Conjugates comprising camphanol and peptides and uses thereof

CN120225216APending Publication Date: 2025-06-27BIOCELLS BEIJING BIOTECH CO LTD
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Patent Information

Application Number
CN202380077799.1
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Priority Date
2022-12-23
Filing Date
2023-12-20
Publication Date
2025-06-27

AI Technical Summary

Technical Problem

Existing treatments for central nervous system damage are difficult to effectively inhibit the interaction between N-methyl-D-aspartate receptors and postsynaptic density protein 95, resulting in difficult to treat nerve damage and related pain and neurodegenerative diseases. cure.

Method used

Development of conjugates containing bohnol and peptides that inhibit the interaction between N-methyl-D-aspartate receptors and postsynaptic density protein 95 by binding to the PDZ domain of postsynaptic density protein 95 , combined with a non-peptidyl polymer as a linker, forming a conjugate with a 1:1 molar ratio.

Benefits of technology

The protective effect against central nervous system damage is significantly improved, the safety and activity of the conjugate are enhanced, and the conjugate can effectively prevent and treat nervous system damage, pain, neurodegenerative diseases, anxiety and epilepsy.

✦ Generated by Eureka AI based on patent content.

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Abstract

Provided are conjugates comprising borneol and a peptide wherein the peptide comprises a variant of LDTEI (SEQ ID NO: 1) or in SEQ ID NO: 1 in which one or more conservative substitutions occur, a variant of LLDTEI (SEQ ID NO: 37), a variant of CLDTEI (SEQ ID NO: 689) or in SEQ ID NO: 37 or 689 in which one or more conservative substitutions occur, or a variant of YEKLLDTEI (SEQ ID NO: 253) or in SEQ ID NO: 253 in which the conservative substitutions are selected from the group consisting of substitutions between aspartic acid (D) and glutamic acid (E), substitution between leucine (L), valine (V) and isoleucine (I) and substitution between threonine (T) and serine (S). Pharmaceutical compositions comprising the conjugates and their medical uses are also provided.
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Description

Conjugates comprising borneol and peptides and uses thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese Patent Application No. 202211666762.6 filed on December 23, 2022, the entire contents of which are incorporated herein by reference in their entirety. Field of the Invention

[0003] The present invention generally relates to the field of medicine. Specifically, the present application provides a conjugate containing borneol and a peptide and a pharmaceutical composition for treating central nervous system damage.

[0004] Background of the Invention

[0005] The applicant is the applicant of the PCT international applications PCT / CN2016 / 080321, PCT / CN2017 / 104750, PCT / CN2017 / 104751, PCT / CN2016 / 109008, PCT / CN2017 / 091792, PCT / CN2017 / 091793 and PCT / CN2017 / 091794, and Chinese patent application CN201711011953.8 Disclosed are active peptides and functional variants thereof that target postsynaptic density protein 95 (PSD-95) and inhibit the interaction between N-methyl-D-aspartate receptors (NMDARs) and PSD-95, pharmaceutically acceptable salts of the active peptides, compounds, conjugates, and pharmaceutical compositions comprising the active peptides and functional variants thereof, and their uses in the medical fields of preventing, ameliorating, and / or treating central nervous system damage, pain associated with the damage, neurodegenerative diseases, and the like. The entire contents of the aforementioned application are incorporated herein by reference.

[0006] On the basis of the above, the applicant of the present application conducted in-depth research and development and prepared a new conjugate containing borneol and peptide targeting PSD-95.

[0007] SUMMARY OF THE INVENTION

[0008] In a first aspect, the present application provides a conjugate comprising borneol and a peptide, wherein the peptide comprises LDTEI (SEQ ID NO: 1) or a variant of SEQ ID NO: 1 in which one or more conservative substitutions occur, wherein the conservative substitutions are selected from substitutions between aspartic acid (D) and glutamic acid (E), substitutions between leucine (L), valine (V) and isoleucine (I), and substitutions between threonine (T) and serine (S).

[0009] In some embodiments of the first aspect, borneol is located on the N-terminal side of the peptide.

[0010] In some embodiments of the first aspect, a variant of SEQ ID NO: 1 is selected from the group consisting of: LDTEL (SEQ ID NO: 2), LDTEV (SEQ ID NO: 3), LDTDI (SEQ ID NO: 4), LDTDL (SEQ ID NO: 5), LDTDV (SEQ ID NO: 6), LDSEI (SEQ ID NO: 7), LDSEL (SEQ ID NO: 8), LDSEV (SEQ ID NO: 9), LDSDI (SEQ ID NO: 10), LDSDL (SEQ ID NO: 11), LDSDV (SEQ ID NO: 12), LETEI (SEQ ID NO: 13), LETEL (SEQ ID NO: 14), LETEV (SEQ ID NO: 15), LETDI (SEQ ID NO: 16), LETDL (SEQ ID NO: 17), LETDV (SEQ ID NO: 18), VDTEI (SEQ ID NO: 19), VDTEL (SEQ ID NO: 20), VDTEV (SEQ ID NO: 21), VDTDI (SEQ ID NO: 22), VDTDL (SEQ ID NO: 23), NO:23), VDTDV (SEQ ID NO:24), IDTEI (SEQ ID NO:25), IDTEL (SEQ ID NO:26), IDTEV (SEQ ID NO:27), IDTDI (SEQ ID NO:28), IDTDL (SEQ ID NO:29), IDTDV (SEQ ID NO:30), IETEI (SEQ ID NO:31), IETEL (SEQ ID NO:32), IETEV (SEQ ID NO:33), IETDI (SEQ ID NO:34), IETDL (SEQ ID NO:35) and IETDV (SEQ ID NO:36).

[0011] In some embodiments of the first aspect, the borneol is dextrorotatory borneol, racemic borneol, or levorotatory borneol.

[0012] One or more amino acid sequences can be added to the N-terminus of SEQ ID NO: 1 to obtain the conjugate comprising borneol and a peptide as described in the various aspects below.

[0013] In a second aspect, the present application provides a conjugate comprising borneol and a peptide, wherein the peptide comprises LLDTEI (SEQ ID NO: 37), CLDTEI (SEQ ID NO: 689), or a variant of SEQ ID NO: 37 or 689 having one or more conservative substitutions, wherein the conservative substitutions are selected from substitutions between D and E, substitutions between L, V and I, and substitutions between T and S.

[0014] In some embodiments of the second aspect, borneol is located on the N-terminal side of the peptide.

