molecular weight is 200 kDa.
(3) Fucosylated chondroitin sulfate: the main chain is a chondroitin sulfate disaccharide repeating unit formed by alternate connection of glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc) through beta-1, 3 and beta-1, 4 glycosidic bonds, and a fucose branched chain which is substituted by sulfate radicals at C2 and C3 is connected at C3 position of the GlcA through alpha-1, 3 glycosidic bonds, and the molecular weight is 3kDa and 50 kDa.
(4) And (3) rhamnosan sulfate: rhamnose (Rha) and glucuronic acid are alternately connected through alpha-1, 4 and beta-1, 4 glycosidic bonds, and the C2 and C3 positions of Rha in the structure contain sulfate groups; the molecular weight is 200 kDa.
Example inhibition of SARS-CoV-2 spike protein by Natural sulfated polysaccharides derived from Marine organisms
Based on SARS-CoV-2-spike protein virus detection system, the effect of fucoidan sulfate (derived from brown algae), iota-carrageenan (derived from red algae), fucosylated chondroitin sulfate (derived from sea cucumber), and rhamnosan sulfate (derived from green algae) on blocking SARS-CoV-2 infected cells was evaluated.
The sulfated polysaccharide sample adopted by the invention can be extracted by adopting conventional reagents, methods and equipment in the technical field.
1) Cell recovery culture: 293T/17 human embryonic kidney cell strain is cultured by mixing 10 percent of fetal calf serum, 1 percent of double antibody and the balance of DMEM medium according to weight percentage, and is cultured for two generations after cells are recovered for later use.
2) Preparing viroid: 293T/17 human embryonic kidney cells were plated in 6-well cell culture plates, 3. mu.g of plasmid was packaged and transfected with a transfection reagent (Lipofiter 3.0) when the cell confluency reached about 60%, and then the 6-well cell culture plates were placed in a carbon dioxide incubator (37 ℃, 5% CO)2) Culturing, transfecting for 48 hr, collecting viroid supernatant, and storing at-80 deg.C.
3) Transient transfection of cells: 293T/17 human embryonic kidney cells were plated on 6-well cell culture plates, and when the degree of cell confluence reached about 70%, 3. mu.g of plasmid (ACE2-pcDNA3.1) was transfected into 293T17 cells using a transfection reagent (Lipofilter 3.0), and the 6-well cell culture plates were cultured in a carbon dioxide incubator for 48 hours.
4) Cell digestion: the 293T/17 human embryonic kidney cells subjected to transient transfection are digested by pancreatin, the cells are resuspended by using a complete culture medium, then the cells are counted by using a cell counting instrument, and the cells are spread on a 96-well cell culture plate, wherein 12000 cells are placed in each well and cultured for 6-8 h.
5) Preparing natural sulfated polysaccharides from marine organism sources with different concentrations: preparing a mother solution with the molar concentration of 1mM by using a compound to be detected, preparing 9 diluents with different concentration gradients in the range of 0.00015-1.00 mM according to the detection concentration difference on a cell strain, and storing the diluents in a 1.5mL transparent EP tube at the temperature of-20 ℃. The prepared 9 compounds to be tested with concentration gradients are respectively diluted by 10 times by complete culture media, and dimethyl sulfoxide (DMSO) solvents with the same volume are adopted as a control.
6) Plate paving: taking out a 96-hole white cell culture plate attached to the wall for 6-8 h in an incubator, taking out 60 mu L of the white cell culture plate per hole, adding 10 mu L of the substance to be detected into the culture plate containing 40 mu L of cell volume, and repeating the culture plate with 2 multiple holes per concentration gradient in the incubator (37 ℃ and 5% CO)2) After 1 hour of medium culture, 50. mu.L of harvested viroid was added to each wellThe final detection concentration of the compound to be detected is 9 concentration gradients with the molar concentration range of 0.00152-10.00 mu M; after the culture plate is placed in an incubator and incubated for 24 hours, 100 mu L of the culture medium is replaced to continue culturing for 48 hours, and then detection is carried out.
