Adamantane-modified antimicrobial peptide mimics and uses thereof

Abstract

The application discloses an adamantane-modified antibacterial peptide mimetic and application thereof. The application obtains a carboxyl end fatty amine-modified compound protected by adamantane amine or Boc through Fmoc amino acid amide condensation, then removes the Fmoc group through piperidine to obtain a series of crude products containing adamantane amine modification and intermediate compounds of Boc-protected fatty amine modification; the intermediate compounds are further modified by adamantane acid through amide condensation to obtain a compound with an amino end, and then other protecting groups are cleaved through trifluoroacetic acid to obtain a series of crude products of adamantane acid modification; after the crude products are purified, the adamantane-modified peptidomimetic is obtained. The adamantane-modified peptidomimetic is used for preparing drugs for infectious diseases caused by sensitive bacteria and drug-resistant bacteria, has high efficient antibacterial activity, low toxicity and is not affected by traditional drug resistance mechanisms.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and particularly relates to an antimicrobial peptide mimicry based on adamantane modification and its application. Background Technology

[0002] The discovery and development of antibiotics in the 20th century was a key achievement in the medical field, significantly reducing the incidence and mortality of diseases caused by bacterial infections. However, the widespread proliferation of bacteria resistant to almost all antibiotics on the market renders current treatments ineffective, posing a serious risk. Furthermore, the evolution and spread of multidrug-resistant bacteria not only threaten human health but has also become a major threat to global healthcare. Therefore, there is an urgent need to explore and develop novel antimicrobial agents to combat infections caused by drug-resistant bacteria.

[0003] Cationic antimicrobial peptides (CAMPs) are considered potential antimicrobial agents due to their broad-spectrum antimicrobial activity and unique membrane disruption mechanism. CAMPs are present in almost all organisms, forming the first line of defense in the innate immune system. Most CAMPs exhibit antimicrobial activity against a wide variety of bacteria, fungi, protozoa, and viruses. They typically employ an amphiphilic structure, with hydrophilic and hydrophobic residues separating into opposing regions in the presence of a solvent or when interacting with the cell membrane. The mechanism of action for CAMPs primarily involves interaction with the negatively charged components of the bacterial cell membrane, leading to increased cell permeability and ultimately cell death. Due to the difference in the composition of bacterial cell membrane phospholipids, bacterial membranes are considered to be more negatively charged than mammalian membranes, making AMPs selective for bacteria. Because AMPs target fundamentally different characteristics of bacteria that have specific binding sites compared to traditional antibiotics, bacteria are less likely to develop resistance to them. AMPs appear to be promising candidates for antimicrobial drugs; however, they have some significant drawbacks in clinical use, such as potential toxicity to host cells, poor tissue distribution, and sensitivity to proteases. Furthermore, the high cost of synthesizing AMPs is another obstacle to their use as drug candidates. Summary of the Invention

[0004] To overcome the shortcomings and deficiencies of the prior art, the primary objective of this invention is to provide an antimicrobial peptide mimicry based on adamantane modification.

[0005] Another object of the present invention is to provide the application of the above-mentioned antimicrobial peptide mimics.

[0006] The present invention is achieved as follows: an antimicrobial peptide mimic based on adamantane modification, wherein the antimicrobial peptide mimic is an adamantane-modified peptide having the chemical structural formula shown in formula (I) below, or the antimicrobial peptide mimic is a pharmaceutically acceptable salt of the adamantane-modified peptide, a solvate of the pharmaceutically acceptable salt, or the antimicrobial peptide mimic is a stereoisomer, tautomer, or complex of the adamantane-modified peptide;

[0007]

[0008] (I);

[0009] In formula (I), the R1 group is selected from... , , , Any one of them;

[0010] The R2 group is selected from , , , , , , , , , , , , Any one of them;

[0011] The R3 group is selected from , One of them;

[0012] Where m = 2 or 4; n = 1 or 2; p = 0 to 4; q = 0 or 1.

[0013] Preferably, the adamantane-modified peptide is selected from any one of the following A1 to A42;

[0014]

[0015]

[0016]

[0017]

[0018]

[0019] .

[0020] Preferably, the pharmaceutically acceptable salt includes salts of inorganic bases, salts of organic bases, salts of basic amino acids, salts of inorganic acids, salts of organic acids, or salts of acidic amino acids.

[0021] Preferably, the inorganic base salt is selected from any one of ammonium salts, alkali metal salts, and alkaline earth metal salts;

[0022] Preferably, the salt of the organic base is a salt of any one of cyclohexylamine, benzylamine, octylamine, ethanolamine, diethanolamine, diethylamine, triethylamine, ethylenediamine, procaine, morpholine, pyrroline, piperidine, N-ethylpiperidine, N-methylmorpholine, and piperazine.

[0023] Preferably, the salt of the basic amino acid is a salt of any one of lysine, arginine, ornithine, and histidine.

[0024] Preferably, the salt of the inorganic acid is selected from any one of hydrochloride, bromide, sulfate, phosphate, and phosphate ester;

[0025] Preferably, the salt of the organic acid is selected from any one of acetate, formate, propionate, lactate, citrate, fumarate, maleate, benzoate, tartrate, malate, methanesulfonate, ethanesulfonate, toluenesulfonate, and benzenesulfonate;

[0026] Preferably, the salt of the acidic amino acid is a salt of aspartic acid or glutamic acid.

[0027] Preferably, the alkali metal salt is a sodium or potassium salt; the alkaline earth metal salt is a magnesium or calcium salt.

[0028] The present invention further discloses the use of the antimicrobial peptide mimic in the preparation of medicaments for treating bacterial or drug-resistant bacterial infections.

[0029] Preferably, the dosage form of the drug is selected from any one of oral preparations, injections, mucosal delivery preparations, and topical preparations.

[0030] Preferably, the bacteria or drug-resistant bacteria are selected from any one of the following: drug-resistant bacteria, Gram-positive bacteria, Gram-positive bacilli, Gram-negative cocci, Gram-negative bacilli, Klebsiella pneumoniae, Enterobacter, Hafnia, Enterobacter schoenleinii, Proteus, Providencia, Yersinia, trophotropic Gram-negative bacilli, Pseudomonas aeruginosa, strict anaerobes, mycoplasma, and mycobacteria.

[0031] To address the shortcomings of existing technologies, there is an urgent need for innovative molecular structures that can retain the advantages of antimicrobial peptides while circumventing their limitations. In this context, small-molecule antimicrobial peptide mimics that mimic the structure of AMPs show promise as effective antimicrobial agents. These mimics carry a positive charge, facilitating interaction with the negatively charged bacterial cell membrane or DNA. They exhibit hydrophilic and hydrophobic properties similar to AMPs, resisting enzymatic degradation by avoiding peptide bonds recognized by proteases. Furthermore, they are easy to synthesize, unaffected by traditional antibiotic resistance mechanisms, and less prone to developing resistance common to conventional antibiotics. Based on this, this invention designs and synthesizes a series of small-molecule cationic antimicrobial peptide mimics by adding hydrophilic diamines or hydrophobic adamantane to the amino or carboxyl termini or side chains of amino acids such as phenylalanine, tryptophan, isoleucine, cysteine, methionine, and lysine to enhance the amphiphilicity of the amino acids. This invention, through screening for antibacterial activity, studying antibacterial mechanisms, bacterial resistance, stability, anti-biofilm properties, and therapeutic potential against infections caused by drug-resistant bacteria, has discovered that these antimicrobial peptide mimics possess good potential against drug-resistant bacterial infections and can be used to prepare drugs against bacterial or drug-resistant bacterial infections. The bacteria are selected from drug-resistant bacteria (such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci), Gram-positive bacteria such as Staphylococcus aureus, Staphylococcus epidermidis, streptococci (such as agalactiae, enterococci, Streptococcus pneumoniae, and Streptococcus pyogenes), and Gram-positive bacilli such as anthrax spores. Bacilli, Listeria monocytogenes and Corynebacterium diphtheriae; Gram-negative cocci (such as Neisseria gonorrhoeae) and Gram-negative bacilli, such as Enterobacteriaceae (e.g., Escherichia coli), Haemophilus influenzae, Citrobacter (such as Citrobacter zedoaria and Citrobacter polymorpha), Salmonella and Shigella; as well as Klebsiella pneumoniae (such as Klebsiella pneumoniae and Klebsiella oxytetracycline), Enterobacteriaceae (such as Aeromonas and Polymonas), Hafnia, Enterobacter strychnifolia (such as Enterobacter plastella), Proteus (such as Proteus, Reiterella and Proteus), Providencia, Yersinia, and trophotropic Gram-negative bacilli. In addition, the antibacterial spectrum also includes Pseudomonas aeruginosa (such as Pseudomonas aeruginosa and Meckiae) and strict anaerobes, such as Clostridium fragilis, Peptococcus, anaerobic streptococci and Clostridium spp.; as well as mycoplasma (such as Mycoplasma pneumoniae, Mycoplasma hominis and Mycoplasma urogenitalia), and mycobacteria, such as Mycobacterium tuberculosis.

[0032] Compared with the shortcomings and deficiencies of existing technologies, the present invention has the following beneficial effects:

[0033] (1) The present invention changes the amphiphilicity of the backbone by linking hydrophobic groups and cationic groups such as adamantane and fatty amines to the side chain thiol groups of different amino-terminal amino-terminal and carboxyl-terminal and cysteine, thereby obtaining adamantane-modified peptides that can treat infectious diseases of sensitive and drug-resistant bacteria.

[0034] (2) The antimicrobial peptide mimics of the present invention (adamantane-modified peptides) can cause cell membrane depolarization and disrupt cell membrane integrity, can kill bacteria rapidly, can inhibit biofilm formation, have certain biofilm clearance activity, and are not prone to inducing bacterial resistance. They have good activity against Gram-positive bacteria and show good antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). They can solve the current problem of lack of drugs against drug-resistant bacteria, and can replace or assist the preparation of drugs for treating infectious diseases caused by various drug-resistant bacteria in clinical use. They can be used to prepare drugs for infectious diseases caused by sensitive bacteria and drug-resistant bacteria. They have high antimicrobial activity, low toxicity, and are not affected by traditional drug resistance mechanisms. Attached Figure Description

[0035] Figure 1 Hemolysis rate of mouse erythrocytes at a concentration of 100 μg / mL for adamantane-modified peptides A8, A11, A19, A20, A25, and A35.

[0036] Figure 2 Cytotoxicity test of adamantane-modified peptides A8, A11, A19, A20, A25, and A35 at a concentration of 100 μg / mL on mouse NIH 3T3 fibroblasts.

[0037] Figure 3 The bactericidal kinetics of adamantane-modified peptides A8 and A11 against Staphylococcus aureus were determined at a concentration of 4×MIC.

[0038] Figure 4 To induce drug resistance in Staphylococcus aureus by modifying adamantane-modified peptides A8 and A11, the clinical antibiotic Amoxicillin was used as a positive control.

[0039] Figure 5 The effects of adamantane-modified peptides A8 and A11 on the cell membrane potential of Staphylococcus aureus at concentrations of 1×MIC, 2×MIC, and 4×MIC were investigated; PBS was used as a negative control, and 0.1% Triton X-100 was used as a positive control.

[0040] Figure 6 To detect changes in fluorescence intensity of Staphylococcus aureus after PI absorption induced by adamantane-modified peptides A8 and A11 using flow cytometry; PBS was used as a negative control.

[0041] Figure 7 Fluorescent images of Staphylococcus aureus after treatment with adamantane-modified peptides A8 and A11 and incubation with PI staining solution were obtained using laser confocal microscopy; PBS was used as a negative control.