[0015] In some embodiments of the second aspect, variants of SEQ ID NO: 37 or 689 are selected from: LLDTEL (SEQ ID NO: 38), LLDTEV (SEQ ID NO: 39), LLDTDI (SEQ ID NO: 40), LLDTDL (SEQ ID NO: 41), LLDTDV (SEQ ID NO: 42), LLDSEI (SEQ ID NO: 43), LLDSEL (SEQ ID NO: 44), LLDSEV (SEQ ID NO: 45), LLDSDI (SEQ ID NO: 46), LLDSDL (SEQ ID NO: 47), LLDSDV (SEQ ID NO: 48), LLETEI (SEQ ID NO: 49), LLETEL (SEQ ID NO: 50), LLETEV (SEQ ID NO: 51), LLETDI (SEQ ID NO: 52), LLETDL (SEQ ID NO: 53), LLETDV (SEQ ID NO: 54), LVDTEI (SEQ ID NO: 55), LVDTEL (SEQ ID NO: 56), LVDTEV (SEQ ID NO: 57), LVDTDI (SEQ ID NO: 58), LVDTDL (SEQ ID NO: 59), LVDTDV (SEQ ID NO: 60), LIDTEI (SEQ ID NO: 61), LIDTEL (SEQ ID NO: 62), LIDTEV (SEQ ID NO: 63), LIDTDI (SEQ ID NO: 64), LIDTDL (SEQ ID NO: 65), LIDTDV (SEQ ID NO: 66), LIETEI (SEQ ID NO: 67), LIETEL (SEQ ID NO: 68), LIETEV (SEQ ID NO: 69), LIETDI (SEQ ID NO: 70), LIETDL (SEQ ID NO: 71), LIETDV (SEQ ID NO: 72), LIESDV (SEQ ID NO: 73), LIESDI (SEQ ID NO: 74), LIESDL (SEQ ID NO: 75), LIESEI (SEQ ID NO: 76), LIESEL (SEQ ID NO: 77), LIESEV (SEQ ID NO: 78), LIDSDV (SEQ ID NO: 79), LIDSDI (SEQ ID NO: 8), LIDSDL (SEQ ID NO: 81), LIDSEI (SEQ ID NO: 82), LIDSEL (SEQNO:83)、LIDSEV(SEQ ID NO:84)、LLESDV(SEQ ID NO:85)、LLESDI(SEQ ID NO:86)、LLESDL(SEQ ID NO:87)、LLESEI(SEQ ID NO:88)、LLESEL(SEQ ID NO:89)、LLESEV(SEQ ID NO:90)、LVESDV(SEQ ID NO:91)、LVESDI(SEQ ID NO:92)、LLVESDL(SEQ ID NO:93)、LVESEI(SEQ ID NO:94)、LVESEL(SEQ ID NO:95)、LVESEV(SEQ ID NO:96)、LVDSEI(SEQ ID NO:97)、LVDSEL(SEQ ID NO:98)、LVDSEV(SEQ ID NO:99)、LVDSDI(SEQ ID NO:100)、LVDSDL(SEQ ID NO:101)、LVDSDV(SEQ ID NO:102)、LVETEI(SEQ ID NO:103)、LVETEL(SEQ ID NO:104)、LVETEV(SEQ ID NO:105)、LVETDI(SEQ ID NO:106)、LVETDL(SEQ ID NO:107)、LVETDV(SEQ ID NO:108)、ILDTEI(SEQ ID NO:109)、ILDTEL(SEQ ID NO:110)、ILDTEV(SEQ ID NO:111)、ILDTDI(SEQ ID NO:112)、ILDTDL(SEQ ID NO:113)、ILDTDV(SEQ ID NO:114)、ILDSEI(SEQ ID NO:115)、ILDSEL(SEQ ID NO:116)、ILDSEV(SEQ ID NO:117)、ILDSDI(SEQ ID NO:118)、ILDSDL(SEQ ID NO:119)、ILDSDV(SEQ ID NO:120)、ILETEI(SEQ ID NO:121)、ILETEL(SEQ ID NO:122)、ILETEV(SEQ ID NO:123)、ILETDI(SEQ ID NO:124)、ILETDL(SEQ ID NO:125)、ILETDV(SEQ ID NO:126)、IVDTEI(SEQ ID NO:127)、IVDTEL(SEQ ID NO:128)、IVDTEV(SEQ IDNO:129)、IVDTDI(SEQ ID NO:130)、IVDTDL(SEQ ID NO:131)、IVDTDV(SEQ ID NO:132)、IIDTEI(SEQ ID NO:133)、IIDTEL(SEQ ID NO:134)、IIDTEV(SEQ ID NO:135)、IIDTDI(SEQ ID NO:136)、IIDTDL(SEQ ID NO:137)、IIDTDV(SEQ ID NO:138)、IIETEI(SEQ ID NO:139)、IIETEL(SEQ ID NO:140)、IIETEV(SEQ ID NO:141)、IIETDI(SEQ ID NO:142)、IIETDL(SEQ ID NO:143)、IIETDV(SEQ ID NO:144)、IIESDV(SEQ ID NO:145)、IIESDI(SEQ ID NO:146)、IIETDL(SEQ ID NO:143) NO:147), IIESEI(SEQ ID NO:148), IIESEL(SEQ ID NO:149), IIESEV(SEQ ID NO:150), IIDSDV(SEQ ID NO:151), IIDSDI(SEQ ID NO:152), IIDSDL(SEQ ID NO:153), IIDSEI(SEQ ID NO:154), IIDSEL(SEQ ID NO:155), IIDSEV(SEQ ID NO:156), ILESDV(SEQ ID NO:157), ILESDI(SEQ ID NO:158), ILESDL(SEQ ID NO:159), ILESEI(SEQ ID NO:160), ILESEL(SEQ ID NO:161), ILESEV(SEQ ID NO:162), IVESDV(SEQ ID NO:163), IVESDI(SEQ ID NO:164), IVESDL(SEQ ID NO:165), IVESEI(SEQ ID NO:166)、IVESEL(SEQ ID NO:167)、IVESEV(SEQ ID NO:168)、IVDSEI(SEQ ID NO:169)、IVDSEL(SEQ ID NO:170)、IVDSEV(SEQ ID NO:171)、IVDSDI(SEQ ID NO:172)、IVDSDL(SEQ ID NO:173)、IVDSDV(SEQ ID NO:171)NO:174)、IVETEI(SEQ ID NO:175)、IVETEL(SEQ ID NO:176)、IVETEV(SEQ ID NO:177)、IVETDI(SEQ ID NO:178)、IVETDL(SEQ ID NO:179)、IVETDV(SEQ ID NO:180)、VLDTEI(SEQ ID NO:181)、VLDTEL(SEQ ID NO:182)、VLDTEV(SEQ ID NO:183)、VLDTDI(SEQ ID NO:184)、VLDTDL(SEQ ID NO:185)、VLDTDV(SEQ ID NO:186)、VLDSEI(SEQ ID NO:187)、VLDSEL(SEQ ID NO:188)、VLDSEV(SEQ ID NO:189)、VLDSDI(SEQ ID NO:190)、VLDSDL(SEQ ID NO:191)、VLDSDV(SEQ ID NO:192)、VLETEI(SEQ ID NO:193)、VLETEL(SEQ ID NO:194)、VLETEV(SEQ ID NO:195)、VLETDI(SEQ ID NO:196)、VVLETDL(SEQ ID NO:197)、VLETDV(SEQ ID NO:198)、VVDTEI(SEQ ID NO:199)、VVDTEL(SEQ ID NO:200)、VVDTEV(SEQ ID NO:201)、VVDTDI(SEQ ID NO:202)、VVDTDL(SEQ ID NO:203)、VVDTDV(SEQ ID NO:204)、VIDTEI(SEQ ID NO:205)、VIDTEL(SEQ ID NO:206)、VIDTEV(SEQ ID NO:207)、VIDTDI(SEQ ID NO:208)、VIDTDL(SEQ ID NO:209)、VIDTDV(SEQ ID NO:210)、VIETEI(SEQ ID NO:211)、VIETEL(SEQ ID NO:212)、VIETEV(SEQ ID NO:213)、VIETDI(SEQ ID NO:214)、VIETDL(SEQ ID NO:215)、VIETDV(SEQ ID NO:216)、VIESDV(SEQ ID NO:217)、VIESDI(SEQ ID NO:218)、VIESDL(SEQ IDNO:219)、VIESEI(SEQ ID NO:220)、VIESEL(SEQ ID NO:221)、VIESEV(SEQ ID NO:222)、VIDSDV (SEQ ID NO:223)、VIDSDI(SEQ ID NO:224)、VIDSDL(SEQ ID NO:225)、VIDSEI(SEQ ID NO:226)、VIDSEL(SEQ ID NO:227)、VIDSEV(SEQ ID NO:228)、VLESDV(SEQ ID NO:229)、VLESDI(SEQ ID NO:230)、VLESDL(SEQ ID NO:231)、VLESEI(SEQ ID NO:232)、VLESEL(SEQ ID NO:233)、VLESEV(SEQ ID NO:234)、VVESDV(SEQ ID NO:235)、VVESDI(SEQ ID NO:236)、VVESDL(SEQ ID NO:237)、VVESEI(SEQ ID NO:238)、VVESEL(SEQ ID NO:239)、VVESEV(SEQ ID NO:240)、VVDSEI(SEQ ID NO:241)、VVDSEL(SEQ ID NO:242)、VVDSEV(SEQ ID NO:243)、VVDSDI(SEQ ID NO:244)、VVDSDL(SEQ ID NO:245)、VVDSDV(SEQ ID NO:246)、VVETEI(SEQ ID NO:247)、VVETEL(SEQ ID NO:248)、VVETEV(SEQ ID NO:249)、VVETDI(SEQ ID NO:250)、VVETDL(SEQ ID NO:251)、VVETDV(SEQ ID NO:252)、CLDTEL(SEQ ID NO:690)、CLDTEV(SEQ ID NO:691)、CLDTDI(SEQ ID NO:692)、CLDTDL(SEQ ID NO:693)、CLDTDV(SEQ ID NO:694)、CLDSEI(SEQ ID NO:695)、CLDSEL(SEQ ID NO:696)、CLDSEV(SEQ ID NO:697)、CLDSDI(SEQ ID NO:698)、CLDSDL(SEQ ID NO:699)、CLDSDV(SEQ ID NO:700)、CLETEI(SEQ IDNO:701), CLETEL (SEQ ID NO:702), CLETEV (SEQ ID NO:703), CLETDI (SEQ ID NO:704), CLETDL (SEQ ID NO:705), CLETDV (SEQ ID NO:706), CVDTEI (SEQ ID NO:707), CVDTEL (SEQ ID NO:708), CVDTEV (SEQ ID NO:709), CVDTDI (SEQ ID NO:710), CVDTDL (SEQ ID NO:711), CVDTDV (SEQ ID NO:712), CIDTEI (SEQ ID NO:713), CIDTEL (SEQ ID NO:714), CIDTEV (SEQ ID NO:715), CIDTDI (SEQ ID NO:716), CIDTDL (SEQ ID NO:717), CIDTDV (SEQ ID NO:718), CIETEI (SEQ ID NO:719), CIETEL (SEQ ID NO:720), CIETEV (SEQ ID NO:721), CIETDI (SEQ ID NO:722), CIETDL (SEQ ID NO:723) and CIETDV (SEQ ID NO:724).

