Use of a cornu saigae tatarica keratin BK-58 in the preparation of a drug for preventing or treating psychogenic fever

Abstract

The present application relates to the application of cornu saigae tataricae keratin BK-58 in the preparation of a medicine for preventing and / or treating psychogenic fever, wherein the amino acid sequence of the cornu saigae tataricae keratin BK-58 is shown as SEQ ID NO:1. The present application proves by animal psychogenic fever model experiment that the cornu saigae tataricae keratin BK-58 can significantly reduce the core body temperature of mice caused by psychological stress, and the antipyretic effect is superior to or equivalent to that of cornu saigae tataricae powder. The cornu saigae tataricae keratin BK-58 provided by the present application can be used as a substitute for cornu saigae tataricae to prepare a medicine for relieving psychogenic fever, and has the advantages of definite curative effect, stable source and high safety. The medicine can be prepared into various oral or injection preparations, and is suitable for different patient groups.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to the pharmaceutical use of a keratin fragment BK-58 derived from antelope horn, and particularly to the use of this keratin in the preparation of drugs for the prevention and / or treatment of psychogenic fever. Background Technology

[0002] Fever, referring to an increase in body temperature due to an elevation of the body's temperature set point, is one of the most common clinical conditions. Its onset can be related to various factors, including infection with pathogens, malignant tumors, surgery, and psychological stress. Among these, fever caused by psychological stress, also known as "psychogenic fever," has received increasing attention in recent years. Psychogenic fever refers to an abnormally elevated body temperature triggered by psychological or emotional factors (such as stress, anxiety, and depression). It falls under the category of mental illness. Under psychological stress, patients may experience acute or persistently elevated body temperatures, commonly accompanied by various physical symptoms such as insomnia, fatigue, headache, nausea, and even sudden blindness.

[0003] Psychogenic fever differs from the more well-known infectious fever. Infectious fever is caused by exogenous pyrogens entering the body and producing pyrogenic factors such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). These pyrogenic factors stimulate the preoptic area (POA) of the hypothalamus to produce prostaglandin E2 (PGE2). PGE2 binds to prostaglandin E receptor 3 (EP3), which upregulates the body's temperature set point, causing an abnormal increase in body temperature. However, psychogenic fever is not strongly correlated with inflammatory factors in the body. Psychological stress primarily leads to a rapid increase in body temperature by increasing metabolic heat production and reducing heat loss through the skin.

[0004] Currently, the main types of drugs used in Western medicine to treat psychogenic febrile diseases are: 1. Benzodiazepines: diazepam; 2. 5-HT1A receptor agonists: tandospirone; 3. 5-hydroxytryptamine and norepinephrine reuptake inhibitors: venlafaxine, duloxetine.

[0005] However, since the mechanism of psychogenic fever does not involve an abnormal increase in the body's PGE2 levels, conventional nonsteroidal antipyretics (NSAIDs) are ineffective in relieving stress-induced fever, and many patients do not receive timely and effective treatment. Clinically, psychogenic fever is mainly treated with anti-anxiety medications such as the benzodiazepine sedative-hypnotic drug diazepam and the 5-HT1A receptor agonist tandospirone, combined with psychological intervention. However, this approach is often accompanied by various adverse reactions such as drowsiness, fatigue, nausea, and vomiting, and is not suitable for children. Therefore, finding new therapeutic drugs and targets to prevent and treat psychogenic fever is of great significance.

[0006] Animal-based traditional Chinese medicine has a history of use in my country spanning thousands of years and possesses unique advantages. Among these, antelope horn is particularly effective in treating febrile diseases and has been widely used throughout history. Antelope horn, the horn of the male saiga antelope (Saiga tatarica Linnaeus), is believed to have effects such as clearing the liver and improving eyesight, calming the liver and extinguishing wind, cooling the blood and detoxifying. Clinically, it is often used for persistent high fever, headache, dizziness, and epileptic seizures, especially febrile convulsions in children, with a safe and rapid onset of action. However, the saiga antelope is listed as Critically Endangered (CR) on the IUCN Red List of Threatened Species (2012 ver 3.1), and is completely extinct in China. Furthermore, artificial breeding is difficult, resulting in a small population and limiting its clinical application. In addition, the active ingredients and mechanisms of action of antelope horn are still unclear. Therefore, exploring the active ingredients that contribute to the antipyretic effects of antelope horn and developing alternatives is particularly important. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides an active ingredient that can effectively alleviate psychogenic fever as an alternative to antelope horn, and its pharmaceutical applications. Specifically, this invention aims to provide an antelope horn keratin fragment BK-58 with definite efficacy, stable source, and high safety, for use in the preparation of drugs for the prevention and / or treatment of psychogenic fever.