[0042] Figure 8 To observe the destructive effects of adamantane-modified peptides A8 and A11 on Staphylococcus aureus at a concentration of 4×MIC using cryo-transmission electron microscopy.

[0043] Figure 9 The inhibition rates of adamantane-modified peptides A8 and A11 on Staphylococcus aureus biofilm formation at concentrations of 1×MIC, 2×MIC, and 4×MIC were determined.

[0044] Figure 10 The results of lung colony count and H&E staining of lung tissue sections in mice after treatment with adamantane-modified peptides A8 and A11 for MRSA-infected pneumonia were obtained, with linezolid used as a positive control.

[0045] Figure 11 The results of corneal colony count and H&E staining of corneal tissue sections in mice after treatment with adamantane-modified peptides A8 and A11 for MRSA-infected keratitis were obtained, with linezolid used as a positive control. Detailed Implementation

[0046] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0047] The instruments used in this invention include: a circular decolorizing shaker (SK-O330, Dalong Xingchuang Experimental Instruments (Beijing) Co., Ltd., China), a rotary evaporator (560-00000-00-0, Heidolph, Germany), a time-of-flight mass spectrometer (Maxis 4G, Bruker, Germany), a preparative HPLC (NU3001, Hanbang Technology, China), an analytical chromatograph (A02996, Waters, USA), a freeze dryer (CoolSafe55-4, Gene Company Limited, China), a constant temperature shaker (IS-RDD3, Suzhou Jiemei Electronics Co., Ltd., China), a biosafety cabinet (BSC-1500ⅡB2-X, Jinan Xinbeixi Biotechnology Co., Ltd., China), a constant temperature incubator (LT-BIX300M, Lidetech (Shanghai) Scientific Instruments Co., Ltd.), a benchtop centrifuge (Thermo 75004250, Thermo Fisher Scientific, USA), and a multi-functional microplate reader (FlexStationIII). The following instruments were used: Molecular Instruments (USA), CO2 cell incubator (CLM-170B-8-TC, Taicang Yisigao Medical Instrument Technology Co., Ltd., China), fluorescence microscope (U-LH50HG, Olympus Corporation, Japan), micro-nucleic acid and protein analyzer (E113192, Implen GmbH, Germany), mouse laryngoscope and nebulizer (Yuanseng Kaide Biotechnology Co., Ltd., China), tissue cryo-morcerator (JXFSPRP-CLN-48, Shanghai Jingxin Industrial Development Co., Ltd., China), and flow cytometer (NovoCyte Quanteon, Agilent).

[0048] The reagents used were as follows: o-benzotriazole-N,N,N,N'-tetramethyl-hexafluorophosphate (HBTU), 1-hydroxybenzotriazole (HOBT), N,N-diisopropylethylamine (DIPEA), trifluoroacetic acid (TFA), and dichloromethane (DCM) were purchased from Heinz Technologies (China). N,N-dimethylformamide (DMF) was supplied by BASF (Germany). Acetonitrile was supplied by Shanghai CINC High Purity Solvent Co., Ltd. (Shanghai, China). D and L-type amino acids were purchased from Merrill Chemical Technology Co., Ltd. Diethyl ether, piperidine, and hydrochloric acid were purchased from Shantou Xilong Chemical Co., Ltd. (Shantou, China). Dimethyl sulfoxide (DMSO) and 5,3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide (MTT) were purchased from Tianjin Guangfu Reagent Co., Ltd. MH broth medium was purchased from Qingdao High-tech Park Haibo Biotechnology Co., Ltd., and PBS buffer was purchased from Wuhan Saiwei Biotechnology Co., Ltd. Triton X-100 was purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd. RPMIDMEM culture medium was purchased from Shanghai Datihill Biotechnology Co., Ltd. Fetal bovine serum (FBS) was purchased from Shanghai Datihill Biotechnology Co., Ltd. Trypsin cell digestion solution was purchased from Beijing Lanjieke Technology Co., Ltd. Agar powder was purchased from Beijing Lanjieke Technology Co., Ltd.

[0049] Example 1

[0050] The synthetic routes for adamantane-modified peptides A1, A3, A5, A7, A9, A11, A13, A15, A18, A28, A29, A31, A33, A35, A37, A39, and A41 are as follows:

[0051]

[0052] In a typical reaction, commercially available amino acids (0.5 mmol, 1 eq), HOBT (0.6 mmol, 81.08 mg, 1.2 eq), HBTU (0.6 mmol, 227.54 mg, 1.2 eq), and DIPEA (1.2 mmol, 155.1 mg, 2.4 eq) were added to 30 mL of DMF, followed by the addition of adamantane ethylamine solution (0.12 mmol). The reaction was carried out at room temperature for 3 h, and the reaction progress was monitored using a silica gel plate. After the reaction was completed, 120 mL of saturated brine and 60 mL of ethyl acetate were added and the mixture was shaken and washed. The organic phase was retained, and then the organic layer was washed with brine and dried with anhydrous sodium sulfate. The organic phase was then evaporated under reduced pressure to obtain the intermediate product in a yield of over 95%.

[0053] The intermediate obtained requires no further processing. Piperidine (1.5 mL), DBU (1.5 mL), and tetrahydrofuran (47 mL) are added, and the mixture is stirred for 1 hour. The solvent is removed under reduced pressure, and ice-cold diethyl ether is added to precipitate the crude product. If the crude product contains unwanted side-chain protecting groups, it can be dissolved in DCM, and TFA and TIS can be added and reacted at room temperature for 3 hours to obtain the final desired crude product.

[0054] Finally, the final compound was obtained by further HPLC purification (see Example 7 for details).

[0055] Example 2

[0056] The synthetic routes for adamantane-modified peptides A25 and A26 are as follows:

[0057]

[0058] In a typical reaction, commercially available amino acids (0.5 mmol, 1 eq), HOBT (0.6 mmol, 81.08 mg, 1.2 eq), HBTU (0.6 mmol, 227.54 mg, 1.2 eq), and DIPEA (1.2 mmol, 155.1 mg, 2.4 eq) were added to 30 mL of DMF, followed by the addition of adamantane methylamine solution (0.12 mmol). The reaction was carried out at room temperature for 3 h, and the reaction progress was monitored using a silica gel plate.

[0059] After the reaction was completed, 120 mL of saturated brine and 60 mL of ethyl acetate were added and the mixture was shaken and washed. The organic phase was retained, and then the organic layer was washed with brine and dried with anhydrous sodium sulfate. The organic phase was then evaporated under reduced pressure to obtain the intermediate product in a yield of more than 95%.

[0060] The intermediate obtained requires no further processing. Piperidine (1.5 mL), DBU (1.5 mL), and tetrahydrofuran (47 mL) are added, and the mixture is stirred for 1 hour. The solvent is removed under reduced pressure, and ice-cold diethyl ether is added to precipitate the crude product. If the crude product contains unwanted side-chain protecting groups, it can be dissolved in DCM, and TFA and TIS can be added and reacted at room temperature for 3 hours to obtain the final desired crude product.

[0061] Finally, the final compound was obtained by further HPLC purification (see Example 7 for details).

[0062] Example 3

[0063] The synthetic routes for adamantane-modified peptides A21 and A23 are as follows:

[0064]

[0065] In a typical reaction, commercially available amino acids (0.5 mmol, 1 eq), HOBT (0.6 mmol, 81.08 mg, 1.2 eq), HBTU (0.6 mmol, 227.54 mg, 1.2 eq), and DIPEA (1.2 mmol, 155.1 mg, 2.4 eq) were added to 30 mL of DMF, followed by the addition of adamantane solution (0.12 mmol). The reaction was carried out at room temperature for 3 h, and the reaction progress was monitored using a silica gel plate. After the reaction was complete, 120 mL of saturated brine and 60 mL of ethyl acetate were added and the mixture was shaken and washed, retaining the organic phase. The organic layer was then washed with brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure to obtain the intermediate product in a yield of over 95%.

[0066] The intermediate obtained requires no further processing. Piperidine (1.5 mL), DBU (1.5 mL), and tetrahydrofuran (47 mL) are added, and the mixture is stirred for 1 hour. The solvent is removed under reduced pressure, and ice-cold diethyl ether is added to precipitate the crude product. If the crude product contains unwanted side-chain protecting groups, it can be dissolved in DCM, and TFA and TIS can be added and reacted at room temperature for 3 hours to obtain the final desired crude product.

[0067] Finally, the final compound was obtained by further HPLC purification (see Example 7 for details).

[0068] Example 4

[0069] The synthetic routes for adamantane-modified peptides A22 and A24 are as follows:

[0070]

[0071] In a typical reaction, commercially available amino acids (0.5 mmol, 1 eq), HOBT (0.6 mmol, 81.08 mg, 1.2 eq), HBTU (0.6 mmol, 227.54 mg, 1.2 eq), and DIPEA (1.2 mmol, 155.1 mg, 2.4 eq) were added to 30 mL of DMF and stirred to dissolve. N-Boc-ethylenediamine (0.6 mmol, 1.2 eq) was then added, and the mixture was stirred at room temperature for 3 h. The reaction progress was monitored using a silica gel plate. After the reaction was complete, the mixture was washed with 120 mL of saturated brine and 60 mL of ethyl acetate, retaining the organic phase. The organic layer was then washed with brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure to obtain the intermediate product in over 95% yield.

[0072] The obtained intermediate product required no further processing. Piperidine (1.5 mL), DBU (1.5 mL), and tetrahydrofuran (47 mL) were added, and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure, and the crude product was precipitated by adding ice-cold diethyl ether. The crude product was dissolved in DMF solution, and 1.2 eq adamantane carboxylic acid, 1.5 eq condensing agents HBTU and HOBT, and 2 eq DIPEA were added to the system. The reaction was carried out at room temperature for 3 hours, and the reaction progress was monitored using a silica gel plate. After the reaction was completed, the product was extracted with saturated brine and EA, and dried by rotary evaporation to obtain the intermediate product.

[0073] The intermediate obtained requires no further processing. Trifluoroacetic acid (8 mL), dichloromethane (20 mL), and TIS (200 μL) are added and stirred for 3 h. The solvent is removed under reduced pressure, and the target product is precipitated by adding ice-cold diethyl ether.

[0074] Finally, the final compound was obtained by further HPLC purification (see Example 7 for details).

[0075] Example 5

[0076] The synthetic routes for adamantane-modified peptides A2, A4, A6, A8, A10, A12, A14, A16, A17, A20, A27, A30, A32, A34, A36, A38, A40, and A42 are as follows:

[0077]

[0078] In a typical reaction, commercially available amino acids (0.5 mmol, 1 eq), HOBT (0.6 mmol, 81.08 mg, 1.2 eq), HBTU (0.6 mmol, 227.54 mg, 1.2 eq), and DIPEA (1.2 mmol, 155.1 mg, 2.4 eq) were added to 30 mL of DMF and stirred to dissolve. N-Boc-ethylenediamine (0.6 mmol, 1.2 eq) was then added, and the mixture was stirred at room temperature for 3 h. The reaction progress was monitored using a silica gel plate. After the reaction was complete, the mixture was washed with 120 mL of saturated brine and 60 mL of ethyl acetate, retaining the organic phase. The organic layer was then washed with brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure to obtain the intermediate product in over 95% yield.

[0079] The obtained intermediate product required no further processing. Piperidine (1.5 mL), DBU (1.5 mL), and tetrahydrofuran (47 mL) were added, and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure, and the intermediate product was precipitated by adding ice-cold diethyl ether. The obtained crude product was dissolved in DMF solution, and 1.2 eq adamantaneacetic acid, 1.5 eq condensing agents HBTU and HOBT, and 2 eq DIPEA were added to the system. The reaction was carried out at room temperature for 3 hours, and the reaction progress was monitored using a silica gel plate. After the reaction was completed, the product was extracted with saturated brine and EA, and dried by rotary evaporation to obtain the intermediate product.

[0080] The intermediate obtained did not require further processing. Trifluoroacetic acid (8 mL), dichloromethane (20 mL), and TIS (200 μL) were added and stirred for 3 h. The solvent was removed under reduced pressure, and the target product was precipitated by adding ice-cold diethyl ether. Finally, the final compound was obtained by further HPLC purification.

[0081] The synthesis of adamantane-modified peptide A20 requires modification of the crude product from the previous step with a quaternary ammonium salt. The crude product is dissolved in methanol solution, and a certain amount of MeI and KHCO3 are added. The reaction is carried out at room temperature for 72 h. After evaporating the solvent, 120 mL of water and 60 mL of ethyl acetate are added and the mixture is shaken and washed. The organic phase is retained, and then the organic layer is washed with brine and dried with anhydrous sodium sulfate. The organic phase is then evaporated under reduced pressure to obtain the crude product A20.

[0082] Finally, the final compound was obtained by further HPLC purification (see Example 7 for details).

[0083] Example 6

[0084] The synthetic route for adamantane-modified peptide A19 is as follows:

[0085]

[0086] In a typical reaction, commercially available Fmoc-Cys(Dpm)-OH (0.5 mmol, 1 eq), HOBT (0.6 mmol, 81.08 mg, 1.2 eq), HBTU (0.6 mmol, 227.54 mg, 1.2 eq), and DIPEA (1.2 mmol, 155.1 mg, 2.4 eq) were added to 30 mL of DMF and stirred to dissolve. N-Boc-butanediamine (0.6 mmol, 1.2 eq) was then added, and the mixture was stirred at room temperature for 3 h. The reaction progress was monitored using a silica gel plate. After the reaction was complete, the mixture was washed with 120 mL of saturated brine and 60 mL of ethyl acetate, retaining the organic phase. The organic layer was then washed with brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure to obtain the intermediate product in over 95% yield.

[0087] The obtained intermediate product required no further processing. Piperidine (1.5 mL), DBU (1.5 mL), and tetrahydrofuran (47 mL) were added, and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure, and the intermediate product was precipitated by adding ice-cold diethyl ether. The obtained crude product was dissolved in DMF solution, and 1.2 eq adamantaneacetic acid, 1.5 eq condensing agents HBTU and HOBT, and 2 eq DIPEA were added to the system. The reaction was carried out at room temperature for 3 hours, and the reaction progress was monitored using a silica gel plate. After the reaction was completed, the product was extracted with saturated brine and EA, and dried by rotary evaporation to obtain the intermediate product.

[0088] The intermediate obtained requires no further processing. Trifluoroacetic acid (8 mL), dichloromethane (20 mL), and TIS (200 μL) are added and stirred for 3 h. The solvent is removed under reduced pressure, and the target product is precipitated by adding ice-cold diethyl ether.

[0089] Finally, the final compound was obtained by further HPLC purification (see Example 7 for details).

[0090] Example 7 Purification and preparation of adamantane-modified peptides

[0091] The crude adamantane-modified peptides synthesized in Examples 1-6 were separated and purified by high-performance liquid chromatography (HPLC). Specifically, the crude peptide samples were washed with diethyl ether to precipitate the peptides, and the remaining diethyl ether was removed by rotary evaporation. The precipitate was then dissolved and purified by gradient elution using an acetonitrile (0.1% TFA) / water (0.1% TFA) system. The purified products were identified by mass spectrometry and freeze-dried to obtain the adamantane-modified peptides. The structure and NMR characterization of the synthesized adamantane-modified peptides are as follows:

[0092] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A1: 1H NMR (400 MHz, DMSO-d6) δ8.31 – 8.23 ​​(m, 3H), 7.88 (dd, J = 51.4, 9.4 Hz, 1H), 7.40 – 7.20 (m, 5H), 4.22 (s, 1H), 3.42 (ddt, J = 15.8, 9.0, 6.9 Hz, 1H), 2.99 (t, J = 7.8 Hz,2H), 1.96 – 1.88 (m, 2H), 1.85 – 1.77 (m, 2H), 1.65 – 1.54 (m, 4H), 1.46 (d,J = 11.4 Hz, 5H), 1.24 (d, J = 12.2 Hz, 1H), 1.15 (d, J = 11.1 Hz, 1H), 0.93 (d, J = 6.9 Hz, 2H), 0.68 (d, J = 6.9 Hz, 2H). 13 C10 NMR (101 MHz, DMSO-d6) δ 167.05, 134.95, 129.51, 128.37, 127.03, 53.41, 52.77, 37.68, 37.24, 36.50, 35.35, 27.69, 13.95. Compound molecular weight data: theoretical molecular weight C10 21 H 20 N2O [M+H] + =327.2401, molecular weight determined by mass spectrometry. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 95.02%.

[0093] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A2: 1H NMR (400 MHz, DMSO-d6) δ8.19 (t, J = 5.7 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.87 (s, 3H), 7.25 (d, J= 5.8 Hz, 4H), 7.22 – 7.12 (m, 1H), 4.48 (ddd, J = 10.3, 8.1, 4.7 Hz, 1H), 3.33 – 3.24 (m, 2H), 3.03 (dd, J = 13.9, 4.8 Hz, 1H), 2.75 (dd, J = 13.8,10.4 Hz, 1H), 2.55 (s, 1H), 1.85 – 1.74 (m, 5H), 1.58 (d, J = 12.6 Hz, 3H), 1.49 – 1.35 (m, 7H), 1.26 (dt, J = 12.3, 2.6 Hz, 3H). 13 C10 NMR (101 MHz, DMSOd6) δ 172.12, 170.01, 137.89, 129.08, 127.92, 126.14, 54.00, 49.76, 41.81, 40.37, 38.34, 37.22, 36.31, 32.06, 27.93. Compound molecular weight data: theoretical molecular weight C10 23 H 33 N3O2 [M+H] + =384.2635, molecular weight determined by mass spectrometry was 384.3535. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 100.00%.

[0094] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A3: 1H NMR (400 MHz, DMSO-d6) δ11.05 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 5.3 Hz, 3H), 8.04 (d, J = 9.4 Hz,1H), 7.67 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.13 – 7.05 (m, 1H), 7.05 – 6.98 (m, 1H), 4.08 (q, J= 6.6Hz, 1H), 3.48(dt, J = 9.4, 5.7 Hz, 1H), 3.22 (dd, J = 14.4, 7.1 Hz, 1H), 3.04(dd, J =14.4, 7.9 Hz, 1H), 1.82 – 1.77 (m, 3H), 1.56 (d, J = 12.1 Hz, 3H), 1.43 (d, J= 11.9 Hz, 3H), 1.25 (q, J = 12.3 Hz, 7H), 0.96 (d, J = 6.9 Hz, 3H). 13 C10 NMR (101 MHz, DMSO d6) δ 167.68, 136.25, 126.92, 124.64, 121.08, 118.40, 111.40, 107.04, 52.77, 52.61, 37.61, 36.42, 35.34, 27.80, 27.59, 13.92. Compound molecular weight data: theoretical molecular weight C10 23 H 31 N3O [M+H] + =366.2566, molecular weight determined by mass spectrometry: 366.3206. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 95.37%.

[0095] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A4: 1H NMR (400 MHz, DMSO-d6) δ10.84 (d, J = 2.5 Hz, 1H), 8.17 (t, J = 5.8 Hz, 1H), 7.88 – 7.83 (m, 3H),7.58 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.08 – 7.02 (m, 1H), 6.97 (t, J = 7.4 Hz, 1H), 4.49 (ddd, J = 9.5, 7.5, 5.2Hz, 1H), 3.29 (d, J = 5.9 Hz, 1H), 3.12 (dd, J = 14.6, 5.2 Hz, 1H), 2.92 (dd,J = 14.6, 9.5 Hz, 1H), 2.81 (q, J = 6.4 Hz, 2H), 1.85 (d, J = 12.5 Hz, 1H),1.80 – 1.76 (m, 4H), 1.56 (d, J = 11.3 Hz, 4H), 1.46 – 1.37 (m, 6H), 1.33 –1.27 (m, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 172.58, 170.13, 136.11, 127.13, 123.73, 120.76, 118.35, 118.12, 111.20, 109.92, 53.41, 49.70, 41.83, 38.39, 36.34, 32.15, 28.00, 27.94, 27.49. Compound molecular weight data: theoretical molecular weight C10 25 H 34 N4O2 [M+H] + =423.2733, molecular weight determined by mass spectrometry was 423.2733. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 97.44%.

[0096] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A5: 1H NMR (400 MHz, DMSO-d6) δ8.04 (q, J = 9.4, 8.1 Hz, 3H), 7.92 (d, J = 9.3 Hz, 1H), 3.65 (q, J = 5.7 Hz,1H), 3.55 (td, J = 9.1, 6.9 Hz, 2H), 1.95 (q, J = 3.2 Hz, 3H), 1.86 – 1.75(m, 1H), 1.67 (d, J = 12.0 Hz, 3H), 1.58 (t, J = 12.3 Hz, 4H), 1.49 (dd, J =13.9, 2.8 Hz, 6H), 1.12 (dtt, J = 18.2, 7.1, 4.1 Hz, 1H), 1.00 – 0.92 (m,5H), 0.91 – 0.83 (m, 4H). 13 C10 NMR (101 MHz, DMSO-d6) δ 167.20, 57.01, 56.40, 53.00, 37.95, 36.53, 35.29, 27.71, 23.76, 14.66, 14.06, 11.01. Compound molecular weight data: theoretical molecular weight C10 18 H 32 N2O [M+H] + =293.2965, molecular weight determined by mass spectrometry: 293.3183. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 96.87%.

[0097] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A6: 1 H NMR (400 MHz, DMSO-d6) δ8.18 (t, J = 5.7 Hz, 1H), 7.85 (s, 1H), 7.82 (d, J = 7.9 Hz, 3H), 3.36 – 3.21(m, 2H), 2.83 (dq, J = 12.7, 6.3 Hz, 2H), 1.97 (d, J = 12.6 Hz, 1H), 1.94 –1.84 (m, 4H), 1.77 – 1.61 (m, 4H), 1.61 – 1.37 (m, 11H), 1.12 (dt, J = 13.5,7.7 Hz, 1H), 0.81 (dt, J = 7.4, 4.0 Hz, 7H). 13C10 NMR (101 MHz, DMSO-d6) δ 171.99, 170.39, 57.11, 49.42, 42.01, 38.36, 36.43, 36.19, 35.58, 32.32, 28.01, 24.48, 15.43, 10.71. Compound molecular weight data: theoretical molecular weight C10 20 H 35 N3O2 [M+H] + =350.2703, molecular weight determined by mass spectrometry: 350.3603. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 100.00%.

[0098] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A7: 1 H NMR (400 MHz, DMSO-d6) δ8.37 – 8.15 (m, 3H), 8.12 (d, J = 9.2 Hz, 1H), 8.02 (d, J = 9.3 Hz, 1H), 3.99– 3.91 (m, 1H), 3.54 (dt, J = 9.4, 6.4 Hz, 1H), 2.96 – 2.89 (m, 2H), 1.98 –1.91 (m, 4H), 1.65 – 1.58 (m, 5H), 1.49 (s, 7H), 0.98 (dd, J = 6.9, 2.9 Hz, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 166.03, 54.11, 53.20, 37.83, 36.51, 35.36, 27.70, 25.29, 13.98. Compound molecular weight data: theoretical molecular weight C10 15 H 26 N1OS [M+H] + =282.1805, molecular weight determined by mass spectrometry was 283.1805. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 95.67%.