[0016] In some embodiments of the second aspect, the borneol is dextrorotatory borneol, racemic borneol, or levorotatory borneol.

[0017] In a third aspect, the present application provides a conjugate comprising borneol and a peptide, wherein the peptide comprises YEKLLDTEI (SEQ ID NO: 253) or a variant of SEQ ID NO: 253 having one or more conservative substitutions, wherein the conservative substitutions are selected from substitutions between D and E, substitutions between L, V and I, and substitutions between T and S.

[0018] In some embodiments of the third aspect, borneol is located on the N-terminal side of the peptide.

[0019] In some embodiments of the third aspect, variants of SEQ ID NO: 253 are selected from: YEKLLDTEL (SEQ ID NO: 254), YEKLLDTEV (SEQ ID NO: 255), YEKLLDTDI (SEQ ID NO: 256), YEKLLDTDL (SEQ ID NO: 257), YEKLLDTDV (SEQ ID NO: 258), YEKLLDSEI (SEQ ID NO: 259), YEKLLDSEL (SEQ ID NO: 260), YEKLLDSEV (SEQ ID NO: 261), YEKLLDSDI (SEQ ID NO: 262), YEKLLDSDL (SEQ ID NO: 263), YEKLLDSDV (SEQ ID NO: 264), YEKLLETEI (SEQ ID NO: 265), YEKLLETEL (SEQ ID NO: 266), YEKLLETEV (SEQ ID NO: 267), YEKLLETDI (SEQ ID NO: 268), YEKLLETDL (SEQ ID NO: 269), YEKLLETDV (SEQ ID NO: 270), YEKLVDTEI (SEQ ID NO: 271), YEKLVDTEL (SEQ ID NO: 272), YEKLVDTEV (SEQ ID NO: 273), YEKLVDTDI (SEQ ID NO: 274), YEKLVDTDL (SEQ ID NO: 275), YEKLVDTDV (SEQ ID NO: 276), YEKLIDTEI (SEQ ID NO: 277), YEKLIDTEL (SEQ ID NO: 278), YEKLIDTEV (SEQ ID NO: 279), YEKLIDTDI (SEQ ID NO: 280), YEKLIDTDL (SEQ ID NO: 281), YEKLIDTDV (SEQ ID NO: 282), YEKLIETEI (SEQ ID NO: 283), YEKLIETEL (SEQ ID NO: 284), YEKLIETEV (SEQ ID NO: 285), YEKLIETDI (SEQ ID NO: 286), YEKLIETDL (SEQ ID NO: 287), YEKLIETDV (SEQ ID NO: 288), YEKLIESDV (SEQ ID NO: 289), YEKLIESDI (SEQ ID NO: 290), YEKLIESDL (SEQ ID NO: 291), YEKLIESEI (SEQ ID<h2 style=";text-align:left;direction:ltr">NO:292)、YEKLIESEL(SEQ ID NO:293)、YEKLIESEV(SEQ ID NO:294)、YEKLIDSDV(SEQ ID NO:295)、YEKLIDSDI(SEQ ID NO:296)、YEKLIDSDL(SEQ ID NO:297)、YEKLIDSEI(SEQ ID NO:298)、YEKLIDSEL(SEQ ID NO:299)、YEKLIDSEV(SEQ ID NO:300)、YEKLLESDV(SEQ ID NO:301)、YEKLLESDI(SEQ ID NO:302)、YEKLLESDL(SEQ ID NO:303)、YEKLLESEI(SEQ ID NO:304)、YEKLLESEL(SEQ ID NO:305)、YEKLLESEV(SEQ ID NO:306)、YEKLVESDV(SEQ ID NO:307)、YEKLVESDI(SEQ ID NO:308)、YEKLLVESDL(SEQ ID NO:309)、YEKLVESEI(SEQ ID NO:310)、YEKLVESEL(SEQ ID NO:311)、YEKLVESEV(SEQ ID NO:312)、YEKLVDSEI(SEQ ID NO:313)、YEKLVDSEL(SEQ ID NO:314)、YEKLVDSEV(SEQ ID NO:315)、YEKLVDSDI(SEQ ID NO:316)、YEKLVDSDL(SEQ ID NO:317)、YEKLVDSDV(SEQ ID NO:318)、YEKLVETEI(SEQ ID NO:319)、YEKLVETEL(SEQ ID NO:320)、YEKLVETEV(SEQ ID NO:321)、YEKLVETDI(SEQ ID NO:322)、YEKLVETDL (SEQ ID NO:323)、YEKLVETDV(SEQ ID NO:324)、YEKILDTEI(SEQ ID NO:325)、YEKILDTEL(SEQ ID NO:326)、YEKILDTEV(SEQ ID NO:327)、YEKILDTDI(SEQ ID NO:328)、YEKILDTDL(SEQ ID NO:329)、YEKILDTDV(SEQ ID NO:330)、YEKILDSEI(SEQ ID NO:331)、YEKILDSEL(SEQID NO:332)、YEKILDSEV(SEQ ID NO:333)、YEKILDSDI(SEQ ID NO:334)、YEKILDSDL(SEQ ID NO:335)、YEKILDSDV(SEQ ID NO:336)、YEKILETEI(SEQ ID NO:337)、YEKILETEL(SEQ ID NO:338)、YEKILETEV(SEQ ID NO:339)、YEKILETDI(SEQ ID NO:340)、YEKILETDL(SEQ ID NO:341)、YEKILETDV(SEQ ID NO:342)、YEKIVDTEI(SEQ ID NO:343)、YEKIVDTEL(SEQ ID NO:344)、YEKIVDTEV(SEQ ID NO:345)、YEKIVDTDI(SEQ ID NO:346)、YEKIVDTDL(SEQ ID NO:347)、YEKIVDTDV(SEQ ID NO:348)、YEKIIDTEI(SEQ ID NO:349)、YEKIIDTEL(SEQ ID NO:350)、YEKIIDTEV(SEQ ID NO:351)、YEKIIDTDI(SEQ ID NO:352)、YEKIIDTDL(SEQ ID NO:353)、YEKIIDTDV(SEQ ID NO:354)、YEKIIETEI(SEQ ID NO:355)、YEKIIETEL(SEQ ID NO:356)、YEKIIETEV(SEQ ID NO:357)、YEKIIETDI(SEQ ID NO:358)、YEKIIETDL(SEQ ID NO:359)、YEKIIETDV(SEQ ID NO:360)、YEKIIESDV(SEQ ID NO:361)、YEKIIESDI(SEQ ID NO:362)、YEKIIESDL(SEQ ID NO:363)、YEKIIESEI(SEQ ID NO:364)、YEKIIESEL(SEQ ID NO:365)、YEKIIESEV(SEQ ID NO:366)、YEKIIDSDV(SEQ ID NO:367)、YEKIIDSDI(SEQ ID NO:368)、YEKIIDSDL(SEQ ID NO:369)、YEKIIDSEI(SEQ ID NO:370)、YEKIIDSEL(SEQ ID NO:371)、YEKIIDSEV(SEQID NO:372)、YEKILESDV(SEQ ID NO:373)、YEKILESDI(SEQ ID