[0008] In a first aspect, the present invention provides antelope keratin BK-58 or a variant thereof, wherein the antelope keratin BK-58 comprises the amino acid sequence shown in SEQ ID NO: 1.

[0009] In some embodiments, the variant comprises an amino acid sequence obtained by substitution, deletion, or insertion of one or more amino acids based on SEQ ID NO: 1. In some embodiments, the variant has at least 85%, 90%, or more than 95% identity with SEQ ID NO: 1 and has a function equivalent to or better than SEQ ID NO: 1.

[0010] In a second aspect, the present invention provides a nucleic acid encoding the antelope keratin BK-58 or a variant thereof described in the first aspect.

[0011] Thirdly, the present invention provides a carrier comprising the nucleic acid described in the second aspect.

[0012] Fourthly, the present invention provides a host cell comprising the nucleic acid described in the second aspect or the vector described in the third aspect.

[0013] Fifthly, the present invention provides the use of the antelope keratin BK-58 or a variant thereof described in the first aspect or the nucleic acid described in the second aspect in the preparation of a medicament for the prevention and / or treatment of psychogenic fever.

[0014] In some implementations, the psychogenic fever is an abnormal increase in body temperature caused by psychological or emotional factors, including stress, anxiety, and depression.

[0015] In some embodiments, the drug is a gastrointestinal or parenteral administration formulation.

[0016] In some embodiments, the gastrointestinal delivery formulation is selected from tablets, capsules, granules, oral solutions, or oral emulsions;

[0017] In some embodiments, the gastrointestinal drug delivery formulation further comprises one or more of a pharmaceutically acceptable filler, diluent, binder, disintegrant, wetting agent, or lubricant.

[0018] In some embodiments, the parenteral administration formulation is selected from large-volume injections, small-volume injections, lyophilized powder injections, or fat emulsion injections.

[0019] In some embodiments, the parenteral administration formulation further comprises one or more of a pharmaceutically acceptable pH adjuster, antioxidant, osmotic pressure regulator, lyophilization protectant, solubilizer, preservative, or chelating agent.

[0020] In a sixth aspect, the present invention provides a pharmaceutical composition for the prevention and / or treatment of psychogenic fever, comprising the antelope keratin BK-58 or a variant thereof as described in the first aspect, and pharmaceutically acceptable excipients.

[0021] In some embodiments, the pharmaceutical composition is a gastrointestinal or parenteral administration formulation.

[0022] In some embodiments, the gastrointestinal administration formulation is selected from tablets, capsules, granules, oral solutions, or oral emulsions.

[0023] In some embodiments, the gastrointestinal drug delivery formulation further comprises one or more of a pharmaceutically acceptable filler, diluent, binder, disintegrant, wetting agent, or lubricant.

[0024] In some embodiments, the parenteral administration formulation is selected from large-volume injections, small-volume injections, lyophilized powder injections, or fat emulsion injections.

[0025] In some embodiments, the parenteral administration formulation further comprises one or more of a pharmaceutically acceptable pH adjuster, antioxidant, osmotic pressure regulator, lyophilization protectant, solubilizer, preservative, or chelating agent.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1) This invention is the first to discover and confirm that the antelope keratin fragment BK-58 has a significant effect in relieving psychogenic fever, providing a new active ingredient and drug option for the prevention and / or treatment of psychogenic fever.

[0028] 2) The keratin BK-58 provided by this invention can be stably prepared by genetic engineering methods, does not depend on endangered animal antelope horn resources, and has the advantages of stable source and sustainable production.