7) Reading a plate: the Renilla luciferase detection reagent was allowed to stand at room temperature, the cell culture plate was removed and allowed to stand for 10 minutes, allowed to equilibrate to room temperature, 15. mu.L of detection reagent was added to each well, the plate was shaken on an orbital shaker for 2 minutes to induce cell lysis, the plate was allowed to stand at room temperature for 10 minutes, and the luminescence signal was measured on an MD (Molecular Devices, Meigu molecules) SpectraMaxParadigm plate reader.
8) And (3) data analysis: using the SpectraMax Paradigm readings, the corresponding per-well fluorescence values, RLU, were obtained. The data were processed using the following formula: RLU (%) ═ RLU (RLU)Drug)/(RLUDMSO) 100%. Cell viability was calculated in EXCEL for compounds at various concentrations and IC was calculated for each compound using GraphPad 7.0Prism software as a graph50The value is obtained. The results are shown in the following table,
| compound (I) | IC50(μM) |
| Heparin | 10.0 |
| Fucosan sulfate | 0.06 |
| iota-carrageenan | 0.27 |
| Fucosylated chondroitin sulfate | 0.25 |
| Rhamnosan sulfate | 0.44 |
As shown in figure 1, the series of marine organism-derived natural sulfated polysaccharides all have obvious inhibition effect on blocking novel coronavirus (SARS-CoV-2) infected cells, and the effect of the compounds including fucoidan sulfate, carrageenan, fucosylation chondroitin sulfate, rhamnosan sulfate and other marine organism-derived natural sulfated polysaccharides on blocking virus infected cells is stronger than that of Heparin (Heparin).
EXAMPLE two inhibitory Effect of Marine-derived Natural sulfated polysaccharides on SARS-CoV-2 Main protease
The SARS-CoV-2 major protease can hydrolyze a fluorescent polypeptide substrate to cause the substrate to fluoresce. The activity of the main protease is inhibited by the marine natural sulfated polysaccharide, and the fluorescence intensity is reduced compared with that of a blank control. Wherein the primary protease and the fluorescent polypeptide substrate are obtained by methods reported in W.Dai et al, Science 10.1126/science.abb4489 (2020).
(1) Preparation of TE buffer solution
Adding 100 μ L disodium ethylene diamine tetraacetate (EDTA-2Na) aqueous solution with molar concentration of 0.5M into 2.5mL Tris-HCl buffer solution with molar concentration of 1M, diluting to 50mL, adjusting pH to 7.3, filtering with 0.22 μ M filter membrane, and storing at-4 deg.C.
(2) Screening of main protease inhibitory activity of marine organism-derived sulfated polysaccharides
Adding 87 μ L TE buffer solution into 96-well cell culture plate, adding 1 μ L main protease with molar concentration of 19.7 μ M, mixing, and adding H2O (2 μ L), fucoidan sulfate aqueous solution derived from seaweed (2 μ L, molar concentration 15 μ M; molecular weight 260.1kDa), iota-carrageenan derived from Eucheuma (2 μ L, molar concentration 15 μ M; molecular weight 200kDa), keratin sulfate derived from shark bone (2 μ L, molar concentration 15 μ M, molecular weight 45.98kDa), and fucosylated chondroitin sulfate derived from sea cucumber (2 μ L, molar concentration 15 μ M, molecular weight 42kDa) were sequentially added to each well,shaking up, reacting at room temperature for 30min, adding 10 μ L substrate with molar concentration of 20 μ M into each well, and rapidly detecting fluorescence intensity by using a microplate reader. The sulfated polysaccharide sample adopted by the invention can be extracted by adopting conventional reagents, methods and equipment in the technical field.
(3) Detection conditions of microplate reader
Continuously detecting the fluorescence intensity of each hole within 10min under the conditions of excitation wavelength of 320nm, emission wavelength of 405nm and detection temperature of 27 ℃ to obtain a time-fluorescence intensity dynamic curve.