[0099] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A8: 1H NMR (400 MHz, DMSO-d6) δ8.36 – 8.26 (m, 1H), 8.16 (d, J = 8.1 Hz, 1H), 8.06 (s, 3H), 4.31 (td, J =7.6, 5.3 Hz, 1H), 3.32 (q, J = 6.2 Hz, 2H), 2.91 – 2.65 (m, 4H), 2.39 (t, J =8.4 Hz, 1H), 1.98 (d, J = 12.7 Hz, 1H), 1.93 – 1.88 (m, 4H), 1.69 – 1.60 (m,4H), 1.60 – 1.51 (m, 9H). 13 C10 NMR (101 MHz, DMSO-d6) δ 170.47, 170.26, 55.17, 49.63, 42.01, 38.32, 36.42, 32.29, 28.02, 25.84. Compound molecular weight data: theoretical molecular weight C10 17 H 29 N3O2S [M+H] + =340.2046, molecular weight determined by mass spectrometry. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 95.99%.

[0100] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A9: 1 H NMR (400 MHz, DMSO-d6) δ8.19 (d, J = 5.3 Hz, 3H), 7.94 (d, J = 5.7 Hz, 1H), 7.92 (d, J = 6.0 Hz, 3H), 3.84 (s, 7H), 2.74 (dt, J = 11.1, 5.7 Hz, 2H), 1.76 – 1.64 (m, 5H), 1.60 –1.54 (m, 5H), 1.48 (d, J = 14.5 Hz, 6H), 0.97 (dd, J = 11.1, 6.9 Hz, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 167.83, 52.73, 52.03, 38.44, 37.89, 36.54, 35.59, 30.78, 27.67, 26.38, 21.36, 13.96. Compound molecular weight data: theoretical molecular weight C 18 H 33N3O [M+H] + =308.2657, molecular weight determined by mass spectrometry was 308.2657. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 98.75%.

[0101] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A10: 1 H NMR (400 MHz, DMSO-d6) δ8.15 (t, J = 5.8 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.89 (s, 3H), 7.82 (s,3H), 4.11 (td, J = 8.5, 5.4 Hz, 1H), 3.33 – 3.25 (m, 2H), 2.84 (s, 2H), 2.74 (p, J = 5.4, 4.6 Hz, 2H), 1.96 – 1.83 (m, 6H), 1.64 (t, J 12.5 Hz, 5H), 1.58– 1.51 (m, 10H), 1.40 – 1.19 (m, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 172.45, 158.42, 52.45, 49.55, 42.00, 38.62, 38.40, 36.41, 36.30, 32.27, 30.82, 28.00, 26.59, 22.36. Compound molecular weight data: theoretical molecular weight C10 20 H 36 N4O2 [M+H] + =365.2870, molecular weight determined by mass spectrometry. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.03%.

[0102] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A11: 1H NMR (400 MHz, DMSO-d6) δ8.15 (t, J = 5.8 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.89 (s, 3H), 7.82 (s,3H), 4.11 (td, J = 8.5, 5.4 Hz, 1H), 3.33 – 3.25 (m, 2H), 2.84 (s, 2H), 2.74 (p, J = 5.4, 4.6 Hz, 2H), 1.96 – 1.83 (m, 6H), 1.64 (t, J = 12.5 Hz, 5H), 1.58 – 1.51 (m, 10H), 1.40 – 1.19 (m, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 172.45, 158.42, 52.45, 49.55, 42.00, 38.62, 38.40, 36.41, 36.30, 32.27, 30.82, 28.00, 26.59, 22.36. Compound molecular weight data: theoretical molecular weight C10 28 H 36 N2OS [M+H] + =449.2566, molecular weight determined by mass spectrometry. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 95.74%.

[0103] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A12: 1 H NMR (400 MHz, DMSO-d6) δ8.16 (t, J = 5.8 Hz, 1H), 7.79 (d, J = 27.7 Hz, 3H), 7.39 – 7.30 (m, 10H), 6.75 – 6.65 (m, 1H), 5.34 (d, J = 9.0 Hz, 2H), 4.38 – 4.20 (m, 2H), 3.35 –3.24 (m, 8H), 2.83 (q, J = 6.1 Hz, 3H), 2.58 (ddd, J = 16.0, 7.9, 3.4 Hz,2H), 1.53 (dq, J = 11.2, 3.4 Hz, 4H), 1.42 (p, J = 5.5 Hz, 5H). 13C10 NMR (101MHz, DMSO-d6) δ 172.22, 171.29, 158.22, 157.91, 156.94, 141.51, 141.32, 128.52, 128.03, 127.08, 53.93, 52.81, 52.59, 44.39, 38.58, 38.29, 36.33, 33.51, 25.24, 24.01. Compound molecular weight data: theoretical molecular weight C10 30 H 39 N3O2S [M+H] + =506.2833, molecular weight determined by mass spectrometry: 506.3533. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 98.44%.

[0104] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A13: 1 H NMR (400 MHz, DMSO-d6) δ8.31 (s, 3H), 8.18 (d, J = 9.3 Hz, 1H), 3.61 – 3.49 (m, 1H), 2.89 (dd, J =14.0, 6.3 Hz, 1H), 2.79 (dd, J = 14.0, 7.4 Hz, 1H), 2.14 (s, 3H), 1.93 (t, J= 3.3 Hz, 3H), 1.68 – 1.56 (m, 7H), 1.49 (d, J = 3.6 Hz, 6H), 0.99 (d, J =6.9 Hz, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 166.57, 52.89, 51.30, 37.78, 36.51, 35.69, 34.73, 27.71, 14.92, 13.89. Compound molecular weight data: theoretical molecular weight C10 16 H 28 N2OS [M+H] + =297.1962, molecular weight determined by mass spectrometry. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 97.24%.

[0105] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A14: 1H NMR (400 MHz, DMSO-d6) δ8.32 (t, J = 5.7 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.82 (s, 3H), 7.32 – 7.29(m, 3H), 4.44 (q, J = 7.5 Hz, 1H), 3.82 – 3.68 (m, 2H), 3.31 (q, J = 6.5 Hz, 2H), 2.85 (q, J = 6.4 Hz, 2H), 2.74 (dd, J = 13.5, 6.5 Hz, 1H), 1.97 – 1.83(m, 5H), 1.65 (d, J = 12.3 Hz, 3H), 1.62 – 1.48 (m, 9H). 13 C10 NMR (101 MHz, DMSO-d6) δ 171.11, 170.20, 51.88, 49.61, 41.98, 38.33, 36.41, 36.39, 35.27, 32.30, 28.02, 14.97. Compound molecular weight data: theoretical molecular weight C10 18 H 31 N3O2S [M+H] + =354.2172, molecular weight determined by mass spectrometry. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 100.00%.

[0106] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A15: 1 H NMR (400 MHz, DMSO-d6) δ8.35 (s, 3H), 8.18 (d, J = 9.4 Hz, 1H), 7.39 – 7.24 (m, 5H), 4.03 (td, J =6.7, 3.6 Hz, 1H), 3.90 – 3.76 (m, 2H), 3.61 – 3.47 (m, 1H), 2.86 – 2.72 (m,2H), 1.94 (dt, J = 10.2, 3.4 Hz, 3H), 1.67 (d, J = 11.8 Hz, 2H), 1.62 (d, J =4.7 Hz, 2H), 1.57 (s, 2H), 1.49 (dd, J = 10.3, 5.9 Hz, 7H), 0.99 (dd, J =11.9, 6.9 Hz, 3H). 13C10 NMR (101 MHz, DMSO-d6) δ 166.50, 137.78, 128.96, 128.41, 127.03, 53.21, 51.59, 37.76, 36.52, 35.73, 34.97, 32.24, 27.71, 14.02. Compound molecular weight data: theoretical molecular weight C10N. 22 H 32 N2OS [M+H] + =373.2250, molecular weight determined by mass spectrometry. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 98.09%.

[0107] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A16: 1 H NMR (400 MHz, DMSO-d6) δ11.05 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 5.3 Hz, 3H), 8.04 (d, J = 9.4 Hz,1H), 7.67 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 2.4 Hz,1H), 7.13 – 7.05 (m, 1H), 7.05 – 6.98 (m, 1H), 4.08 (q, J = 6.6 Hz, 1H), 3.48(dt, J = 9.4, 5.7 Hz, 1H), 3.22 (dd, J = 14.4, 7.1 Hz, 1H), 3.04 (dd, J =14.4, 7.9 Hz, 1H), 1.82 – 1.77 (m, 3H), 1.56 (d, J = 12.1 Hz, 3H), 1.43 (d, J= 11.9 Hz, 3H), 1.25 (q, J = 12.3 Hz, 7H), 0.96 (d, J = 6.9 Hz, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 167.68, 136.25, 126.92, 124.64, 121.08, 118.40, 111.40, 107.04, 52.77, 52.61, 37.61, 36.42, 35.34, 27.80, 27.59, 13.92. Compound molecular weight data: theoretical molecular weight C10 24 H 35 N3O2S [M+H]+ =430.2477, the molecular weight was determined by mass spectrometry to be 430.2477. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 100.00%.

[0108] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A17: 1 H NMR (400 MHz, DMSO-d6) δ8.34 (s, 3H), 8.17 (d, J = 9.3 Hz, 1H), 7.33 – 7.25 (m, 2H), 6.92 – 6.82 (m,2H), 4.00 (t, J = 6.8 Hz, 1H), 3.78 (s, 2H), 3.72 (s, 3H), 3.54 (dq, J = 8.7,6.7 Hz, 1H), 2.79 – 2.69 (m, 2H), 1.96 – 1.89 (m, 3H), 1.73 – 1.50 (m, 8H),1.47 (d, J = 4.6 Hz, 5H), 1.00 (d, J = 6.9 Hz, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 166.54, 158.29, 130.13, 129.47, 113.72, 55.03, 52.82, 51.60, 37.76, 36.47, 35.74, 34.36, 32.14, 27.70, 13.92. Compound molecular weight data: theoretical molecular weight C10 16 H 28 N2OS [M+H] + =403.2343, the molecular weight was determined by mass spectrometry to be 403.2343. The purity of the compound was determined by reversed-phase high-performance liquid chromatography (RP-HPLC) to be 100.00%.

[0109] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A18: 1H NMR (400 MHz, DMSO-d6) δ8.33 (t, J = 5.7 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.93 – 7.83 (m, 3H), 7.27– 7.19 (m, 2H), 6.90 – 6.82 (m, 2H), 4.43 (td, J = 7.8, 6.5 Hz, 1H), 3.71 (d,J = 12.0 Hz, 6H), 3.37 – 3.27 (m, 2H), 2.86 (h, J = 6.1 Hz, 2H), 2.72 (dd, J= 13.5, 6.5 Hz, 1H), 1.94 (d, J = 12.6 Hz, 1H), 1.90 (dd, J = 6.5, 3.5 Hz,3H), 1.69 – 1.51 (m, 13H). 13 C10 NMR (101 MHz, DMSO-d6) δ 171.01, 170.18, 158.14, 130.00, 129.95, 113.68, 54.98, 51.98, 49.60, 42.00, 38.33, 36.40, 34.40, 32.49, 32.34, 28.03. Compound molecular weight data: theoretical molecular weight C10 25 H 37 N3O3S [M+H] + =460.2588, the molecular weight determined by mass spectrometry is 460.2558. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) is 100.00%.