[0029] 3) The antipyretic effect of the keratin BK-58 of this invention is better than or equivalent to that of antelope horn powder, and it does not have the adverse reactions such as drowsiness and fatigue of traditional anti-anxiety drugs. It has high safety and is especially suitable for pediatric patients.

[0030] 4) The keratin BK-58 of this invention can be formulated into a variety of oral or injectable preparations to meet the medication needs of different patients. Attached Figure Description

[0031] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0032] Figure 1 A shows the core body temperature change curves of mice in each group. The real-time body temperature changes after cage change stress were observed in the blank control group, model group, SAH-P group (antelope horn powder group), and BK-58 group.

[0033] Figure 1 B shows the curves of ΔT (body temperature change) over time in each group of mice after stress. The differences in body temperature changes at different time points after modeling are compared among the model group, SAH-P group, and BK-58 group.

[0034] Figure 1 C is a bar chart comparing ΔTmax (maximum body temperature change) after stress in each group of mice. *** indicates P < 0.001 compared to the model group.

[0035] Figure 1 D- Figure 1 F is a bar chart comparing the area under the curve (AUC) of body temperature differences in mice at different time intervals (0.5 h, 1 h, 1.5 h) after stress. * indicates P < 0.05 compared with the model group, ** indicates P < 0.01, and *** indicates P < 0.001. Detailed Implementation

[0036] In this invention, unless otherwise stated, the following terms have the following meanings:

[0037] "Psychogenic fever" refers to an abnormally elevated body temperature caused by psychological or emotional factors (such as stress, anxiety, depression, etc.), and falls under the category of mental illness. Unlike infectious fever, psychogenic fever is not directly related to elevated levels of inflammatory factors in the body (such as IL-1, IL-6, TNF-α, etc.). Psychological stress mainly leads to a rapid increase in body temperature by increasing the production of metabolic heat and reducing heat loss from the skin.

[0038] "ΔT" refers to the change in body temperature, which is the difference between the body temperature after stress and the baseline body temperature.

[0039] "ΔTmax" refers to the maximum change in body temperature after stress.

[0040] "SAH-P" refers to Saiga Antler Horn Powder.

[0041] “BK-58” refers to the antelope horn keratin fragment of the present invention, with the amino acid sequence CGFPICSTGGTCGSSPCQPTCCQTSCCQPTSIQTSCCQPISIQTSCCQPTCLQTSGCETGCGVGGSIGYGQLGSSGAVSSRTRWCRPDCRVEGTSLPPC (SEQ ID NO: 1). Invention Details

[0043] This invention provides the application of the antelope horn keratin fragment BK-58 in the preparation of drugs for the prevention and / or treatment of psychogenic fever. During in-depth research on the antipyretic active components of antelope horn, the inventors first discovered and isolated a keratin fragment with a specific short peptide sequence, BK-58, and confirmed that this fragment can significantly alleviate psychological stress-induced fever. The invention is described in detail below regarding its preparation method, mechanism of action, administration regimen, and pharmaceutical composition. This description is a general overview of the technical solution of this invention; specific implementation conditions can be found in the examples section.

[0044] 1. Preparation of keratin BK-58

[0045] The keratin BK-58 of this invention is an artificial recombinant protein that can be produced on a large scale through genetic engineering, thereby avoiding direct reliance on endangered saiga antelope resources.

[0046] 1.1 Expression System

[0047] The expression systems suitable for this invention include, but are not limited to, prokaryotic expression systems (such as *Escherichia coli* BL21(DE3), *Rosetta*, etc.), yeast expression systems (such as *Pichia pastoris*), or eukaryotic expression systems (such as insect cell-baculovirus systems). Among these, prokaryotic expression systems are preferred due to their ease of operation, low cost, and high expression levels. The expression vector can be a vector with a histidine tag (His-tag), a GST tag, or other affinity tags to facilitate subsequent purification.