NO:374)、YEKILESDL(SEQ ID NO:375)、YEKILESEI(SEQ ID NO:376)、YEKILESEL(SEQ ID NO:377)、YEKILESEV(SEQ ID NO:378)、YEKIVESDV(SEQ ID NO:379)、YEKIVESDI(SEQ ID NO:380)、YEKIVESDL(SEQ ID NO:381)、YEKIVESEI(SEQ ID NO:382)、YEKIVESEL(SEQ ID NO:383)、YEKIVESEV(SEQ ID NO:384)、YEKIVDSEI(SEQ ID NO:385)、YEKIVDSEL(SEQ ID NO:386)、YEKIVDSEV(SEQ ID NO:387)、YEKIVDSDI(SEQ ID NO:388)、YEKIVDSDL(SEQ ID NO:389)、YEKIVDSDV(SEQ ID NO:390)、YEKIVETEI(SEQ ID NO:391)、YEKIVETEL(SEQ ID NO:392)、YEKIVETEV(SEQ ID NO:393)、YEKIVETDI(SEQ ID NO:394)、YEKIVETDL(SEQ ID NO:395)、YEKIVETDV(SEQ ID NO:396)、YEKVLDTEI(SEQ ID NO:397)、YEKVLDTEL(SEQ ID NO:398)、YEKVLDTEV(SEQ ID NO:399)、YEKVLDTDI(SEQ ID NO:400)、YEKVLDTDL(SEQ ID NO:401)、YEKVLDTDV(SEQ ID NO:402)、YEKVLDSEI(SEQ ID NO:403)、YEKVLDSEL(SEQ ID NO:404)、YEKVLDSEV(SEQ ID NO:405)、YEKVLDSDI(SEQ ID NO:406)、YEKVLDSDL(SEQ ID NO:407)、YEKVLDSDV(SEQ ID NO:408)、YEKVLETEI(SEQ ID NO:409)、YEKVLETEL(SEQ ID NO:410)、YEKVLETEV(SEQ ID NO:411)、YEKVLETDI(SEQID NO:412)、YEKVVLETDL(SEQ ID NO:413)、YEKVLETDV(SEQ ID NO:414)、YEKVVDTEI(SEQ ID NO:415)、YEKVVDTEL(SEQ ID NO:416)、YEKVVDTEV(SEQ ID NO:417)、YEKVVDTDI(SEQ ID NO:418)、YEKVVDTDL(SEQ ID NO:419)、YEKVVDTDV(SEQ ID NO:420)、YEKVIDTEI(SEQ ID NO:421)、YEKVIDTEL(SEQ ID NO:422)、YEKVIDTEV(SEQ ID NO:423)、YEKVIDTDI(SEQ ID NO:424)、YEKVIDTDL(SEQ ID NO:425)、YEKVIDTDV(SEQ ID NO:426)、YEKVIETEI(SEQ ID NO:427)、YEKVIETEL(SEQ ID NO:428)、YEKVIETEV(SEQ ID NO:429)、YEKVIETDI(SEQ ID NO:430)、YEKVIETDL(SEQ ID NO:431)、YEKVIETDV(SEQ ID NO:432)、YEKVIESDV(SEQ ID NO:433)、YEKVIESDI(SEQ ID NO:434)、YEKVIESDL(SEQ ID NO:435)、YEKVIESEI(SEQ ID NO:436)、YEKVIESEL(SEQ ID NO:437)、YEKVIESEV(SEQ ID NO:438)、YEKVIDSDV(SEQ ID NO:439)、YEKVIDSDI(SEQ ID NO:440)、YEKVIDSDL(SEQ ID NO:441)、YEKVIDSEI(SEQ ID NO:442)、YEKVIDSEL(SEQ ID NO:443)、YEKVIDSEV(SEQ ID NO:444)、YEKVLESDV(SEQ ID NO:445)、YEKVLESDI(SEQ ID NO:446)、YEKVLESDL(SEQ ID NO:447)、YEKVLESEI(SEQ ID NO:448)、YEKVLESEL(SEQ ID NO:449)、YEKVLESEV(SEQ ID NO:450)、YEKVVESDV(SEQ ID NO:451)、YEKVVESDI(SEQID NO:452)、YEKVVESDL(SEQ ID NO:453)、YEKVVESEI(SEQ ID NO:454)、YEKVVESEL(SEQ ID NO:455)、YEKVVESEV(SEQ ID NO:456)、YEKVVDSEI(SEQ ID NO:457)、YEKVVDSEL(SEQ ID NO:458)、YEKVVDSEV(SEQ ID NO:459)、YEKVVDSDI(SEQ ID NO:460)、YEKVVDSDL(SEQ ID NO:461)、YEKVVDSDV(SEQ ID NO:462)、YEKVVETEI(SEQ ID NO:463)、YEKVVETEL(SEQ ID NO:464)、YEKVVETEV(SEQ ID NO:465)、YEKVVETDI(SEQ ID NO:466)、YEKVVETDL(SEQ ID NO:467)、YEKVVETDV(SEQ ID NO:468)、YDKLLDTEI(SEQ ID NO:469)、YDKLLDTEL(SEQ ID NO:470)、YDKLLDTEV(SEQ ID NO:471)、YDKLLDTDI(SEQ ID NO:472)、YDKLLDTDL(SEQ ID NO:473)、YDKLLDTDV(SEQ ID NO:474)、YDKLLDSEI(SEQ ID NO:475)、YDKLLDSEL(SEQ ID NO:476)、YDKLLDSEV(SEQ ID NO:477)、YDKLLDSDI(SEQ ID NO:478)、YDKLLDSDL(SEQ ID NO:479)、YDKLLDSDV(SEQ ID NO:480)、YDKLLETEI(SEQ ID NO:481)、YDKLLETEL(SEQ ID NO:482)、YDKLLETEV(SEQ ID NO:483)、YDKLLETDI(SEQ ID NO:484)、YDKLLETDL(SEQ ID NO:485)、YDKLLETDV(SEQ ID NO:486)、YDKLVDTEI(SEQ ID NO:487)、YDKLVDTEL(SEQ ID NO:488)、YDKLVDTEV(SEQ ID NO:489)、YDKLVDTDI(SEQ ID NO:490)、YDKLVDTDL(SEQ ID NO:491)、YDKLVDTDV(SEQID NO:492)、YDKLIDTEI(SEQ ID NO:493)、YDKLIDTEL(SEQ ID NO:494)、YDKLIDTEV(SEQ ID NO:495)、YDKLIDTDI(SEQ ID NO:496)、YDKLIDTDL(SEQ ID NO:497)、YDKLIDTDV(SEQ ID NO:498)、YDKLIETEI(SEQ ID NO:499)、YDKLIETEL(SEQ ID NO:500)、YDKLIETEV(SEQ ID NO:501)、YDKLIETDI(SEQ ID NO:502)、YDKLIETDL(SEQ ID NO:503)、YDKLIETDV(SEQ ID NO:504)、YDKLIESDV(SEQ ID NO:505)、YDKLIESDI(SEQ ID NO:506)、YDKLIESDL(SEQ ID NO:507)、YDKLIESEI(SEQ ID NO:508)、YDKLIESEL(SEQ ID NO:509)、YDKLIESEV(SEQ ID NO:510)、YDKLIDSDV(SEQ ID NO:511)、YDKLIDSDI(SEQ ID NO:512)、YDKLIDSDL(SEQ ID NO:513)、YDKLIDSEI(SEQ ID NO:514)、YDKLIDSEL(SEQ ID NO:515)、YDKLIDSEV(SEQ ID NO:516)、YDKLLESDV(SEQ ID NO:517)、YDKLLESDI(SEQ ID NO:518)、YDKLLESDL(SEQ ID NO:519)、YDKLLESEI(SEQ ID NO:520)、YDKLLESEL(SEQ ID NO:521)、YDKLLESEV(SEQ ID NO:522)、YDKLVESDV(SEQ ID NO:523)、YDKLVESDI(SEQ ID NO:524)、YDKLLVESDL(SEQ ID NO:525)、YDKLVESEI(SEQ ID NO:526)、YDKLVESEL(SEQ ID NO:527)、YDKLVESEV(SEQ ID NO:528)、YDKLVDSEI(SEQ ID NO:529)、YDKLVDSEL(SEQ ID NO:530)、YDKLVDSEV(SEQ ID NO:531)、YDKLVDSDI(SEQID NO:532)、YDKLVDSDL(SEQ ID NO:533)、YDKLVDSDV(SEQ ID NO:534)、YDKLVETEI(SEQ ID NO:535)、YDKLVETEL(SEQ ID NO:536)、YDKLVETEV(SEQ ID NO:537)、YDKLVETDI(SEQ ID NO:538)、YDKLVETDL(SEQ ID NO:539)、YDKLVETDV(SEQ ID NO:540)、YDKILDTEI(SEQ ID NO:541)、YDKILDTEL(SEQ ID NO:542)、YDKILDTEV(SEQ ID NO:543)、YDKILDTDI(SEQ ID NO:544)、YDKILDTDL(SEQ ID NO:545)、YDKILDTDV(SEQ ID NO:546)、YDKILDSEI(SEQ ID NO:547)、YDKILDSEL(SEQ ID NO:548)、YDKILDSEV(SEQ ID NO:549)、YDKILDSDI(SEQ ID NO:550)、YDKILDSDL(SEQ ID NO:551)、YDKILDSDV(SEQ ID NO:552)、YDKILETEI(SEQ ID NO:553)、YDKILETEL(SEQ ID NO:554)、YDKILETEV(SEQ ID NO:555)、YDKILETDI(SEQ ID NO:556)、YDKILETDL(SEQ ID NO:557)、YDKILETDV(SEQ ID NO:558)、YDKIVDTEI(SEQ ID NO:559)、YDKIVDTEL(SEQ ID NO:560)、YDKIVDTEV(SEQ ID NO:561)、YDKIVDTDI(SEQ ID NO:562)、YDKIVDTDL(SEQ ID NO:563)、YDKIVDTDV(SEQ ID NO:564)、YDKIIDTEI(SEQ ID NO:565)、YDKIIDTEL(SEQ ID NO:566)、YDKIIDTEV(SEQ ID NO:567)、YDKIIDTDI(SEQ ID NO:568)、YDKIIDTDL(SEQ ID NO:569)、YDKIIDTDV(SEQ ID NO:570)、YDKIIETEI(SEQ ID NO:571)、YDKIIETEL(SEQID NO:572)、YDKIIETEV(SEQ ID NO:573)、YDKIIETDI(SEQ ID NO:574)、YDKIIETDL(SEQ ID NO:575)、YDKIIETDV(SEQ ID NO:576)、YDKIIESDV(SEQ ID NO:577)、YDKIIESDI(SEQ ID NO:578)、YDKIIESDL(SEQ ID NO:579)、YDKIIESEI(SEQ ID NO:580)、YDKIIESEL(SEQ ID NO:581)、YDKIIESEV(SEQ ID NO:582)、YDKIIDSDV(SEQ ID NO:583)、YDKIIDSDI(SEQ ID NO:584)、YDKIIDSDL(SEQ ID NO:585)、YDKIIDSEI(SEQ ID NO:586)、YDKIIDSEL(SEQ ID NO:587)、YDKIIDSEV(SEQ ID NO:588)、YDKILESDV(SEQ ID NO:589)、YDKILESDI(SEQ ID NO:590)、YDKILESDL(SEQ ID NO:591)、YDKILESEI(SEQ ID NO:592)、YDKILESEL(SEQ ID NO:593)、YDKILESEV(SEQ ID NO:594)、YDKIVESDV(SEQ ID NO:595)、YDKIVESDI(SEQ ID NO:596)、YDKIVESDL(SEQ ID NO:597)、YDKIVESEI(SEQ ID NO:598)、YDKIVESEL(SEQ ID NO:599)、YDKIVESEV(SEQ ID NO:600)、YDKIVDSEI(SEQ ID NO:601)、YDKIVDSEL(SEQ ID NO:602)、YDKIVDSEV(SEQ ID NO:603)、YDKIVDSDI(SEQ ID NO:604)、YDKIVDSDL(SEQ ID NO:605)、YDKIVDSDV(SEQ ID NO:606)、YDKIVETEI(SEQ ID NO:607)、YDKIVETEL(SEQ ID NO: 608)、YDKIVETEV(SEQ ID NO:609)、YDKIVETDI(SEQ ID NO:610)、YDKIVETDL(SEQ ID NO:611)、YDKIVETDV(SEQID NO:612)、YDKVLDTEI(SEQ ID NO:613)、YDKVLDTEL(SEQ ID NO:614)、YDKVLDTEV(SEQ ID NO:615)、YDKVLDTDI(SEQ ID NO:616)、YDKVLDTDL(SEQ ID NO:617)、YDKVLDTDV(SEQ ID NO:618)、YDKVLDSEI(SEQ ID NO:619)、YDKVLDSEL(SEQ ID NO:620)、YDKVLDSEV(SEQ ID NO:621)、YDKVLDSDI(SEQ ID NO:622)、YDKVLDSDL(SEQ ID NO:623)、YDKVLDSDV(SEQ ID NO:624)、YDKVLETEI(SEQ ID NO:625)、YDKVLETEL(SEQ ID NO:626)、YDKVLETEV(SEQ ID NO:627)、YDKVLETDI(SEQ ID NO:628)、YDKVVLETDL(SEQ ID NO:629)、YDKVLETDV(SEQ ID NO:630)、YDKVVDTEI(SEQ ID NO:631)、YDKVVDTEL(SEQ ID NO:632)、YDKVVDTEV(SEQ ID NO:633)、YDKVVDTDI(SEQ ID NO:634)、YDKVVDTDL(SEQ ID NO:635)、YDKVVDTDV(SEQ ID NO:636)、YDKVIDTEI(SEQ ID NO:637)、YDKVIDTEL(SEQ ID NO:638)、YDKVIDTEV(SEQ ID NO:639)、YDKVIDTDI(SEQ ID NO:640)、YDKVIDTDL(SEQ ID NO:641)、YDKVIDTDV(SEQ ID NO:642)、YDKVIETEI(SEQ ID NO:643)、YDKVIETEL(SEQ ID NO:644)、YDKVIETEV(SEQ ID NO:645)、YDKVIETDI(SEQ ID NO:646)、YDKVIETDL(SEQ ID NO:647)、YDKVIETDV(SEQ ID NO:648)、YDKVIESDV(SEQ ID NO:649)、YDKVIESDI(SEQ ID NO:650)、YDKVIESDL(SEQ ID NO:651)、YDKVIESEI(SEQID NO:652), YDKVIESEL (SEQ ID NO:653), YDKVIESEV (SEQ ID NO:654), YDKVIDSDV (SEQ ID NO:655), YDKVIDSDI (SEQ ID NO:656), YDKVIDSDL (SEQ ID NO:657), YDKVIDSEI (SEQ ID NO:658), YDKVIDSEL (SEQ ID NO:659), YDKVIDSEV (SEQ ID NO:660), YDKVLESDV (SEQ ID NO:661), YDKVLESDI (SEQ ID NO:662), YDKVLESDL (SEQ ID NO:663), YDKVLESEI (SEQ ID NO:664), YDKVLESEL (SEQ ID NO:665), YDKVLESEV (SEQ ID NO:666), YDKVVESDV (SEQ ID NO:667), YDKVVESDI (SEQ ID NO:668), YDKVVESDL (SEQ ID NO:669), YDKVVESEI (SEQ ID NO:670), YDKVVESEL (SEQ ID NO:671), YDKVVESEV (SEQ ID NO:672), YDKVVDSEI (SEQ ID NO:673), YDKVVDSEL (SEQ ID NO:674), YDKVVDSEV (SEQ ID NO:675), YDKVVDSDI (SEQ ID NO:676), YDKVVDSDL (SEQ ID NO:677), YDKVVDSDV (SEQ ID NO:678), YDKVVETEI (SEQ ID NO:679), YDKVVETEL (SEQ ID NO:680), YDKVVETEV (SEQ ID NO:681), YDKVVETDI (SEQ ID NO:682), YDKVVETDL (SEQ ID NO:683) and YDKVVETDV (SEQ ID NO:684).

