WO2021155798A1 - Utilisation d'un polypeptide immun dans un médicament antiviral - Google Patents

Utilisation d'un polypeptide immun dans un médicament antiviral Download PDF

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Publication number
WO2021155798A1
WO2021155798A1 PCT/CN2021/075008 CN2021075008W WO2021155798A1 WO 2021155798 A1 WO2021155798 A1 WO 2021155798A1 CN 2021075008 W CN2021075008 W CN 2021075008W WO 2021155798 A1 WO2021155798 A1 WO 2021155798A1
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peptide
polypeptide
coronavirus
gly
replication
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PCT/CN2021/075008
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Chinese (zh)
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程云
虞瑞鹤
赵万洲
梅其炳
武琰涛
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程云
虞瑞鹤
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention belongs to the field of medical technology. Specifically, the present invention relates to the application of immunogenic peptides and derivatives thereof in antiviral drugs, and in particular to the application of the peptides or derivatives thereof in preparing drugs for inhibiting human coronavirus.
  • the peptide with the sequence of GQTYTSG (herein referred to as 7P) is an immunogenic peptide originally designed based on the hepatitis C virus.
  • Peptide 7P and its derivatives are also proposed that 7P and its derivatives can also be used to prevent and treat liver damage, especially to prevent or treat immune liver damage and hepatotoxic chemicals. Liver damage.
  • Coronavirus has a huge impact on human health, and their genetic recombination may lead to the emergence of new strains, research and development of new antiviral strategies are crucial.
  • the technical problem solved by the present invention is to provide a new application of immune polypeptides in suppressing viruses, so as to provide a basis for antiviral research and strategy implementation.
  • an application of an immune polypeptide or its derivative in the preparation of a drug for inhibiting human coronavirus replication refers to the peptide represented by the following formula I or its pharmaceutically acceptable
  • Xaa1 is deletion, Ala, Gly, Val, Leu or Ile,
  • Xaa2 is Thr or Ser
  • Xaa3 is Tyr, Phe or Trp
  • Xaa4 is deletion, Ala, Gly, Val, Leu, Ile, or Pro.
  • the inhibition of human coronavirus replication is achieved by combining the immune polypeptide with the 3CL protease protease, especially by competing for binding to the active center of the protease, thereby inhibiting rapid virus replication.
  • coronavirus is a large virus family. Whenever a new strain appears, it poses new challenges to suppression and treatment technologies. The global epidemic in 2020 is due to a previous The unknown coronavirus (known as the "new coronavirus") spreads widely and infects many people, which can be said to far exceed other similar viruses.
  • the human coronavirus may especially be the above-mentioned new coronavirus and coronaviruses of similar nature.
  • the new coronavirus (COVID-19) that caused pneumonia in 2020 also includes The mutated virus that may appear due to COVID-19.
  • the inhibitory activity of the 7P peptide with the sequence GQTYTSG on human coronaviruses was studied, and it was proved that it can inhibit the rapid replication of the coronavirus, which can suggest that 7P or its derivatives are the effective ingredients of the corresponding anti-coronavirus drugs. , And can be used as the only active ingredient of the drug.
  • the present invention provides the application of the above-mentioned immune polypeptide or its derivative in the preparation of a medicine for the treatment of pneumonia.
  • the pneumonia is caused by a coronavirus
  • the immune polypeptide or its derivative is the peptide represented by the following formula I or its pharmacologically Acceptable salt or ester:
  • Xaa1 is deletion, Ala, Gly, Val, Leu or Ile,
  • Xaa2 is Thr or Ser
  • Xaa3 is Tyr, Phe or Trp
  • Xaa4 is deletion, Ala, Gly, Val, Leu, Ile, or Pro.
  • the pneumonia caused by coronavirus infection targeted by the present invention specifically includes pneumonia caused by new coronaviruses such as COVID-19 and coronaviruses of similar nature or mutations thereof, for example, due to COVID-19 in 2020
  • the pneumonia epidemic caused by -19 infection, the pneumonia caused by COVID-19 is also called the new type of coronavirus pneumonia.
  • the active ingredient of the medicine for treating pneumonia provided by the present invention may contain or only use the above-mentioned immune polypeptide as the only effective ingredient, for example, 7P peptide or its derivative is the only effective ingredient, thereby providing a novel anti-coronavirus drug.