[0048] 1.2 Expression Conditions

[0049] Key parameters affecting the expression efficiency and solubility of keratin BK-58 include: induction temperature (generally 4-37℃), induction time (2-24 hours), IPTG concentration (0.05-1.0 mM) or lactose concentration, and culture medium composition (LB, TB, M9, etc.). Typically, lower temperatures (15-25℃) and lower concentrations of inducers (0.1-0.5 mM) are beneficial for increasing the proportion of soluble protein and reducing inclusion body formation. Those skilled in the art can optimize these parameters using conventional SDS-PAGE analysis based on the strain and vector used.

[0050] 1.3 Purification and Renaturation

[0051] Regardless of the expression system used, recombinant proteins must be purified. For His-tagged fusion proteins, one-step purification can be performed using nickel-NTA (Ni-NTA). When the target protein exists in inclusion body form, it must first be washed and denatured (common denaturing agents include urea and guanidine hydrochloride, typically at 4-8 M concentrations), followed by refolding via gradient dialysis or rapid dilution. The refolding buffer is usually neutral PBS or Tris buffer, and redox pairs (such as reduced / oxidized glutathione), arginine, glycerol, and nonionic surfactants can be added to assist refolding. The purified protein is then assessed for purity by SDS-PAGE (generally >90%), followed by endotoxin removal steps (such as Triton X-114 extraction and polymyxin B affinity chromatography), sterile filtration, and lyophilization.

[0052] 2. Pharmacodynamic evaluation of keratin BK-58 for the prevention or treatment of psychogenic fever

[0053] 2.1 Selection and establishment of animal models

[0054] The establishment of a psychogenic fever model can employ various psychological stress paradigms, including but not limited to: cage-changing stress, restraint stress, electric shock fear stress, predator odor exposure, and social failure stress. This embodiment of the invention uses the cage-changing stress model because it is simple to operate, the stressor is pure, and it has good reproducibility. The key indicator for model success is an increase in core body temperature of ≥1.0℃ within 30-60 minutes after stress.

[0055] 2.2 Dosing regimen

[0056] Keratin BK-58 can be administered orally (by gavage, free access), intraperitoneally, intravenously, or subcutaneously. Administration can be given before stress (prophylactic) or after stress (therapeutic). The dosage range is generally 1-100 mg / kg body weight, preferably 10-50 mg / kg, depending on the dosage form and route of administration. Dosage frequency can be single or multiple (e.g., continuous administration for 3-7 days). Positive control drugs may include antelope horn powder, diazepam, or tandospirone.

[0057] 2.3 Body temperature monitoring

[0058] Body temperature monitoring can be performed using implantable wireless temperature sensors (such as Anipill, DST micro-T), rectal thermometry, or infrared thermal imaging. Among these, implantable sensors are preferred because they provide unrestricted, continuous, and high-precision body temperature recording, avoiding additional stress on animals caused by human intervention. Monitoring time should cover at least 30 minutes before stress and 1.5 hours after stress.

[0059] 2.4 Efficacy Evaluation Indicators

[0060] Key efficacy indicators include: absolute core body temperature (T, ℃) at various time points after stress; body temperature change (ΔT = Tpost-stress - Tbaseline); maximum body temperature change (ΔTmax); area under the body temperature curve (AUC, which can be calculated for specific time intervals such as 0-0.5 h, 0-1 h, 0-1.5 h, 0-2 h, etc.); and depyresis rate (time required to reduce from peak temperature to basal body temperature).

[0061] Secondary observational indicators may include: behavioral indicators (such as the elevated maze and open field test reflecting anxiety levels), serum stress hormone levels (corticosterone, adrenaline), and changes in hypothalamic neurotransmitters (5-HT, NE, DA), etc., to explore the mechanism of action.

[0062] 3. Pharmaceutical Composition

[0063] The keratin BK-58 of the present invention can be formulated into various pharmaceutical composition forms for clinical use.

[0064] 3.1 Parenteral preparations

[0065] The keratin BK-58 of this invention can be prepared into various injectable formulations, including large-volume injections, small-volume injections, lyophilized powder injections, and fat emulsion injections. The pharmaceutically acceptable excipients can be selected from one or more of the following: pH adjusters, antioxidants, osmotic pressure regulators, medium- or long-chain fat emulsions, lyophilization protectants, solubilizers / co-solvents, preservatives, and chelating agents.