[0020] In some embodiments of the third aspect, the borneol is dextrorotatory borneol, racemic borneol, or levorotatory borneol.

[0021] In some embodiments of the third aspect, the conservative substitution is further selected from substitutions between lysine (K), arginine (R) and histidine (H), and substitutions between tyrosine (Y), phenylalanine (F) and tryptophan (W).

[0022] In some embodiments of any of the foregoing aspects, in a single conjugate molecule, the molar ratio of borneol to the peptide is 1:1.

[0023] In some embodiments of any of the foregoing aspects, borneol is linked to the peptide via a linker.

[0024] In some embodiments of any of the foregoing aspects, the linker is selected from the group consisting of: glycine, non-peptidyl polymers such as polyethylene glycol (PEG) or fatty acid chains of varying lengths (e.g., stearoyl, palmitoyl, octanoyl, etc.); homopolymeric amino acids (e.g., polyhistidine, polyarginine, polylysine, or polyalanine) or heteropolymeric amino acids; and chemical groups (e.g., carbonyl, alkylene (e.g., C 1-6 alkylene), constrained alkylene (e.g., branched alkylene, cyclic alkylene, fused alkylene, adamantylene), alkyleneoxy, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, aryl, heteroaryl, or heterocyclic group, etc.).

[0025] In some embodiments of any of the foregoing aspects, the linker is selected from the group consisting of:

[0026] In some embodiments of any of the above aspects, one end of the linker is connected to the side chain of the N-terminal amino acid residue, the C-terminal amino acid residue, or the middle amino acid residue of the peptide.

[0027] In some embodiments of any of the aforementioned aspects, one end of the linker is connected to the N-terminus of the peptide.

[0028] In some embodiments of any of the above aspects, the other end of the linker is connected to the O atom of borneol.

[0029] In some embodiments of any of the aforementioned aspects, the peptide can bind to the PDZ1 / 2 domain of postsynaptic density protein 95 (PSD-95) and inhibit the interaction between N-methyl-D-aspartate receptor (NMDAR) and PSD-95.

[0030] In a fourth aspect, the present application provides a pharmaceutical composition comprising the conjugate described in any one of the above aspects and a pharmaceutically acceptable carrier.

[0031] In some embodiments of the fourth aspect, the pharmaceutical composition is used to treat, improve or prevent damage to the nervous system of a mammal or a disease or pain caused by the damage, a neurodegenerative disease, anxiety or epilepsy, or is used as a neuroprotective agent.

[0032] In a fifth aspect, the present application provides the use of the conjugate described in any one of the first to third aspects or the pharmaceutical composition described in the fourth aspect in the preparation of a drug or neuroprotectant for treating, improving or preventing the following diseases in mammals: nervous system damage and diseases or pain related to the damage, neurodegenerative diseases, anxiety or epilepsy.

[0033] In a sixth aspect, the present application provides a method for treating, ameliorating or preventing the following diseases in mammals, comprising administering to an individual in need thereof the conjugate described in any one of the first to third aspects or the pharmaceutical composition described in the fourth aspect: nervous system damage and diseases or pain associated with the damage, neurodegenerative diseases, anxiety or epilepsy.