  • another aspect of the present invention also provides a drug, which is a drug for inhibiting the replication of human coronavirus and/or a drug for treating pneumonia caused by coronavirus infection, wherein the drug includes An immune polypeptide or a derivative thereof, wherein the immune polypeptide or a derivative thereof is a polypeptide represented by the following formula I or a pharmaceutically acceptable salt or ester thereof:
  • Xaa1 is deletion, Ala, Gly, Val, Leu or Ile,
  • Xaa2 is Thr or Ser
  • Xaa3 is Tyr, Phe or Trp
  • Xaa4 is deletion, Ala, Gly, Val, Leu, Ile, or Pro.
  • the human coronavirus is COVID-19, or its mutant virus; the inhibition of human coronavirus replication is through the combination of immune polypeptide and 3CL protease protease, thereby inhibiting virus replication; the immune polypeptide has the following sequence The 7P peptide: GQTYTSG; this 7P peptide is the only effective ingredient in drugs that inhibit human coronavirus replication.
  • a method for the treatment of respiratory diseases or pneumonia caused by coronavirus infection which comprises administering to a patient a drug containing the polypeptide represented by the following formula I or a pharmaceutically acceptable salt or ester thereof as an active ingredient:
  • Xaa1 is deletion, Ala, Gly, Val, Leu or Ile,
  • Xaa2 is Thr or Ser
  • Xaa3 is Tyr, Phe or Trp
  • Xaa4 is deletion, Ala, Gly, Val, Leu, Ile, or Pro.
  • the respiratory disease or pneumonia is caused by a coronavirus infection;
  • the coronavirus is COVID-19, or a variant virus thereof;
  • the immune polypeptide is a 7P peptide with the following sequence: GQTYTSG; the 7P peptide is the The only active ingredient in the medicine.
  • the implementation of the present invention has significant value for further effectively inhibiting the mechanism of coronavirus replication, as well as for the development of clinical medications and treatment plans for related diseases caused by coronavirus infection.
  • Figure 1 shows the high-resolution crystal structure of COVID-19 coronavirus 3CL hydrolase (Mpro).
  • Figure 2 shows the effect of the binding mode of the ligand molecule in the crystal structure of the 3CL hydrolase protein.
  • Figure 2 shows the effect of the binding mode of the ligand molecule in the crystal structure of the 3CL hydrolase protein.
  • A shows the binding mode of the natural ligand and 3CL protease in the protein crystal structure
  • C shows the superimposing effect of the docking conformational binding mode of the short peptide 7P in the protein crystal structure with the binding mode ranked first in the docking score and the binding mode of the ligand in the protein crystal structure.
  • Figure 3 shows the docking conformation distribution diagram of the top 10 binding modes of the short peptide 7P docking score in the experimental example.
  • the present invention is a new achievement based on the existing technology and research against the coronavirus.
  • the large open reading frame (ORF) 1a/1ab gene located at the 5'end of the genome is responsible for the expression of two large replicase polyproteins (pp).
  • These virus-encoded 3CL pro and papain-like protease (Papain-like Protease) cooperate or cleave after translation to produce 16 non-structural proteins responsible for virus replication.
  • 3CL pro is also called the main protease because it has 11 cleavage sites in pp1a and pp1ab, while papain-like protease has only 3 cleavage sites.
  • 3CL pro has three different domains. Domains I and II are largely composed of several anti-parallel ⁇ -barrels and long loop regions connected to domain III. Domain III is composed of several globular alpha helices ( ⁇ -helices) and functioning protein dimerization. The active site is located in the chymotrypsin-like fold between the I and II domains. It contains the catalytic dimer of His41, which acts as a proton acceptor, and Cys144/5 nucleophilic attack on the carbonyl carbon of the substrate.
  • coronavirus 3CL pro have high sequence homology, and the main chain structure and substrate are conserved.
  • the substrate binding site of 3CL pro has two deeply buried S1 and S2 subsites, and the shallowly buried S1, S3 and S4 subsites have varying degrees of solvent exposure.
  • the substrate specificity of coronavirus 3CL pro is mainly determined by P1, P2 and P1'. In theory, since these viruses have highly homologous binding sites and substrate conservation, it is reasonable to predict that broad-spectrum inhibitor strategies may be successful. Therefore, this study of the present invention will provide further evidence for the identification of broad-spectrum 3CL pro inhibitors.
  • 3CL pro is also known as the main protease (Mpro), which plays a key role in the virus life cycle, including the processing of polyproteins and virus replication.