(4) Data processing
Performing linear fitting based on the obtained time-fluorescence intensity dynamic curve to obtain the slope k of the corresponding curve of the marine natural sulfated polysaccharide and the slope k of the corresponding curve of the blank control0
The inhibition rate of natural sulfated polysaccharide (molar concentration is 300nM) to main protease is (1-k/k)0)×100％
| Compound (I) | Inhibition rate/%) |
| Heparin | 72.2 |
| Fucosan sulfate | 92.3 |
| iota-carrageenan | 62.8 |
| Fucosylated chondroitin sulfate | 65.9 |
| Rhamnosan sulfate | 75.0 |
As shown in figure 2, fucoidan from brown algae, carrageenan from red algae, and fucosylated chondroitin sulfate from sea cucumber all have 50% higher inhibition rate on SARS-CoV-2 major protease activity.
EXAMPLE three inhibitory Effect of fucoidan sulfate at various concentrations on SARS-CoV-2 Main protease
(1) Inhibition experiment of fucoidan on main protease activity
Adding 87 μ L TE buffer solution into 96-well cell culture plate, adding 1 μ L main protease with molar concentration of 19.7 μ M, mixing, and adding 2 μ L LH2O and 9 seaweed-derived fucoidan sulfate aqueous solutions with the concentration gradient within the molar concentration range of 0.5 nM-45 μ M are sequentially and respectively added into each hole, the mixture is shaken up, after the reaction is carried out for 30min at room temperature, 10 μ L of substrate with the molar concentration of 20 μ M is added into each hole, and the fluorescence intensity is rapidly detected by adopting an enzyme-labeling instrument. The sulfated polysaccharide sample adopted by the invention can be extracted by adopting conventional reagents, methods and equipment in the technical field.
(2) Detection conditions of microplate reader
Continuously detecting the fluorescence intensity of each hole within 10min under the conditions of excitation wavelength of 320nm, emission wavelength of 405nm and detection temperature of 27 ℃ to obtain a time-fluorescence intensity dynamic curve.
(3) Data processing
Performing linear fitting based on the obtained time-fluorescence intensity dynamic curve to obtain the slope k of the fucoidan sulfate corresponding curve and the slope k of the blank control corresponding curve at different concentrations0
Inhibition rate of fucoidan to main protease (1-k/k) at different concentrations0)×100％
(4)IC50Computing
IC was obtained using software origin 8.1, plotting the logarithm of the concentration against the inhibition, and using non-linear fitting50The value is obtained.
(5) Results
As shown in FIG. 3, fucoidan derived from marine organism has good inhibitory effect on main protease activity and corresponding IC50Value 5.68 ± 0.43nM (nmol/L)
Experimental results show that the marine organism-derived natural sulfated polysaccharide provided by the invention has an obvious effect of inhibiting coronavirus proliferation, can inhibit the combination of Spike protein (Spike) on the surface of coronavirus and host cells, and can inhibit the activities of main protease (Mpro) and papain-like (PLpro), thereby effectively blocking coronavirus from infecting host cells.
Claims (9)
1. The application of the marine organism-derived natural sulfated polysaccharide as a medicine for resisting coronavirus and diseases caused by coronavirus is characterized in that the marine organism-derived natural sulfated polysaccharide and pharmaceutically acceptable salt are applied to preparation of a medicine combined with Spike protein (Spike), preparation of an inhibitor of main protease (Mpro) or preparation of a papain-like (PLpro) inhibitor, the marine organism-derived natural sulfated polysaccharide has any structural characteristic as follows, the molecular weight range of the marine organism-derived natural sulfated polysaccharide is 3-600 kDa, and the marine organism-derived natural sulfated polysaccharide comprises the following components:
(1) fucoidan (also called fucoidan) has one of the following structural features: (a) the I-type structure fucoidin comprises a main chain which is composed of alpha-1, 3-connected sulfated fucose; (b) the fucoidin with the type II structure comprises a main chain of sulfated fucose alternately connected with alpha-1, 3 and alpha-1, 4; (c) the fucoidan with III-type structure comprises a main chain consisting of beta-1, 4-glucuronic acid and alpha-1, 2-mannose, and a branch structure consisting of alpha-1, 3-sulfated fucooligosaccharide; (d) other types of fucoidan, the backbone of which consists of sulfated fucose in α -1,2 and α -1,3 and/or α -1, 4-linkages;