[0034] In any one of the fourth to sixth aspects, the disease is stroke or nervous system damage caused by stroke.

[0035] In any one of the fourth to sixth aspects, the cerebral stroke includes ischemic stroke, hemorrhagic stroke, and hemorrhagic stroke converted from ischemic stroke.

[0036] In any one of the fourth to sixth aspects, the stroke is ischemic stroke.

[0037] In any one of the fourth to sixth aspects, the nervous system damage is caused by excitotoxicity.

[0038] In any one of the fourth to sixth aspects, the nervous system damage caused by excitotoxicity includes damage to central nervous system (CNS) neurons selected from cerebral stroke or spinal cord injury, ischemic or traumatic injury to the brain or spinal cord, including acute CNS injury, ischemic stroke or spinal cord injury, and damage caused by hypoxia, ischemia, mechanical injury and neurodegenerative diseases, anxiety, epilepsy, and stroke.

[0039] In any one of aspects 4 to 6, the injury or pain is located in the peripheral nervous system or the central nervous system.

[0040] In any one of aspects 4 to 6, the neurodegenerative disease comprises Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, or Huntington's disease.

[0041] BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 shows the structure of 4-nitrophenyl ((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) carbonate 1 H NMR spectroscopy ( 1 H-NMR) chart.

[0043] FIG2 shows the HPLC chromatogram of B-YEKLLDTEI.

[0044] Figure 3 shows the 1 H NMR spectroscopy ( 1 H-NMR) chart.

[0045] Figure 4 shows the 13 C NMR spectroscopy ( 13 C-NMR) chart.

[0046] FIG5 shows the HPLC chromatogram of B-LDTEI.

[0047] Figure 6 shows the B-LDTEI 1 H NMR spectroscopy ( 1 H-NMR) chart.

[0048] Figure 7 shows the B-LDTEI 13 C NMR spectroscopy ( 13 C-NMR) chart.

[0049] Figure 8 shows the protective effect of a conjugate comprising borneol and a peptide against N-methyl-D-aspartate (NMDA)-induced primary neuronal cell damage, wherein A is a bar graph of cell death ratios, and B is a fluorescent image of the cells.

[0050] FIG9 shows the protective effects of conjugates of borneol and peptides containing different linkers on N-methyl-D-aspartate (NMDA)-induced primary neuronal cell injury.

[0051] Figure 10 shows the protective effect of a conjugate comprising borneol and a peptide on primary neuronal cell damage induced by hemin, wherein A is a bar graph of cell death ratios, and B is a fluorescent image of the cells.

[0052] FIG11 shows the results of the percentage of cerebral infarct volume after treatment of rats with ischemia-reperfusion using TAT-9-mer, B-9-mer-1, and B-9-mer-2.

[0053] FIG12 shows the results of the percentage of cerebral infarct volume after treatment of ischemia-reperfusion rats with TAT-5-mer, B-5-mer, TAT-6-mer and B-6-mer.

[0054] FIG13 shows a bar graph of the area of ​​blue plaques induced by the conjugates or chimeric peptides comprising borneol and a peptide shown in Table 1. FIG.

[0055] FIG14 shows photographs of blue spots induced by TAT-9-mer, B-9-mer-1, and B-9-mer-2 in rat skin.

[0056] FIG15 shows photographs of blue spots induced by TAT-5-mer, B-5-mer, TAT-6-mer and B-6-mer in rat skin.

[0057] Detailed Description of the Invention

[0058] As described in the "Background of the Invention" section of the specification, the PCT international applications PCT / CN2016 / 080321, PCT / CN2017 / 104750, PCT / CN2017 / 104751, PCT / CN2016 / 109008, PCT / CN2017 / 091792, PCT / CN2017 / 091793 and PCT / CN2017 / 091794, as well as Chinese patent application CN201711011953.8 disclose active peptides and functional variants thereof that target postsynaptic density protein 95 (PSD-95) and inhibit the interaction between N-methyl-D-aspartate receptor (NMDAR) and PSD-95, pharmaceutically acceptable salts of the active peptides, compounds, conjugates and pharmaceutical compositions containing the active peptides and functional variants thereof, and their uses in the medical fields of preventing, ameliorating and / or treating central nervous system damage, pain associated with the damage, neurodegenerative diseases, etc. For example, PCT / CN2016 / 080321 reports that YEKLLDTEI (SEQ ID NO: 253) can effectively inhibit the interaction between NMDAR and PSD-95 proteins, and therefore has important medical applications in the treatment of nerve damage. The inventors of this application prepared a new conjugate by linking borneol to the active peptide shown in SEQ ID NO: 253. This new conjugate has protective effects against central nervous system damage and improved safety, such as hypoallergenicity. Furthermore, the inventors discovered that even after certain truncation of the N-terminus of SEQ ID NO: 253, the design concept of borneol conjugation is still applicable.

[0059] definition

[0060] Unless otherwise specified, the terms used in this application have the meanings that are commonly understood by those skilled in the art.

[0061] The single-letter or three-letter abbreviations used for amino acids in this application follow international conventions.

[0062] As used herein, the term "conjugate" refers to a new substance formed by combining two or more parts with independent functions. Specifically, the conjugate of the present application comprises borneol and a peptide, which can be connected by a linker.

[0063] As used herein, the term "non-peptidyl polymer" refers to a biocompatible polymer comprising one or more repeating units linked to each other by covalent bonds other than peptide bonds. Non-peptidyl polymers useful in the present invention include, but are not limited to, polyethylene glycol, polypropylene glycol, copolymers of ethylene glycol and propylene glycol, polyoxyethylated polyols, polyvinyl alcohol, polysaccharides, dextran, polyethylene ethyl ether, biodegradable polymers such as PLA (poly(lactic acid)), PVP (polyvinyl pyrrolidone) and PLGA (polylactic-glycolic acid), lipopolymers, chitin, hyaluronic acid, fatty acid chains of varying lengths (e.g., stearoyl, palmitoyl, octanoyl, etc.), and combinations thereof. Non-peptidyl polymer derivatives known in the art and readily prepared by techniques of the art are also encompassed within the scope of the present invention. The non-peptidyl polymer has a molecular weight in the range of 0.5 kDa to 100 kDa, preferably 0.5 kDa to 20 kDa. The non-peptidyl polymer linked to the polypeptide may be a single polymer or a combination of different types of polymers. The non-peptidyl polymer has reactive groups at both ends, including but not limited to: aldehyde, propionaldehyde, butyraldehyde, maleimide, and succinimide derivatives. The succinimide derivative may be a propionate succinimidyl ester group, a hydroxysuccinimide group, a succinimidyl carboxymethyl group, or a succinimidyl carbonate group. The reactive groups at both ends of the non-peptidyl polymer may be the same or different. When polyethylene glycol having reactive hydroxyl groups at both ends is used as the non-peptidyl polymer, the hydroxyl groups may be activated into various reactive groups by known chemical reactions, or commercially available polyethylene glycol having modified reactive groups may be used.

[0064] As used herein, the term "alkylene" refers to a fully saturated, straight-chain divalent hydrocarbon chain radical. 40 Non-limiting examples of alkylene groups include ethylene, propylene, butylene, and the like.

[0065] As used herein, the term "alkenylene" refers to a straight or branched divalent hydrocarbon chain radical having 2 to 40 carbon atoms and having one or more carbon-carbon double bonds. 40 Non-limiting examples of alkenylene groups include ethenylene, propenylene, butenylene, and the like.