  • the polyproteins pp1a and pp1ab were subsequently cleaved into 16 non-structural functional proteins (nsp1 to nsp16). These proteins are mainly involved in the proteolytic process and viral RNA synthesis, including genome replication and subgenomic mRNA synthesis.
  • the remaining genome contains 9 orf, which encode 4 structural proteins-ear protein (S), nucleocapsid protein (N), membrane protein (M) and envelope protein (E), and 5 accessory proteins (3a -c, 7a and 7b).
  • inhibitors targeting 3CL pro including pyridine n-oxide derivatives, peptidomimetic analogs, covalent inhibitors and peptidyl compounds, have been evaluated.
  • Natural products of herbal extracts may become the main resource for the development of antiviral drugs.
  • Previous studies have shown that natural compounds have antiviral activity against 3CL pro of SARs-CoV and interfere with virus replication. There is currently no antiviral drug for 3CL pro.
  • the drug screening work against the new coronavirus COVID-19 was carried out.
  • the similarity of the new coronavirus 3CL hydrolase (3C-like Proteinase, 3CL protease, 3CL pro ) and SARS reaches 96%. Through this strategy, it is suggested that potential 3CL hydrolase inhibitors can be obtained.
  • 3CL protease protease that is synthesized and cleaved. Therefore, 3CL protease is an important target for research on inhibiting the replication and reproduction of coronaviruses.
  • results of this molecular simulation docking show that artificially synthesized immune peptides derived from the E1-C end of the hepatitis C virus HCV envelope, such as GQTYTSG synthetic peptide, combined with the active center of 3CL protease protease, showing that the synthetic peptide and 3CL protease protein
  • the competitive binding of hydrolase (3CL pro ) substrates is expected to inhibit the replication and reproduction of coronaviruses (such as COVID-19), and it is possible to treat such coronavirus infections.
  • the immune polypeptide studied in the present invention can also be called immune 7 peptide, especially 7P peptide, which itself is a previously disclosed product. Therefore, the definition of the immune polypeptide, the method of obtaining it, and related drugs are all You can refer to the published content. For ease of reading, a brief explanation is as follows.
  • “Pharmaceutically acceptable ester” refers to an ester suitable for contact with human or animal tissues without excessive toxicity, irritation, or allergic reactions. Generally, esterification modification can reduce the hydrolysis of peptides by proteases in the body.
  • the terminal amino group, carboxyl group or side chain group of the peptide of the present invention can be modified to form a pharmaceutically acceptable ester. Modifications to amino acid side chain groups include, but are not limited to, the esterification reaction of threonine and serine side chain hydroxyl groups with carboxylic acids.
  • the terminal group is protected with a protective group known to those skilled in the field of protein chemistry, such as acetyl, trifluoroacetyl, Fmoc (9-fluorenyl-methoxycarbonyl), Boc (tert-butoxycarbonyl), Alloc (allyloxycarbonyl), C1-3 alkyl, C6-12 aralkyl, etc.
  • a protective group known to those skilled in the field of protein chemistry, such as acetyl, trifluoroacetyl, Fmoc (9-fluorenyl-methoxycarbonyl), Boc (tert-butoxycarbonyl), Alloc (allyloxycarbonyl), C1-3 alkyl, C6-12 aralkyl, etc.
  • 7P is sufficient for treatment under physiological conditions without modification, so we can choose not to modify the N-terminal amino group and the C-terminal carboxyl group and amino acid side chain groups of the polypeptide of formula I.
  • the N-terminal chemical group is still the ⁇ -amino group (-NHB 2B ) on the first amino acid
  • the C-terminal chemical group is the C-terminal amino acid carboxyl group (-COOH), so it is also called amino acid 7 peptide.
  • “Pharmaceutically acceptable salt” refers to a salt suitable for contact with human or animal tissues without excessive toxicity, irritation, or allergic reactions. Pharmaceutically acceptable salts are well known in the art. This salt can be prepared during the final separation and purification of the polypeptide of the present invention, or the peptide can be separately prepared by reacting the peptide with a suitable organic or inorganic acid or base.
  • Representative acid addition salts include, but are not limited to, acetate, dihexanoate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate , Camphorate, camphorsulfonate, glycerophosphate, hemisulfate, heptanoate, caproate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate Acid salt, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, 3-phenylpropionate, propionate, succinate, tartrate , Phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.
  • the preferred acids that can be used to form pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid, and citric acid.