[0110] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A19: 1H NMR (400 MHz, DMSO-d6) δ8.11 (t, J = 5.7 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 7.6 Hz, 3H),7.46 – 7.38 (m, 4H), 7.32 (q, J = 7.7 Hz, 4H), 7.27 – 7.20 (m, 2H), 5.36 (s,1H), 4.48 (q, J = 7.6 Hz, 1H), 3.06 (q, J = 6.5 Hz, 2H), 2.75 (h, J = 6.1 Hz,2H), 2.59 (dd, J = 13.2, 6.7 Hz, 1H), 2.41 (dd, J = 13.2, 7.8 Hz, 1H), 1.93 –1.83 (m, 5H), 1.63 (d, J = 12.1 Hz, 4H), 1.53 (d, J = 11.7 Hz, 10H), 1.49 –1.38 (m, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 170.11, 158.18, 141.34, 128.48, 128.04, 127.07, 52.42, 51.69, 49.61, 41.98, 38.41, 37.89, 36.38, 33.66, 32.30, 28.02, 25.89, 24.33. Compound molecular weight data: theoretical molecular weight C10 32 H 43 N3O2S [M+H] + =534.3155, molecular weight determined by mass spectrometry is 534.3955. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) is 98.61%.

[0111] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A20: 1H NMR (400 MHz, DMSO-d6) δ8.45 (t, J = 5.7 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.48 – 7.39 (m, 4H), 7.37– 7.30 (m, 4H), 7.27 – 7.21 (m, 2H), 5.35 (s, 1H), 4.46 (q, J = 7.6 Hz, 1H), 3.50 (d, J = 6.2 Hz, 2H), 3.33 (t, J = 6.4 Hz, 2H), 3.05 (s, 9H), 2.63 (dd, J= 13.4, 6.7 Hz, 1H), 2.42 (dd, J = 13.3, 8.0 Hz, 1H), 1.93 – 1.82 (m, 5H), 1.61 (t, J = 13.0 Hz, 4H), 1.54 (d, J = 6.3 Hz, 9H). 13 C10 NMR (101 MHz, DMSO-d6) δ 170.91, 170.08, 141.21, 128.53, 128.00, 127.14, 63.54, 52.59, 52.40, 51.69, 49.58, 41.99, 36.36, 33.32, 33.18, 32.29, 28.00. Compound molecular weight data: theoretical molecular weight C10 33 H 46 N3O2S+ [M+H] + =548.3295, molecular weight determined by mass spectrometry was 548.3245. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.47%.

[0112] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A21: 1 H NMR (400 MHz, DMSO-d6) δ6.50 (s, 1H), 3.79 (tt, J = 5.1, 3.5 Hz, 1H), 3.22 (dd, J = 7.8, 5.2 Hz, 1H), 3.08 (dd, J = 7.8, 5.2 Hz, 1H), 2.89 – 2.77 (m, 2H), 2.10 – 2.01 (m, 3H), 1.96 (d, J = 5.1 Hz, 6H), 1.78 (t, J = 6.4 Hz, 1H), 1.65 (t, J = 5.5 Hz, 6H). 13C10 NMR (101 MHz, DMSO-d6) δ 173.06, 56.44, 51.08, 41.90, 36.29, 30.52, 29.75, 28.75. Compound molecular weight data: theoretical molecular weight C10... 13 H 21 N2OS [M+H] + =255.1526, molecular weight determined by mass spectrometry: 255.1322. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.77%.

[0113] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A22: 1 H NMR (400 MHz, DMSO-d6) δ7.59 (d, J = 8.1 Hz, 1H), 6.84 (t, J = 4.8 Hz, 1H), 4.45 (dt, J = 8.1, 4.2Hz, 1H), 4.08 (t, J = 6.3 Hz, 2H), 3.28 (qdt, J = 14.8, 4.8, 4.0 Hz, 2H), 3.00 (tt, J = 6.3, 4.0 Hz, 2H), 2.88 (dd, J = 6.7, 4.2 Hz, 2H), 2.03 (hept, J= 5.5 Hz, 3H), 1.87 – 1.80 (m, 7H), 1.71 (d, J = 11.4 Hz, 6H). 13 C10 NMR (101MHz, DMSO-d6) δ 177.65, 173.69, 56.78, 42.27, 41.66, 38.69, 36.22, 30.22, 29.31, 28.37. Compound molecular weight data: theoretical molecular weight C10 16 H 27 N3O2S [M+H] + =326.1897, molecular weight determined by mass spectrometry: 326.1823. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 97.17%.

[0114] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A23: 1H NMR (400 MHz, DMSO-d6) δ7.34 – 7.21 (m, 10H), 6.61 (s, 1H), 4.98 (t, J = 0.9 Hz, 1H), 3.94 (dt, J =5.3, 3.6 Hz, 1H), 3.42 (dd, J = 8.0, 5.2 Hz, 1H), 3.30 (dd, J = 8.1, 5.1 Hz,1H), 3.01 – 2.89 (m, 2H), 2.10 – 2.01 (m, 3H), 1.96 (d, J = 5.1 Hz, 6H), 1.65(t, J = 5.4 Hz, 6H). 13 C10 NMR (101 MHz, DMSO-d6) δ 172.01, 141.62, 128.67, 128.02, 127.89, 60.34, 55.04, 51.08, 41.90, 36.29, 34.61, 30.52, 29.75. Compound molecular weight data: theoretical molecular weight C10 26 H 32 N2OS [M+H] + =421.2308, molecular weight determined by mass spectrometry was 421.2301. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.26%.

[0115] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A24: 1 H NMR (400 MHz, DMSO-d6) δ7.92 (d, J = 7.8 Hz, 1H), 7.34 – 7.21 (m, 10H), 7.06 (d, J = 9.7 Hz, 1H), 4.99 (t, J = 0.9 Hz, 1H), 4.45 (dt, J = 7.9, 4.3 Hz, 1H), 4.08 (t, J = 6.3Hz, 2H), 3.28 (qdt, J = 14.8, 4.8, 4.0 Hz, 2H), 3.11 – 2.96 (m, 4H), 2.02(dq, J = 11.1, 5.5 Hz, 3H), 1.85 (d, J = 5.2 Hz, 6H), 1.71 (d, J = 11.4 Hz, 6H). 13C10 NMR (101 MHz, DMSO-d6) δ 177.63, 172.19, 141.65, 128.67, 128.02, 127.89, 60.27, 55.65, 42.27, 41.66, 38.69, 36.22, 33.08, 30.22, 29.31. Compound molecular weight data: theoretical molecular weight C10 29 H 37 N3O2S [M+H] + = 492.2679, molecular weight determined by mass spectrometry: 492.2329. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 96.16%.

[0116] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A25: 1 H NMR (400 MHz, DMSO-d6) δ6.72 (t, J = 6.4 Hz, 1H), 3.64 (tt, J = 6.2, 5.3 Hz, 1H), 3.08 (d, J = 6.5Hz, 2H), 2.90 (tq, J = 6.8, 2.2 Hz, 2H), 2.83 (dd, J = 8.1, 6.2 Hz, 1H), 2.71 (dd, J = 8.1, 6.2 Hz, 1H), 2.51 (t, J = 6.8 Hz, 2H), 2.05 – 1.93 (m, 3H), 1.93 – 1.84 (m, 2H), 1.66 (t, J = 5.7 Hz, 6H), 1.50 (d, J = 5.1 Hz, 6H). 13 CNMR (101 MHz, DMSO-d6) δ 174.95, 53.06, 49.78, 39.85, 39.78, 38.60, 37.97, 37.89, 35.57, 34.04, 30.37, 29.59, 29.54. Compound molecular weight data: theoretical molecular weight C 15 H 27 N3O[M+H] + = 266.2227, molecular weight determined by mass spectrometry is 266.2322. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) is 97.23%.

[0117] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A26: 1H NMR (400 MHz, DMSO-d6) δ7.34 – 7.21 (m, 10H), 6.74 (t, J = 6.4 Hz, 1H), 4.98 (t, J = 0.9 Hz, 1H), 3.92 (tt, J = 5.7, 4.2 Hz, 1H), 3.30 (dd, J = 7.9, 5.7 Hz, 1H), 3.20 (dd, J =8.1, 5.7 Hz, 1H), 3.08 (d, J = 6.4 Hz, 2H), 3.04 – 2.91 (m, 2H), 2.05 – 1.95(m, 3H), 1.66 (d, J = 11.4 Hz, 6H), 1.50 (d, J = 5.1 Hz, 6H). 13 C10 NMR (101MHz, DMSO-d6) δ 173.67, 141.62, 128.67, 128.02, 127.89, 60.32, 54.22, 49.77, 39.78, 37.89, 35.57, 34.68, 30.37, 29.54. Compound molecular weight data: theoretical molecular weight C10 27 H 34 N2OS[M+H] + = 435.2465, molecular weight determined by mass spectrometry: 435.2411. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.71%.

[0118] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A27: 1 H NMR (400 MHz, DMSO-d6) δ7.84 (d, J = 7.7 Hz, 1H), 7.05 – 6.99 (m, 3H), 6.75 – 6.69 (m, 2H), 6.14 (s,1H), 4.43 (dt, J = 7.7, 6.6 Hz, 1H), 4.08 (t, J = 6.3 Hz, 2H), 3.35 – 3.20(m, 2H), 3.07 – 3.00 (m, 3H), 3.00 – 2.95 (m, 1H), 2.07 (s, 2H), 2.00 (dtd, J= 10.9, 5.8, 5.0 Hz, 3H), 1.69 – 1.60 (m, 12H). 13C10 NMR (101 MHz, DMSO-d6) δ 173.59, 172.65, 156.46, 130.77, 128.87, 115.72, 55.42, 46.99, 42.27, 41.66, 40.65, 37.89, 37.44, 34.57, 30.45, 29.63. Compound molecular weight data: theoretical molecular weight C10 23 H 33 N3O3[M+H] + = 400.2595, molecular weight determined by mass spectrometry: 400.2493. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 98.63%.

[0119] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A28: 1 H NMR (400 MHz, DMSO-d6) δ7.05 (dt, J = 8.6, 1.0 Hz, 2H), 6.75 – 6.69 (m, 2H), 6.38 (d, J = 7.7 Hz,1H), 6.14 (s, 1H), 3.88 (p, J = 5.9 Hz, 1H), 3.57 (dq, J = 7.5, 5.2 Hz, 1H), 2.89 (dd, J = 5.9, 1.4 Hz, 2H), 2.53 (dd, J = 8.0, 6.0 Hz, 1H), 2.37 (dd, J =8.0, 5.9 Hz, 1H), 2.02 (dq, J = 10.8, 5.4 Hz, 3H), 1.66 (t, J = 5.5 Hz, 6H), 1.57 (d, J = 5.2 Hz, 6H), 1.03 (d, J = 5.3 Hz, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 174.70, 156.84, 130.70, 127.25, 115.38, 54.93, 54.55, 39.55, 38.76, 37.65, 36.77, 35.29, 16.30. Compound molecular weight data: theoretical molecular weight C10 21 H 30 N₂O₂[M+H] + = 343.2380, molecular weight determined by mass spectrometry: 343.2236. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.67%.