[0066] pH adjuster: selected from one or more of the following: sodium hydroxide solution, ammonia, hydrochloric acid, dilute sulfuric acid, citric acid, acetic acid, maleic acid, lactic acid, phosphoric acid, tartaric acid, tris(hydroxymethyl)aminomethane, sodium carbonate, sodium bicarbonate, sodium acetate, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, ethanolamine, triethanolamine, ethylenediamine, monosodium glutamate, and boric acid, preferably ammonia, sodium hydroxide solution, and hydrochloric acid. pH range 3-11, preferably 6-11, more preferably 6.5-8.

[0067] Antioxidants: selected from one or more of sodium bisulfite, sodium metabisulfite, potassium bisulfite, sodium thiosulfate, vitamin C, enediol palmitate, tocopherol, hydroquinone, propyl gallate, dihydroguaiacol, tert-butyl-p-hydroxyanisole, dibutylcresol, L-cysteine, L-methionine, L-lysine, L-valine, proline, histidine, cystine, disodium edetate, and calcium sodium edetate.

[0068] Osmotic pressure regulator: selected from one or more of glucose, sodium chloride, potassium chloride, glycerol, mannitol, sorbitol, xylitol, and sodium lactate Ringer's solution, preferably sodium chloride.

[0069] Freeze-drying protectant: selected from one or more of sucrose, lactose, and mannitol, with lactose being preferred.

[0070] Solubilizers / co-solvents: selected from one or more of the following: amides, urea derivatives, amines, amino acids, alcohols, inorganic acids and their salts, sugars, glycosides, saponins, hexamethylenetetramine, morpholine, sodium cholate, monovalent soaps, aloxo OT, sodium lauryl sulfate, cyclodextrin, polyoxyethylene monostearate, higher fatty acid esters of sucrose, Tween 80, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil.

[0071] Preservatives: selected from one or more of benzyl alcohol, hydroxypropyl butyl ester, hydroxypropyl methyl ester, phenol, chlorobutanol, and thimerosal, with benzyl alcohol being preferred.

[0072] Chelating agent: selected from EDTA salts, preferably disodium EDTA salt.

[0073] 3.2 Gastrointestinal Administration Formulations

[0074] The keratin BK-58 of this invention can also be prepared into oral solid dosage forms or oral liquid dosage forms. Oral solid dosage forms include tablets (plain tablets, coated tablets, sustained-release tablets), capsules (hard capsules, soft capsules, sustained-release capsules), powders, pellets, micro-pellets, granules, etc.

[0075] Pharmaceutical excipients can be selected from one or more of fillers, diluents, binders, disintegrants, wetting agents, and lubricants, and colorants, sweeteners, etc. can also be added according to clinical needs.

[0076] Filler or diluent: selected from one or more of starch, pregelatinized starch, lactose, glucose, mannitol, sorbitol, cellulose, xylitol, dextrose, fructose, calcium sulfate, light magnesium oxide, and sucrose.

[0077] Adhesive: Selected from one or more of polyvinylpyrrolidone, microcrystalline cellulose, starch paste, syrup, maltose, microcrystalline glucose, sodium carboxymethyl cellulose, honey, sodium carboxymethyl dextran, and dextrin.

[0078] Disintegrant: Selected from one or more of starch, sodium carboxymethyl starch, croscarmellose sodium cellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, and microcrystalline cellulose.

[0079] Wetting agent: selected from distilled water or ethanol.

[0080] Lubricant: Selected from one or more of the following: talc, magnesium stearate, liquid paraffin, magnesium dodecyl sulfate, sodium dodecyl sulfate, long-chain fat emulsion, stearic acid, polyethylene glycol, micronized silica gel, and hydrogenated vegetable oil.

[0081] All of the above-mentioned dosage forms of drugs can be prepared according to conventional methods in the pharmaceutical field.