(2) fucosylated chondroitin sulfate, its structural features are as follows: a chondroitin sulfate disaccharide repeating unit with a main chain formed by alternately connecting glucuronic acid (GlcA) and N-acetylgalactosamine (GalNAc) through beta-1, 3 and beta-1, 4 glycosidic bonds, and a sulfated fucooligosaccharide branch chain is connected at the C3 position of the GlcA through an alpha-1, 3 glycosidic bond;
(3) the sulfated galactan has the following structural characteristics: galactose (Gal) consisting of β -1, 3-linked and α -1, 4-linked galactose or β -1, 3-linked and α -1, 4-linked-3, 6-lacto galactose (AnG), and galactose containing different sulfate groups at the C2, C4 or C6 positions;
(4) and (3) rhamnosan sulfate: the structure is characterized as follows: is formed by connecting rhamnose (Rha) and glucuronic acid alternately through alpha-1, 4 and beta-1, 4 glycosidic bonds; or Rha and iduronic acid are alternately connected through alpha-1, 4 glycosidic bonds; or rhamnose (Rha) and xylose (Xyl) are alternately connected through alpha-1, 4 and beta-1, 4 glycosidic bonds; or alternatively connected by alpha-1, 2 and alpha-1, 3-rhamnose; and the C2 and/or C3 position of the structure Rha contains a sulfate group.
2. The use of claim 1, wherein the type I fucoidan has a branched structure of other sugar residues; the fucoidan with type II structure also has other sugar residue branched structure.
3. The use of claim 1, wherein the coronavirus is selected from the group consisting of one or more of SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS-CoV.
4. Use according to claim 1, wherein the natural sulfated polysaccharides are derived from marine plants or marine animals.
5. Use according to claim 1, wherein the native sulfated polysaccharides inhibit viral replication and amplification by binding to the Spike protein (Spike) of a coronavirus, as an inhibitor to inhibit its infection into cells, by inhibiting the activity of the coronavirus main protease (Mpro) and/or the papain-like protease (PLpro).
6. Use according to claim 1, wherein the natural sulfated polysaccharide, a pharmaceutically acceptable salt, is used in the preparation of a coronavirus inhibitor.
7. Use according to claim 1, wherein the natural sulfated polysaccharide, a pharmaceutically acceptable salt, is used for the manufacture of a medicament for the prevention and/or treatment of a coronavirus infection, or for the prevention and/or treatment of a disease or condition associated with a coronavirus infection.
8. Use according to claim 1, wherein the use is in a kit or reagent for binding of a native sulfated polysaccharide, a pharmaceutically acceptable salt, to Spike protein (Spike), a kit or reagent for the preparation of an inhibitor of the main protease (Mpro), or a kit or reagent for the preparation of an inhibitor of the papain-like protease (PLpro).
9. The use of claim 1, wherein the natural sulfated polysaccharide, the pharmaceutically acceptable salt, and the additional one or more than two active agents for preventing and/or treating coronavirus infection are mixed to form a pharmaceutical composition for preventing and/or treating coronavirus infection.
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| CN112220799A (en) * | 2020-11-02 | 2021-01-15 | 江苏泰德医药有限公司 | Product for inhibiting virus and application |
| CN113181207A (en) * | 2021-02-06 | 2021-07-30 | 中国海洋大学 | Use of oligomannuronic acid phosphate for the preparation of a medicament for the prevention and treatment of novel coronavirus infections |
| WO2022219071A1 (en) * | 2021-04-13 | 2022-10-20 | Philip Morris Products S.A. | Composition comprising a eukaryotic microalgae or an extract thereof for use in the treatment of a viral disease |
| WO2022217763A1 (en) * | 2021-04-14 | 2022-10-20 | 大连工业大学 | Sulfated abalone polysaccharide and application thereof in inhibiting sars-cov-2 |
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| CN114732827B (en) * | 2022-06-10 | 2022-09-27 | 中国海洋大学 | Application of sulfated polysaccharides from different marine organisms and pharmaceutical composition thereof |
| WO2024078312A1 (en) * | 2022-10-14 | 2024-04-18 | 华东理工大学 | Anti-sars-cov-2 use of sulfonated polysaccharide |
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