[0120] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A29: 1 H NMR (400 MHz, DMSO-d6) δ5.96 (d, J = 7.8 Hz, 1H), 3.57 (dq, J = 7.9, 5.2 Hz, 1H), 3.39 (td, J = 6.4,5.6 Hz, 1H), 2.97 (dd, J = 7.7, 6.4 Hz, 1H), 2.89 (dd, J = 7.9, 6.4 Hz, 1H), 2.05 – 1.97 (m, 4H), 1.97 – 1.92 (m, 1H), 1.66 (td, J = 5.5, 4.0 Hz, 6H), 1.57 (d, J = 5.2 Hz, 6H), 1.03 (d, J = 5.3 Hz, 3H), 0.92 (d, J = 6.4 Hz, 6H). 13 C10 NMR (101 MHz, DMSO-d6) δ 173.02, 58.32, 54.97, 39.62, 39.55, 38.84, 38.76, 36.77, 35.36, 35.29, 31.44, 18.69, 16.30. Compound molecular weight data: theoretical molecular weight C10 17 H 30 N₂O[M+H] + = 279.2431, molecular weight determined by mass spectrometry is 279.2456. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) is 99.45%.

[0121] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A30: 1 H NMR (400 MHz, DMSO-d6) δ7.51 (d, J = 8.1 Hz, 1H), 6.74 (t, J = 4.6 Hz, 1H), 4.27 (dd, J = 8.1, 6.5Hz, 1H), 4.08 (t, J = 6.3 Hz, 2H), 3.30 – 3.22 (m, 2H), 3.00 (tt, J = 6.3,4.0 Hz, 2H), 2.12 – 2.02 (m, 3H), 2.02 – 1.96 (m, 3H), 1.69 – 1.60 (m, 12H),0.89 (dd, J = 6.5, 2.1 Hz, 6H). 13C10 NMR (101 MHz, DMSO-d6) δ 173.13, 173.06, 58.61, 47.01, 42.33, 41.66, 40.65, 37.89, 34.57, 30.64, 30.45, 29.63, 18.95. Compound molecular weight data: theoretical molecular weight C10N. 19 H 33 N3O2 [M+H] + = 336.2646, the molecular weight determined by mass spectrometry is 336.2596. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) is 98.64%.

[0122] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A31: 1 H NMR (400 MHz, DMSO-d6) δ6.51 (d, J = 7.5 Hz, 1H), 3.97 (h, J = 5.3 Hz, 1H), 3.57 (dq, J = 7.5, 5.2Hz, 1H), 3.09 (dd, J = 7.9, 5.5 Hz, 1H), 2.96 (dd, J = 7.9, 5.5 Hz, 1H), 2.02 (dq, J = 10.8, 5.4 Hz, 3H), 1.66 (td, J = 5.5, 4.1 Hz, 6H), 1.57 (d, J = 5.2Hz, 6H), 1.33 (d, J = 5.1 Hz, 3H), 1.03 (d, J = 5.3 Hz, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 174.22, 54.88, 50.47, 39.62, 39.55, 38.84, 38.76, 36.76, 35.36, 35.29, 18.25, 16.29. Compound molecular weight data: theoretical molecular weight C10N. 15 H 26 N₂O[M+H] + = 251.2118, molecular weight determined by mass spectrometry: 251.2165. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 97.31%.

[0123] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A32: 1H NMR (400 MHz, DMSO-d6) δ7.35 (d, J = 7.3 Hz, 1H), 6.94 (t, J = 4.5 Hz, 1H), 4.36 (dq, J = 7.3, 6.1Hz, 1H), 4.08 (t, J = 6.3 Hz, 2H), 3.29 – 3.19 (m, 2H), 3.00 (tt, J = 6.3,4.0 Hz, 2H), 2.00 (ddd, J = 10.9, 5.8, 5.1 Hz, 5H), 1.69 – 1.60 (m, 13H),1.32 (d, J = 6.0 Hz, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 173.17, 172.73, 50.42, 46.96, 42.29, 41.68, 40.65, 37.89, 34.57, 30.45, 29.63, 17.85. Compound molecular weight data: theoretical molecular weight C10 17 H 29 N3O2 [M+H] + = 308.2118, molecular weight determined by mass spectrometry: 308.2009. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.40%.

[0124] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A33: 1 H NMR (400 MHz, DMSO-d6) δ6.34 (d, J = 7.7 Hz, 1H), 3.61 – 3.52 (m, 2H), 2.74 (dd, J = 8.0, 5.4 Hz, 1H), 2.55 (dd, J = 7.9, 5.5 Hz, 1H), 2.02 (dq, J = 10.8, 5.4 Hz, 3H), 1.77 –1.63 (m, 7H), 1.59 – 1.48 (m, 8H), 1.03 (d, J = 5.3 Hz, 3H), 0.92 (dd, J =7.1, 1.1 Hz, 6H). 13C10 NMR (101 MHz, DMSO-d6) δ 174.97, 54.94, 52.43, 41.76, 39.62, 39.55, 38.84, 38.76, 36.76, 35.36, 35.29, 25.01, 22.40, 16.30. Compound molecular weight data: theoretical molecular weight C10 18 H 31 N₂O[M+H] + =293.2587, molecular weight determined by mass spectrometry: 293.2519. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.35%.

[0125] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A34: 1 H NMR (400 MHz, DMSO-d6) δ7.38 (d, J = 7.1 Hz, 1H), 6.92 (t, J = 4.9 Hz, 1H), 4.30 – 4.23 (m, 1H), 4.08(t, J = 6.3 Hz, 2H), 3.35 – 3.20 (m, 2H), 3.00 (tt, J = 6.3, 4.0 Hz, 2H), 2.07 (s, 2H), 2.00 (ddd, J = 10.9, 5.8, 5.1 Hz, 3H), 1.69 – 1.49 (m, 15H), 0.91 – 0.83 (m, 6H). 13 C10 NMR (101 MHz, DMSO-d6) δ 174.31, 172.80, 52.93, 46.99, 42.26, 41.68, 40.95, 40.65, 37.89, 34.57, 30.45, 29.63, 24.78, 22.40. Compound molecular weight data: theoretical molecular weight C10... 20 H 35 N₂O₂[M+H] + = 350.2802, the molecular weight determined by mass spectrometry is 350.2749. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) is 97.25%.

[0126] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A35: 1H NMR (400 MHz, DMSO-d6) δ6.26 (d, J = 7.7 Hz, 1H), 3.61 – 3.51 (m, 2H), 3.30 (dd, J = 7.9, 5.1 Hz, 1H), 2.93 (dd, J = 8.1, 5.1 Hz, 1H), 2.61 (dtd, J = 7.3, 5.5, 3.5 Hz, 2H),2.01 (dt, J = 10.7, 5.4 Hz, 3H), 1.98 – 1.92 (m, 2H), 1.92 – 1.87 (m, 1H),1.66 (t, J = 5.5 Hz, 6H), 1.57 (s, 6H), 1.03 (d, J = 5.3 Hz, 3H). 13 C10 NMR (101MHz, DMSO-d6) δ 174.64, 54.95, 53.39, 39.55, 38.76, 36.76, 35.29, 35.21, 22.43, 16.30. Compound molecular weight data: theoretical molecular weight C10 16 H 27 N2OS [M+H] + =297.1995, molecular weight determined by mass spectrometry: 297.1976. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.67%.

[0127] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A36: 1 H NMR (400 MHz, DMSO-d6) δ7.91 (d, J = 7.0 Hz, 1H), 6.82 (t, J = 4.9 Hz, 1H), 4.27 (dt, J = 7.0, 4.9Hz, 1H), 4.08 (t, J = 6.3 Hz, 2H), 3.28 (qdt, J = 14.7, 4.8, 3.9 Hz, 2H), 3.00 (tt, J = 6.3, 4.0 Hz, 2H), 2.60 (dtd, J = 6.9, 5.8, 3.8 Hz, 2H), 1.69 –1.60 (m, 12H). 13C10 NMR (101 MHz, DMSO-d6) δ 174.13, 172.77, 53.70, 46.99, 42.26, 41.68, 40.65, 37.89, 34.57, 33.77, 30.45, 29.63, 22.23. Compound molecular weight data: theoretical molecular weight C10 18 H 30 N3O2S [M+H] + =354.2210, molecular weight determined by mass spectrometry: 354.2212. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.24%.

[0128] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A37: 1 H NMR (400 MHz, DMSO-d6) δ6.26 (d, J = 7.5 Hz, 1H), 3.64 – 3.53 (m, 2H), 3.14 (dd, J = 7.9, 5.9 Hz,1H), 3.00 – 2.91 (m, 2H), 2.85 (dd, J = 8.1, 5.9 Hz, 1H), 2.02 (dq, J = 10.8,5.4 Hz, 3H), 1.80 – 1.72 (m, 4H), 1.66 (td, J = 5.5, 4.0 Hz, 6H), 1.61 – 1.51(m, 8H), 1.03 (d, J = 5.3 Hz, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 174.76, 54.94, 54.00, 40.27, 39.62, 39.55, 38.84, 38.76, 36.76, 35.36, 35.29, 30.82, 27.67, 16.30. Compound molecular weight data: theoretical molecular weight C10 17 H 30 N3OS [M+H] + =294.2540, molecular weight determined by mass spectrometry: 294.2543. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.34%.

[0129] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A38: 1H NMR (400 MHz, DMSO-d6) δ7.82 (d, J = 7.5 Hz, 1H), 6.83 (t, J = 4.9 Hz, 1H), 4.32 – 4.24 (m, 1H), 4.08(t, J = 6.3 Hz, 2H), 3.28 (qdt, J = 14.7, 4.7, 3.9 Hz, 2H), 3.04 – 2.89 (m,4H), 2.07 (s, 2H), 2.00 (ddd, J = 10.9, 5.8, 5.1 Hz, 3H), 1.88 – 1.68 (m,6H), 1.67 – 1.60 (m, 12H). 13 C10 NMR (101 MHz, DMSO-d6) δ 174.38, 172.77, 54.13, 46.99, 42.26, 41.68, 40.65, 40.48, 37.89, 34.57, 30.45, 29.63, 29.07, 27.11. Compound molecular weight data: theoretical molecular weight C10N. 19 H 33 N4O2S [M+H] + =251.2755, molecular weight determined by mass spectrometry: 251.2613. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.23%.

[0130] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A39: 1 H NMR (400 MHz, DMSO-d6) δ6.26 (d, J = 7.7 Hz, 1H), 3.64 – 3.53 (m, 2H), 2.93 – 2.87 (m, 2H), 2.82 (dd,J = 7.9, 6.0 Hz, 1H), 2.69 (dd, J = 8.0, 6.0 Hz, 1H), 2.51 (t, J = 6.8 Hz, 2H), 2.02 (dq, J = 10.8, 5.4 Hz, 3H), 1.91 (qd, J = 4.8, 3.8 Hz, 2H), 1.66(td, J = 5.5, 4.0 Hz, 6H), 1.57 (d, J = 5.2 Hz, 6H), 1.03 (d, J = 5.3 Hz, 3H). 13C10 NMR (101 MHz, DMSO-d6) δ 175.04, 54.94, 52.98, 39.62, 39.55, 38.84, 38.76, 38.60, 36.76, 35.36, 35.29, 34.06, 16.30. Compound molecular weight data: theoretical molecular weight C10 16 H 28 N3OS[M+H] + = 280.2383, molecular weight determined by mass spectrometry is 280.2423. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) is 99.12%.