[0082] Example 1: Preparation of Antelope Horn Keratin BK-58

[0083] Antelope horn keratin BK-58: By constructing a protein-peptide-target database, a peptide was obtained by searching for the target of rapid antipyresis in antelope horn. This peptide belongs to BK-58 and its sequence is shown in SEQ ID NO: 1.

[0084] Plasmid transformation: The nucleotide sequence encoding the amino acid sequence shown in SEQ ID NO: 1 was cloned into the pET-28a expression vector to obtain the recombinant plasmid pET-28a-BK-58. This recombinant plasmid was transformed into BL21(DE3) competent cells and plated on LB plates containing 50 μg / mL kanamycin, and cultured overnight at 37°C inverted.

[0085] Expression condition optimization: Single clones were selected and cultured in 5 tubes of LB medium (containing 50 μg / mL kanamycin) at 37℃ until the OD600 reached 0.7. IPTG was then added to a final concentration of 0.5 mM, and the cells were collected by centrifugation after induction at 37℃ for 4 h. SDS-PAGE analysis confirmed the expression of the target protein. Further optimization revealed that induction at 15℃ with 0.2 mM IPTG for 16 h yielded higher soluble protein expression.

[0086] Scale-up expression: The cloned strain under optimal conditions was cultured at 37℃ in 1 L LB medium (containing 50 μg / mL kanamycin) until the OD600 reached 0.7. After cooling to 15℃, IPTG was added to a final concentration of 0.2 mM and induced for 16 h. The cells were then collected by centrifugation (6,000×g, 15 min, 4℃).

[0087] Purification: The bacterial resuspended in 50 mL Tris-NaCl buffer (20 mM Tris, 150 mM NaCl, pH 8.0), and sonicated (300 W, 3 s on, 5 s off, total 15 min). The precipitate was collected by centrifugation (12,000 × g, 30 min, 4 °C). The precipitate was dissolved in denaturing buffer (20 mM PBS, 8 M Urea, pH 7.4), centrifuged, and the supernatant was subjected to Ni column affinity chromatography. The target protein peak was collected by elution, and SDS-PAGE showed a purity >90%.

[0088] Refolding: Combine the purified samples and add them dropwise to refolding buffer (20 mM PBS, pH 7.4), stirring overnight at 4°C. After refolding, filter the samples to remove bacteria (0.22 μm filter membrane), aliquot, lyophilize, and store at -20°C for later use.

[0089] Example 2: Effect of antelope keratin BK-58 on body temperature in a mouse model of psychogenic fever

[0090] Experimental animals: C57BL / 6J mice, male, 6-8 weeks old, SPF grade, 24 mice in total, 6 mice in each group.

[0091] Body temperature monitoring device implantation: After mice were anesthetized by isoflurane inhalation, Anipill body temperature monitoring capsules were implanted in their abdominal cavity, the wound was sutured, and the mice recovered for one week after the operation.

[0092] Grouping and administration: On the day of the experiment, the participants were randomly divided into stratified groups based on their basal body temperature: (1) blank group (triple-distilled water), (2) model group (triple-distilled water), (3) SAH-P group (antelope horn powder suspension, 123 mg / kg), and (4) BK-58 group (BK-58 solution, 12.3 mg / kg). All groups were administered the drug by gavage at a volume of 0.1 mL / 10g body weight.

[0093] Modeling and monitoring: Two hours after drug administration, mice in the model group, SAH-P group, and BK-58 group were placed in brand-new cages to undergo cage change stress, while the control group received no treatment. The core body temperature of the mice was continuously monitored from 30 minutes before cage change to 90 minutes after cage change, and recorded every 2 minutes.

[0094] result:

[0095] like Figure 1 As shown in Figure A, the body temperature of the blank group remained stable; the body temperature of the model group rose rapidly after cage change stress, with the peak occurring about 30-60 minutes after stress; the body temperature rise of the SAH-P group and the BK-58 group was significantly lower than that of the model group, with the body temperature of the BK-58 group decreasing more rapidly.

[0096] like Figure 1 As shown in B, the ΔT of mice after stress was analyzed in each group. The ΔT of the BK-58 group began to decrease 15 min after modeling and lasted until 90 min, with a slightly better antipyretic effect than the SAH-P group.