  • Cations in pharmaceutically acceptable base addition salts include, but are not limited to, alkali metal or alkaline earth metal ions such as lithium, sodium, potassium, calcium, magnesium, and aluminum, and non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, Tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, diethylamine, ethanolamine, diethanolamine, piperidine, piperazine, etc.
  • Preferred base addition salts include phosphate, tris and acetate. These salts generally can increase the solubility of the polypeptide, and the formed salt does not substantially change the activity of the polypeptide.
  • the polypeptide of the present invention can be used alone or in the form of a pharmaceutically acceptable salt.
  • drug can be used interchangeably unless otherwise specified, and refer to a product containing active ingredients of a drug, and optionally it also contains A pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to non-toxic solid, semi-solid or liquid fillers, diluents, adjuvants, wrapping materials or other preparation excipients.
  • the carrier used can be compatible with the corresponding administration form, and can be formulated into injections, (for injection) freeze-dried powders, sprays, oral solutions, oral suspensions, tablets, capsules, etc., using carriers known to those skilled in the art.
  • the administration is by injection, and it is dissolved in physiological saline as a carrier. Therefore, the drug of the present invention may be an injection or a freeze-dried powder for injection.
  • the drug may be a unit preparation, that is, a preparation that satisfies the active ingredients required for one administration.
  • unit preparations such as a unit (tablet) tablet, a unit (needle) injection or powder injection, etc., where the active ingredient is the amount required for one administration.
  • dose the dose per unit body weight required for one administration of the subject.
  • dose the dose per unit body weight required for one administration of the subject.
  • the weight of an adult is usually set as 60 kg, and this weight value can be used for calculation.
  • the unit body weight dose of different subjects can be calculated through the equivalent dose conversion relationship.
  • the effective human dose can be derived from the dose of experimental animals.
  • dose herein refers to the dose for rats.
  • a factor of 6 can usually be used to convert human and rat doses.
  • the pharmaceutical manufacturer can convert the content of the active ingredient in the unit preparation for application in its pharmaceutical process.
  • the dose of 7P or its derivatives in a unit preparation can be 30-300 ⁇ g/kg rat dose, or 40-180 ⁇ g/kg rat dose, such as 174, 87, or 43.5 ⁇ g/kg Rat dose.
  • the unit preparation contains 300-3000 ⁇ g 7P or its derivatives, preferably 400-1800 ⁇ g 7P or its derivatives, such as 1740, 870, or 435 ⁇ g 7P or its derivatives.
  • the inventors used a molecular docking method to specifically study the binding mode of COVID-19 virus target protein 3CL protease and 7P peptide (GQTYTSG), and further studied the effect of 7P peptide (GQTYTSG) on 3CL. Inhibition of protease activity.
  • the crystal structure of the COVID-19 coronavirus 3CL hydrolase complex analyzed and determined by the research team of Shanghai University of Science and Technology Rao Zihe is to delete the water molecules and small molecular compounds, leaving the protein structure, and the high-resolution crystal structure obtained Figure 1.
  • the coordinates of the crystal structure are from the PDB Protein Data Bank (PDB) (ID: 6LU7).
  • the above-mentioned protein structure is used as the receptor, and the 7P peptide sequence is input.
  • the following parameters are used: three peptide structure models are generated, and the peptide conformation RMSD value is set to The exhaustiveness value of the conformation search is set to 100, and the molecular docking is expanded.
  • MDOCK uses a statistical function of basic knowledge to evaluate the binding ability between short peptides and proteins.
  • the binding ability is reflected logarithmically as an evaluation score (matching scoring).
  • the score value for docking is a negative number. The lower the score value, the stronger the bonding ability or the greater the possibility of bonding.
  • Table 1 shows the docking scores of the top 10 binding modes (Model 1 to Model 1) of short peptide 7P and 3CL protein binding ability.
  • the binding mode (Model 1) ranked No. 1 is very similar to the binding mode of the ligand in the crystal structure of the 3CL protein.
  • FIG 2 A, B, C, and A shows the binding mode of natural ligands, which are represented by a blue stick-shaped model in the color diagram (A);
  • the purple-red stick model represents (B), and it can be seen that the binding conformation of the natural ligand in A is very similar; the effect of superimposing the two also illustrates this point (C).