[0131] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A40: 1 H NMR (400 MHz, DMSO-d6) δ7.83 (d, J = 7.7 Hz, 1H), 6.82 (t, J = 4.9 Hz, 1H), 4.21 (dt, J = 7.7, 5.9Hz, 1H), 4.08 (t, J = 6.3 Hz, 2H), 3.28 (qdt, J = 14.7, 4.8, 3.9 Hz, 2H), 3.04 – 2.91 (m, 4H), 2.80 (q, J = 6.6 Hz, 1H), 2.69 (q, J = 6.5 Hz, 1H), 2.11– 2.01 (m, 3H), 2.01 – 1.96 (m, 3H), 1.96 – 1.90 (m, 1H), 1.69 – 1.60 (m, 12H). 13 C10 NMR (101 MHz, DMSO-d6) δ 174.70, 172.77, 53.36, 46.99, 42.26, 41.68, 40.65, 38.39, 37.89, 34.57, 32.74, 30.45, 29.63. Compound molecular weight data: theoretical molecular weight C10 18 H 31 N4O2S [M+H] + =337.2598, and the molecular weight determined by mass spectrometry was 337.2513. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.19%.

[0132] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A41: 1H NMR (400 MHz, DMSO-d6) δ6.27 (d, J = 7.5 Hz, 1H), 3.66 – 3.53 (m, 2H), 3.16 (dd, J = 8.4, 5.3 Hz, 1H), 2.95 (td, J = 5.9, 2.9 Hz, 2H), 2.94 – 2.87 (m, 1H), 2.65 (dt, J = 7.3, 6.0 Hz, 1H), 2.58 (dt, J = 7.3, 5.9 Hz, 1H), 2.02 (dq, J = 10.8, 5.4 Hz, 3H), 1.66 (td, J = 5.5, 4.1 Hz, 6H), 1.57 (d, J = 5.2 Hz, 6H), 1.02 (d, J = 5.1Hz, 3H). 13 C10 NMR (101 MHz, DMSO-d6) δ 174.21, 54.93, 53.13, 42.75, 39.62, 39.55, 38.84, 38.76, 36.77, 35.36, 35.29, 16.31. Compound molecular weight data: theoretical molecular weight C10 15 H 26 N3OS [M+H] + =266.2227, molecular weight determined by mass spectrometry is 266.3213. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) is 99.38%.

[0133] Nuclear magnetic resonance spectroscopy data of adamantane-modified peptide A42: 1 H NMR (400 MHz, DMSO-d6) δ7.68 (d, J = 7.1 Hz, 1H), 6.96 (t, J = 4.9 Hz, 1H), 4.19 (dt, J = 7.3, 3.7Hz, 1H), 4.04 (t, J = 6.3 Hz, 2H), 3.35 – 3.20 (m, 2H), 3.04 – 2.85 (m, 6H), 2.07 (s, 2H), 2.00 (ddd, J = 10.9, 5.8, 5.1 Hz, 3H), 1.69 – 1.60 (m, 12H). 13CNMR (101 MHz, DMSO-d6) δ 174.57, 173.07, 52.79, 46.99, 42.27, 41.84, 41.66, 40.72, 40.65, 37.89, 34.57, 30.45, 29.69, 29.63. 13 C10 NMR (101 MHz, DMSO-d6) δ 174.57, 173.07, 52.79, 46.99, 42.27, 41.84, 41.66, 40.72, 40.65, 37.89, 34.57, 30.45, 29.69, 29.63. Compound molecular weight data: theoretical molecular weight C10 17 H 29 N4O2S [M+H] + =323.2442, and the molecular weight determined by mass spectrometry was 323.2413. The purity of the compound determined by reversed-phase high-performance liquid chromatography (RP-HPLC) was 99.12%.

[0134] Example 8: Assay of the in vitro antibacterial activity of adamantane-modified peptides

[0135] The purified adamantane-modified peptides A1-A42 from Example 7 were subjected to in vitro antibacterial activity assays. The strains used for the in vitro antibacterial activity assays of the adamantane-modified peptides and control antibiotics included standard strains (including *Escherichia coli* (ATCC 25922, *C. albicans* ATCC 14053), *Staphylococcus aureus* (ATCC 25923, *MRSA* ATCC 43300), *Bacillus subtilis* (ATCC 23875), *Staphylococcus epidermidis* (ATCC 12228), *Enterococcus faecalis* (ATCC 19433, *VRE* ATCC 51299), and *Enterococcus gallinarum* (ATCC 49573), all from the U.S. Culture Collection).

[0136] The minimum inhibitory concentrations (MICs) of adamantane-modified peptides and control antibiotics against the tested strains were determined using the standard two-fold dilution method recommended by the National Clinical and Laboratory Standards Institute (NCCLS). Simply, an appropriate amount of cryopreserved bacterial (or fungal) solution was transferred to fresh MH / SD medium and incubated overnight at 37°C and 180 rpm on a shaker. The bacterial solution was then transferred a second time and incubated on a shaker for another 4-5 hours to obtain bacteria in the logarithmic growth phase. Then, 1×10⁻⁶ [amount missing] was taken... 6CFU / mL bacterial culture was added to 96-well plates at 100 μL per well. Then, the peptide was diluted twice (1-100 μg / mL) to 100 μL per well, twice the final concentration. Fresh culture was used as the negative control. Each concentration was tested in triplicate. After adding the antibiotics, the 96-well plates were incubated at 37°C for 18-24 hours. The results were observed, and the concentration of the cyclic peptide antibiotic at the first clear well after the well that showed visibly turbidity was recorded as the minimum inhibitory concentration (MIC) of that cyclic peptide antibiotic against the bacteria. The statistical results are shown in Table 1 below.

[0137] Table 1. Minimum inhibitory concentrations (MICs) (μg / mL) of adamantane-modified peptides A1-A42 against test bacteria.

[0138] .

[0139] Example 9 Assay of hemolytic activity of mammalian erythrocytes (HC) 50 >100 μg / mL)

[0140] The purified adamantane-modified peptides A1, A3, A7, A8, A11, A12, A19, A20, A21, A22, A23, A24, A25, A26, A27, and A36 from Example 7 were co-incubated with mouse erythrocytes, and the OD of the solution was detected using an enzyme-linked immunosorbent assay (ELISA) reader. 490 The absorbance was used to assess the hemolytic activity of cyclic peptide antibiotics.

[0141] First, whole blood from mice was centrifuged at 1200 rpm for 5 min, and the supernatant was discarded. After washing with PBS, 100% red blood cells were collected and diluted to 8%. The red blood cells were then added to a 96-well plate, and the test peptide solution at a concentration of 100 µg / mL was added. The plate was then incubated in a cell culture incubator for 1 h. After centrifugation at 1500 rpm for 15 min, the supernatant was transferred to another 96-well plate, and the OD was measured using a microplate reader. 490 Finally, according to the formula: Hemolysis rate (%) = (Experimental group OD) 490 - Negative control group OD 490 ) / (Positive control group OD 490 - Negative control group OD 490 Calculate the hemolysis rate of each pseudopeptide by multiplying by 100%.

[0142] like Figure 1 As shown, the hemolysis rates of adamantane-modified peptides A19 and A20 exceeded 80%, while other peptides exhibited weak erythrocyte toxicity. The hemolysis rate of adamantane-modified peptide A8 was less than 5%, and the hemolytic toxicity of peptides A1, A2, A7, A11, A12, A21, A22, A23, A24, A25, A26, A27, and A36 ranged from 10% to 20%.

[0143] Example 10 Cytotoxicity Assay

[0144] The cytotoxicity of the purified adamantane-modified peptides A1, A3, A7, A8, A11, A12, A19, A20, A21, A22, A23, A24, A25, A26, A27 and A36 from Example 7 on mouse NIH 3T3 fibroblasts was determined.

[0145] Cell viability is defined as the number of viable cells in a sample. Cytotoxicity assays are commonly used in drug screening to detect whether a test molecule affects cell proliferation or exhibits direct cytotoxic effects.

[0146] Dilute the cell suspension in good condition to 5 × 10⁻⁶. 4 After adding cells at a concentration of 100 μL / mL to each well of a 96-well plate, the cells were incubated for 24 h. Then, the adamantane-modified peptide solution was added, and the plate was incubated for another 24 h. Next, 10 μL of 5 mg / mL MTT was added to each well, and the plate was incubated in the dark for 3–5 h. The liquid in the 96-well plate was discarded, and 150 μL of dimethyl sulfoxide (DMSO) was added to each well. The plate was shaken for 15 min, and the absorbance at 570 nm was measured. The survival rate (%) was calculated using the formula: OD0.05 = OD0.05 of the experimental group. 570 / Control group OD 570 Calculate cell viability by multiplying by 100%.

[0147] like Figure 2 As shown, the cell survival rate after treatment with adamantane-modified peptides A19 and A20 was less than 60%, while other peptides showed weak toxicity to mouse fibroblasts. Cell survival rates after treatment with A8 and A11 were higher than 90%, while cell survival rates after treatment with A1, A2, A7, A12, A21, A22, A23, A24, A25, A26, A27, and A36 ranged from 70% to 90%.

[0148] Example 11: Determination of bactericidal kinetics

[0149] Using the purified adamantane-modified peptides A8 and A11 from Example 7 as representatives, the effect of cyclic peptide antibiotics on the growth and proliferation of Staphylococcus aureus ATCC 25923 at different time intervals was determined by colony-forming unit (CFU) counting method. The bactericidal kinetics of the cyclic peptide antibiotics were then represented by plotting the time interval on the x-axis and the logarithm of the colony count per milliliter on the y-axis. Simply put, the logarithmic phase concentration of 1.0 × 10⁻⁶ was used... 6CFU / mL of Staphylococcus aureus was added to a 96-well plate, followed by the addition of cyclic peptide antibiotics (final concentration 4×MIC). The plates were co-cultured at 37°C. At time intervals of 0 h, 1 / 6 h, 1 / 2 h, 1 h, 2 h, 4 h, 6 h, and 8 h, appropriate amounts of bacterial suspension were taken out, diluted appropriately, and 100 μL of the diluted bacterial suspension was evenly spread onto MH solid medium using a spreader. After incubation overnight, colony counting was performed.

[0150] Figure 3 The results showed that at a concentration of 4×MIC, the adamantane-modified peptide A8 could kill bacteria within 2 hours, and the peptide A11 could kill bacteria within 6 hours, both demonstrating rapid bacterial killing ability.

[0151] Example 12 Drug Resistance Determination

[0152] The purified adamantane-modified peptides A8 and A11 from Example 7 were selected for the following resistance assays. The potential for cyclic peptide antibiotics to induce bacterial resistance was assessed by determining the minimum inhibitory concentration (MIC) against Staphylococcus aureus ATCC 25923 in 21 consecutive measurements. Simply, Staphylococcus aureus in logarithmic growth phase was diluted and added to a 96-well microtiter plate. The MIC was determined using the classic two-fold dilution method, and the concentration in the first well where no turbidity was observed was recorded as the initial MIC0. Then, half a well containing MIC0 was used as the bacterial culture for the next MIC measurement, and the first MIC was determined in the same manner and recorded as MIC1. Subsequently, the MIC values ​​of cyclic peptide antibiotics against Staphylococcus aureus were continuously measured in the same manner for 21 consecutive measurements, recorded as MIC21. Finally, a graph was plotted with the number of measurements on the x-axis and the ratio of each MIC value to the MIC0 value on the y-axis to represent the assessment of the development of bacterial resistance induced by cyclic peptide antibiotics. The clinical antibiotic Amoxicillin was used as a control.

[0153] like Figure 4 As shown, in the 21-day bacterial resistance test, the MIC values ​​of adamantane-modified peptide A8 were 6.25–12.5 µg / mL, and the MIC values ​​of adamantane-modified peptide A11 were 3.125–6.25 µg / mL, which were 1–2 times different from the initial MIC. The bacteria did not develop resistance to them.

[0154] The initial MIC for the amoxicillin group was 0.16 µg / mL. The MIC value on day 7 was 8 times the initial value, the MIC value on day 12 was 32 times the initial value, and the MIC value on day 15 was 250 times the initial value.