[0097] like Figure 1 As shown in Figure C, the ΔTmax of the model group was 2.44±0.27℃, the ΔTmax of the SAH-P group was 1.70±0.43℃ (P<0.01 vs. model group), and the ΔTmax of the BK-58 group was 1.48±0.26℃ (P<0.001 vs. model group). There was no statistically significant difference between the BK-58 group and the SAH-P group.

[0098] like Figure 1 D、 Figure 1 E and Figure 1 As shown in F, the area under the curve (AUC) of the body temperature difference within 0.5 h, 1 h, and 1.5 h was significantly smaller in the BK-58 group than in the model group (P<0.01 or P<0.001), and was comparable to or slightly better than that in the SAH-P group.

[0099] The above results indicate that antelope horn keratin BK-58 can significantly alleviate psychogenic fever induced by cage-changing stress, and its antipyretic effect is superior to or equivalent to that of raw antelope horn powder. The keratin BK-58 of this invention can be used as a substitute for antelope horn in the preparation of drugs for the prevention and / or treatment of psychogenic fever.

[0100] The above description is merely a preferred embodiment of the present invention and does not constitute any limitation on the present invention. Any simple modifications, alterations, or equivalent structural changes made to the above embodiments based on the technical essence of the present invention shall still fall within the protection scope of the present invention.

Claims

1. Antelope keratin BK-58 or a variant thereof, characterized in that, The antelope keratin BK-58 comprises the amino acid sequence shown in SEQ ID NO: 1; the variant comprises an amino acid sequence obtained by substitution, deletion or insertion of one or more amino acids based on SEQ ID NO: 1; preferably, the variant has at least 85%, 90% or more 95% identity with SEQ ID NO: 1 and has a function equivalent to or better than SEQ ID NO:

1.

2. A nucleic acid encoding the antelope keratin BK-58 or a variant thereof as described in claim 1.

3. A vector comprising the nucleic acid of claim 2.

4. A host cell comprising the nucleic acid of claim 2 or the vector of claim 3.

5. The use of the antelope keratin BK-58 of claim 1 or a variant thereof or the nucleic acid of claim 2 in the preparation of a medicament for the prevention and / or treatment of psychogenic fever.

6. In the application according to claim 5, the psychogenic fever is an abnormal increase in body temperature caused by psychological or emotional factors, including stress, anxiety, and depression.

7. The application according to claim 5 or 6, wherein the drug is a gastrointestinal administration formulation or a parenteral administration formulation.

8. The application according to claim 7, wherein the gastrointestinal drug delivery formulation is selected from tablets, capsules, granules, oral solutions or oral emulsions; preferably, the gastrointestinal drug delivery formulation further comprises one or more of pharmaceutically acceptable fillers, diluents, binders, disintegrants, wetting agents or lubricants.

9. The application according to claim 7, wherein the parenteral administration formulation is selected from large-volume injections, small-volume injections, lyophilized powder injections, or fat emulsion injections; preferably, the parenteral administration formulation further comprises one or more of pharmaceutically acceptable pH adjusters, antioxidants, osmotic pressure regulators, lyophilization protectants, solubilizers, preservatives, or chelating agents.

10. A pharmaceutical composition for the prevention and / or treatment of psychogenic fever, characterized in that, The pharmaceutical composition comprises antelope keratin BK-58 or a variant thereof as described in claim 1, and pharmaceutically acceptable excipients; preferably, the pharmaceutical composition is a gastrointestinal or parenteral formulation; preferably, the gastrointestinal formulation is selected from tablets, capsules, granules, oral solutions, or oral emulsions; the gastrointestinal formulation further comprises one or more pharmaceutically acceptable fillers, diluents, binders, disintegrants, wetting agents, or lubricants; preferably, the parenteral formulation is selected from large-volume injections, small-volume injections, lyophilized powder injections, or fat emulsion injections; preferably, the parenteral formulation further comprises one or more pharmaceutically acceptable pH adjusters, antioxidants, osmotic pressure regulators, lyophilization protectants, solubilizers, preservatives, or chelating agents.

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