  • the 3CL protein is represented by a ribbon model (shown in green in the color picture), and the natural ligand in the crystal structure is represented by a relatively thick stick model (color picture) (Shown in blue in the middle), the 7P docking conformation is represented by a relatively thin rod-shaped model (shown in purple in the color picture), and it is obviously observed that they are more concentrated.
  • the short peptide 7P may bind to the enzyme active pocket region of 3CL protease and compete with the natural substrate to occupy this pocket region.
  • Table 1 The top 10 binding modes of short peptide 7P and 3CL protease
  • the target molecule is docked to the structure of the target 3CL protease.
  • the 7P peptide has a docking conformation that binds to the active pocket region of 3CL protease. It can be considered that the short peptide 7P binds to the active pocket region of 3CL protease and competes with the natural substrate to occupy the pocket region.
  • This experimental example investigates the effect of 7P peptide and control peptide on the enzyme activity of 3C-like Proteinase.
  • the main principle is: both the fluorescent group EDANS and the quenching group DABCYL are connected to the natural substrate of 3CL Pro protease (such as Dabcyl-KTSAVLQSGFRKME- Edans), when the substrate is not cut off, DABCYL can quench the fluorescence of EDANS, so that no fluorescence can be detected; when the substrate is cut off by 3CL Pro , the fluorescence of EDANS is no longer quenched by DABCYL, and then EDANS can be detected.
  • 3CL Pro protease such as Dabcyl-KTSAVLQSGFRKME- Edans
  • Buffer 20mM Tris-HCl buffer, pH 7.0;
  • Standard enzyme solution 3C-like Proteinase dissolved in deionized water to form an enzyme solution with a concentration of 1.2ug/ul;
  • Substrate solution Dabcyl-KTSAVLQSGFRKME-Edans (coronavirus main protease fluorescent substrate, hereinafter referred to as substrate) is stored in deionized water at a concentration of 3mM.
  • Test substance a) The 7P peptide was dissolved in distilled water to a 1mg/ml 7P peptide solution; b) The control polypeptide was dissolved in distilled water into a 1mg/ml control polypeptide solution; the control polypeptide was obtained by chemical synthesis, and its sequence is RKNHVGL is close to the 7P peptide amino acid number and sequence to exclude the non-specificity of the peptide sequence.
  • Testing equipment Microplate reader, using 96-well plate/enzyme plate.
  • the measurement process is as follows: each take 100 ⁇ L The 1st dilution to the 11th dilution were placed in the wells of the 96-well plate/enzyme standard plate (100 ⁇ L per well), excited at the wavelength of 340nm, and measured the absorbance value (RFU value) at the wavelength of 535nm.
  • the enzyme amount in is the abscissa and the RFU value is the ordinate to draw a standard curve, and fit the slope of the standard curve.
  • test group
  • Blank control group Take 10 ⁇ L of the enzyme solution in the above-mentioned buffer replacement step (B) to perform the above process, and measure the change in fluorescence intensity per minute RFU Blank of the blank control group;
  • control peptide has basically no effect on the 3C-like Proteinase activity, while the 7P peptide has a significant inhibitory effect on the 3C-like Proteinase activity.

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Abstract

L'invention concerne l'utilisation d'un polypeptide immun dans un médicament antiviral et l'utilisation d'un polypeptide immun ou d'un dérivé de celui-ci dans la préparation d'un médicament pour inhiber la réplication de coronavirus infectieux humains. L'invention concerne en outre l'utilisation d'un polypeptide immun ou d'un dérivé de celui-ci dans la préparation d'un médicament pour le traitement de la pneumonie, la pneumonie étant provoquée par une infection à coronavirus. La solution est de valeur significative pour la recherche sur le mécanisme d'inhibition plus efficace de la réplication de coronavirus, et le développement de médicaments cliniques et de schémas de traitement pour des maladies associées provoquées par une infection à coronavirus.
PCT/CN2021/075008 2020-02-06 2021-02-03 Utilisation d'un polypeptide immun dans un médicament antiviral WO2021155798A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113735937A (zh) * 2021-10-09 2021-12-03 深圳湾实验室坪山生物医药研发转化中心 靶向2019新型冠状病毒的木瓜蛋白酶样蛋白酶PLpro的稳定多肽类蛋白共价抑制剂
CN113735937B (zh) * 2021-10-09 2023-10-20 深圳湾实验室坪山生物医药研发转化中心 靶向2019新型冠状病毒的木瓜蛋白酶样蛋白酶PLpro的稳定多肽类蛋白共价抑制剂

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