[0155] Example 13 Effects on bacterial cell membranes

[0156] The effects of the peptides on bacterial cell membranes were evaluated by detecting the disruptive effects of adamantane-modified peptides, represented by the purified A8 and A11 peptides from Example 7, on the cell membrane potential of Staphylococcus aureus ATCC 25923 and their induction of PI uptake in Staphylococcus aureus.

[0157] 1. The disruptive effect of adamantane-modified peptides on the membrane potential of Staphylococcus aureus

[0158] The disruptive effect of adamantane-modified peptides on the membrane potential of Staphylococcus aureus was determined by the DiOC2(3) fluorescent probe method. Simply, Staphylococcus aureus ATCC 25923 was incubated at 37°C for 18 hours, centrifuged at 5000 rpm for 10 minutes, and the precipitate was collected. The precipitate was washed three times with 10 mM PBS (pH 7.4) containing 0.1% glucose and then resuspended to OD600 = 0.5. Subsequently, an equal volume of 60 µM DiOC2(3) solution was added to the bacterial suspension, and the suspension was incubated at 37°C in the dark for 15 minutes. Then, the bacterial suspension containing DiOC2(3) (50 μL / well) was added to a 96-well microtiter plate, followed by the addition of 50 μL of cyclic peptide antibiotics at different concentrations (ranging from 1 to 8 times the MIC), and incubated for 30 minutes. Finally, the fluorescence of each well was detected using a microplate reader (Synergy NEO2, Agilent), with an excitation wavelength of 485 nm and two emission wavelengths of 530 nm and 630 nm, respectively. 0.1% Triton X-100 was used as a positive control, and PBS was used as a negative control.

[0159] like Figure 5 As shown, adamantane-modified peptides A8 and A11 disrupt bacterial membrane potential in a concentration-dependent manner, and can completely disrupt bacterial membrane potential at a concentration of 4×MIC.

[0160] 2. Determination of the effects of adamantane-modified peptides A8 and A11 on bacterial cell membrane integrity disruption

[0161] The disruptive effect of adamantane-modified peptides on bacterial cell membrane integrity was assessed by measuring the uptake of the fluorescent dye propidium iodide (PI) by Staphylococcus aureus (ATCC 25923) after treatment with a cyclic peptide antibiotic. Simply, after overnight incubation of Staphylococcus aureus at 37°C, the bacterial culture was centrifuged at 5000 rpm for 10 minutes, washed three times with PBS (10 mM, pH=7.4), and resuspended to 1×10⁻⁶. 9The concentration of CFU / mL was determined. Subsequently, 100 μL of Staphylococcus aureus suspension was thoroughly mixed with an equal volume of cyclic peptide antibiotic solution and incubated at 37°C in a shaker for 1 hour. Then, 10 μL of PI (1 mg / mL) was added and incubated in the dark for 15 minutes for flow cytometry analysis (NovoCyte Quanteon, Agilent). The untreated group served as a negative control; alternatively, 10 μL each of PI (10 µM) and Hoechst 33342 (10 µM) were added and incubated in the dark for 15 minutes for fluorescence inverted microscopy imaging.

[0162] like Figure 6 As shown, after Staphylococcus aureus was treated with adamantane-modified peptides A8 and A11 at a concentration of 4×MIC, the positive rate of PI detected by flow cytometry was greater than 90%, while the positive rate of PI in Staphylococcus aureus treated with PBS was less than 10%. This indicates that adamantane-modified peptides A8 and A11 can disrupt bacterial cell membranes.

[0163] like Figure 7 As shown, Staphylococcus aureus treated with adamantane-modified peptides A8 and A11 exhibited significant red fluorescence, while Staphylococcus aureus treated with PBS did not show any red fluorescence. This indicates that adamantane-modified peptides A8 and A11 can disrupt the bacterial cell membrane, allowing PI to enter the bacteria.

[0164] like Figure 8 As shown, after co-incubation of Staphylococcus aureus with 4×MIC adamantane-modified peptides A8 and A11, cryo-transmission electron microscopy revealed that the Staphylococcus aureus cells in the negative control group (0.9% NaCl) exhibited intact cytoplasmic membranes, while those treated with adamantane-modified peptides A8 and A11 showed disruption of the bacterial cell membranes, resulting in leakage of contents. This further indicates that adamantane-modified peptides A8 and A11 exert their antibacterial effects through a membrane disruption mechanism.

[0165] Example 14: Activity assay for inhibiting Staphylococcus aureus biofilm formation

[0166] In this embodiment, the purified adamantane-modified peptides A8 and A11 from Example 7 were selected for the following determinations.

[0167] The inhibition of Staphylococcus aureus (ATCC 25923) biofilm formation by cyclic peptide antibiotics was determined using the crystal violet method. Simply put, a concentration of 1.0 × 10⁻⁶ was used. 6Log-phase Staphylococcus aureus (CFU / mL) was added to a 96-well plate, followed by the addition of adamantane-modified peptides A8 and A11 at concentrations ranging from 1×MIC to 16×MIC. The plate was then incubated at 37°C. After 24 hours, the surface-dwelling bacteria were removed from the 96-well plate, washed with PBS, fixed with methanol, stained with crystal violet solution for 15 min, and then dissolved in 95% ethanol to determine the OD (octane rating). 570 According to the formula, the biofilm formation inhibition rate (%) = [1 - (experimental group OD] / (experimental group OD)] 570 - Negative control group OD 570 ) / (Positive control group OD570 - Negative control group OD 570 )]×100%.

[0168] like Figure 9 As shown, adamantane-modified peptide A8 inhibited approximately 50% of Staphylococcus aureus biofilm formation at a concentration of 2×MIC, and completely inhibited biofilm formation at the same concentration. Peptide A11 completely inhibited Staphylococcus aureus biofilm formation at a concentration of 1×MIC.

[0169] Example 15 In vivo antibacterial activity assay

[0170] The purified adamantane-modified peptides A8 and A11 from Example 7 were used as representatives for in vivo antibacterial activity testing. Mouse models of MRSA-infected keratitis and mouse models of pneumonia were established, and the therapeutic effects of adamantane-modified peptides A8 and A11 in these animal models were evaluated.

[0171] 1. Mouse keratitis model

[0172] To determine the therapeutic potential of adamantane-modified peptides in a mouse model of pneumonia, female Kunming mice were randomly assigned to an untreated control group, a model group, and treatment groups for adamantane-modified peptides A8, A11, and vancomycin. After anesthetizing mice in the model group, A8, A11, and vancomycin treatment groups, 25 μL of OD250 was administered via a nebulizer needle under visual guidance. 600 Mice were injected with a 0.35 μL MRSA (ATCC 43300) bacterial suspension via the trachea. At 2 and 12 h post-infection, mice in the model group received intraperitoneal injections of saline, while the treatment groups were treated with 5 mg / kg of adamantane-modified peptides A8 and A11, linezolid (5 mg / kg), and vancomycin, respectively. Twenty-four hours post-infection, all mice were sacrificed, and bacterial colony counting and H&E staining histological examination were performed.

[0173] like Figure 10As shown, adamantane-modified peptides A8 and A11 (5 mg / kg) effectively reduced the bacterial load in the lungs (colony loads of 2.30 × 10⁻⁶ and 2.30 × 10⁻⁶, respectively) within 24 hours. 6 CFU / mL and 1.77×10 6 CFU / mL, p<0.001), compared with the vancomycin (5 mg / kg) treatment group (colony load 8.05 × 10⁻⁶). 6 The concentration of CFU / mL (p<0.001) was comparable. H&E staining results showed that the alveolar morphology of the adamantane-modified peptide A8 and A11 treatment groups was intact, and no obvious inflammatory cells and capillary congestion were observed. This was similar to the lung characteristics of the linezolid and uninfected groups. In contrast, the alveolar wall capillary congestion and increased inflammatory cells were observed in the model group. The alveolar wall was thickened, the alveolar tissue was reduced, and the capillary congestion and increased inflammatory cells were observed in the model group.

[0174] 2. Mouse pneumonia model

[0175] To test the in vivo antibacterial activity of the peptides in a mouse model of keratitis, Kunming mice were randomly divided into a negative control group, an adamantane-modified peptide A8 treatment group, an adamantane-modified peptide A11 treatment group, and a linezolid control group. After anesthetizing the mice in the model group, treatment group, and linezolid control group, the cornea was scraped with a needle and then infected with 10 μL of MRSA bacterial suspension to establish a keratitis model. Twelve hours post-infection, mice in the adamantane-modified peptide A8, A11, and linezolid control groups were treated with multiple eye drops of 10 μL of 1 mg / mL adamantane-modified peptide A8, A11, and linezolid, respectively. Simultaneously, the model group received 10 μL of 0.9% saline each time. Eight hours after treatment, the mice were sacrificed, and their ocular tissues were collected for bacterial colony counting and H&E staining histological examination.

[0176] like Figure 11 As shown, the bacterial load in the eyeballs of the model group was significantly higher after 8 hours of treatment with saline solution, with an average colony load of 2.93 × 10⁻⁶. 7 CFU / mL, while the ocular bacterial load was significantly reduced after treatment with adamantane-modified peptides A8 and A11 and linezolid, with average colony loads of 4.83 × 10⁻⁶ CFU / mL. 6 CFU / mL, 7.05×10 6 CFU / mL and 8.05×10 6CFU / mL. There was no significant difference in colony loading between the adamantane-modified peptides A8 and A11 and the positive control group linezolid (p>0.5). H&E staining results showed that the model group had corneal defects and a large number of inflammatory cells, while the adamantane-modified peptides A8, A11, and linezolid treatment groups showed relatively intact corneal epithelial cells and basal layer, with fewer inflammatory cells.

[0177] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An antimicrobial peptide mimicry based on adamantane modification, characterized in that, The antimicrobial peptide mimic is a pharmaceutically acceptable salt of an adamantane-modified peptide mimic; The adamantane-modified peptide is selected from any one of the following A1 to A42; ； The pharmaceutically acceptable salts include salts of inorganic bases, salts of organic bases, salts of basic amino acids, salts of inorganic acids, salts of organic acids, or salts of acidic amino acids.

2. The antimicrobial peptide mimicry as described in claim 1, characterized in that, The inorganic base salt is selected from any one of ammonium salts, alkali metal salts, and alkaline earth metal salts; The salt of the organic base is a salt of any one of the organic bases selected from cyclohexylamine, benzylamine, octylamine, ethanolamine, diethanolamine, diethylamine, triethylamine, ethylenediamine, morpholine, pyrroline, piperidine, N-ethylpiperidine, N-methylmorpholine, and piperazine. The salt of the basic amino acid is a salt of any one of lysine, arginine, ornithine, and histidine. The inorganic acid salt is selected from any one of hydrochloride, bromide, sulfate, phosphate, and phosphate ester; The salt of the organic acid is selected from any one of acetate, formate, propionate, lactate, citrate, fumarate, maleate, benzoate, tartrate, malate, methane sulfonate, ethane sulfonate, toluene sulfonate, and benzene sulfonate; The salt of the acidic amino acid is a salt of aspartic acid or glutamic acid.

3. The antimicrobial peptide mimicry as described in claim 2, characterized in that, The alkali metal salt is a sodium or potassium salt; the alkaline earth metal salt is a magnesium or calcium salt.

4. The use of the antimicrobial peptide mimicry according to any one of claims 1 to 3 in the preparation of a medicament for treating bacterial infections.

5. The application as described in claim 4, characterized in that, The dosage form of the drug is selected from any one of oral dosage, injection, and topical preparations.

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