[0066] As used herein, the term "alkynylene" refers to a straight or branched divalent hydrocarbon chain radical having 2 to 40 carbon atoms and having one or more carbon-carbon triple bonds. 40 Non-limiting examples of alkynylene groups include ethynylene, propynylene, butynylene, and the like.

[0067] The term "aryl" as used herein refers to an unsubstituted or substituted monocyclic or polycyclic aromatic group comprising carbon atoms, preferably a 6- to 10-membered monocyclic or bicyclic aromatic group, such as phenyl, naphthyl, and most preferably phenyl.

[0068] As used herein, the term "heteroaryl" refers to an unsubstituted or substituted stable 5-membered or 6-membered monoaromatic ring system, an unsubstituted or substituted 9-membered or 10-membered benzo-fused heteroaromatic ring system, or a biheteroaromatic ring system, wherein the benzo-fused heteroaromatic ring system or biheteroaromatic ring system consists of carbon atoms and 1 to 4 heteroatoms selected from N, O, or S. The heteroaryl group may be attached to any heteroatom or carbon atom that results in a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl, or isoquinolinyl.

[0069] As used herein, the term "heterocyclic ring" or "heterocycle" refers to an unsubstituted or substituted stable 3- to 20-membered non-aromatic cyclic divalent radical consisting of 2-12 carbon atoms and 1-6 heteroatoms (nitrogen, oxygen or sulfur atoms). Unless otherwise specified in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused or bridged ring system; and the nitrogen, carbon or sulfur atom in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidineyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0070] As used herein, the term "substituted" in the context of referring to substitutions in chemical groups refers to any of the above groups (i.e., alkylene, constrained alkylene, alkene, alkynylene, aryl, heteroaryl, and / or heterocyclyl) wherein at least one hydrogen atom is replaced by at least one non-hydrogen atom including, but not limited to, a halogen atom, a hydroxyl group, an alkoxy group, an ester group, a thiol group, a thioalkyl group, a sulfone group, a sulfonyl group, a sulfoxide group, an amine, an amide, an alkylamine, a dialkylamine, an arylamine, an alkylarylamine, a diarylamine alkyl, alkylamino, alkylsulfonyl, alkylthio, alkylthio, alkylthioalkyl, alkylthioalkylsulfonyl ...

[0071] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferred halogen groups refer to fluorine, chlorine and bromine.

[0072] The term "halo" as used herein refers to fluoro, chloro, bromo or iodo.

[0073] In the context of amino acid substitutions, the term "conservative substitution" as used herein refers to certain amino acid substitutions that can occur frequently in proteins without changing the conformation or function of the protein, which is an established rule in protein chemistry. In the present application, conservative substitutions are selected from substitutions between aspartic acid (D) and glutamic acid (E), substitutions between lysine (K), arginine (R) and histidine (H), substitutions between leucine (L), valine (V) and isoleucine (I), substitutions between threonine (T) and serine (S), and substitutions between tyrosine (Y), phenylalanine (F) and tryptophan (W).

[0074] As used herein, the term "PDZ domain" refers to a modular protein domain of approximately 90 amino acids characterized by significant (e.g., at least 60%) sequence identity to the brain synaptic protein PSD-95, the Drosophila septate junction protein Discs-Large (DLG), and the epithelial tight junction protein Z01 (Z01). PDZ domains are also known as Discs-Large homology repeats ("DHRs") and GLGF repeats. PDZ domains generally exhibit retention of a core consensus sequence (Doyle, DA, 1996, Cell 85:1067-76). Exemplary PDZ domain-containing proteins and PDZ domain sequences are disclosed in U.S. application Ser. No. 10 / 714,537.

[0075] As used herein, the term "NMDA receptor" or "NMDAR" refers to a membrane-associated protein known to interact with NMDA. These receptors can be human or non-human (eg, mouse, rat, rabbit, monkey, etc.).

[0076] The borneol used in the present application may be dextrorotatory borneol, racemic borneol or levorotatory borneol.

[0077] In some specific embodiments of the present application, the borneol used is dextrorotatory borneol, i.e. (+)-2-borneol (CAS: 464-43-7), the structure of which is shown in the figure below:

[0078] In a first aspect of the present application, a conjugate comprising borneol and a peptide is provided.

[0079] In some embodiments of the first aspect, the peptide is derived from a patent application previously filed by the applicant (e.g., described in PCT / CN2016 / 080321) and comprises YEKLLDTEI (SEQ ID NO: 253) or a variant of SEQ ID NO: 253 in which one or more conservative substitutions occur, wherein the conservative substitutions are selected from substitutions between aspartic acid (D) and glutamic acid (E), substitutions between leucine (L), valine (V) and isoleucine (I), and substitutions between threonine (T) and serine (S).

[0080] In some embodiments of the first aspect, variants of SEQ ID NO:253 can be selected from: YEKLLDTEL (SEQ ID NO:254), YEKLLDTEV (SEQ ID NO:255), YEKLLDTDI (SEQ ID NO:256), YEKLLDTDL (SEQ ID NO:257), YEKLLDTDV (SEQ ID NO:258), YEKLLDSEI (SEQ ID NO:259), YEKLLDSEL (SEQ ID NO:260), YEKLLDSEV (SEQ ID NO:261), YEKLLDSDI (SEQ ID NO:262), YEKLLDSDL (SEQ ID NO:263), YEKLLDSDV (SEQ ID NO:264), YEKLLETEI (SEQ ID NO:265), YEKLLETEL (SEQ ID NO:266), YEKLLETEV (SEQ ID NO:267), YEKLLETDI (SEQ ID NO:268), YEKLLETDL (SEQ ID NO:269), YEKLLETDV (SEQ ID NO:270), YEKLVDTEI (SEQ ID NO:271), YEKLVDTEL (SEQ ID NO:272), YEKLVDTEV (SEQ ID NO: 273), YEKLVDTDI (SEQ ID NO:274), YEKLVDTDL (SEQ ID NO:275), YEKLVDTDV (SEQ ID NO:276), YEKLIDTEI (SEQ ID NO:277), YEKLIDTEL (SEQ ID NO:278), YEKLIDTEV (SEQ ID NO:279), YEKLIDTDI (SEQ ID NO:280), YEKLIDTDL (SEQ ID NO:281), YEKLIDTDV (SEQ ID NO:282), YEKLIETEI (SEQ ID NO:283), YEKLIETEL (SEQ ID NO:284), YEKLIETEV (SEQ ID NO:285), YEKLIETDI (SEQ ID NO:286), YEKLIETDL (SEQ ID NO:287), YEKLIETDV (SEQ ID NO:288), YEKLIESDV (SEQ ID NO:289), YEKLIESDI (SEQ ID NO:290), YEKLIESDL (SEQ ID NO:291), YEKLIESEI (SEQ<h2 style=";text-align:left;direction:ltr">ID NO:292)、YEKLIESEL(SEQ ID NO:293)、YEKLIESEV(SEQ ID NO:294)、YEKLIDSDV(SEQ ID NO:295)、YEKLIDSDI(SEQ ID NO:296)、YEKLIDSDL(SEQ ID NO:297)、YEKLIDSEI(SEQ ID NO:298)、YEKLIDSEL(SEQ ID NO:299)、YEKLIDSEV(SEQ ID NO:300)、YEKLLESDV(SEQ ID NO:301)、YEKLLESDI(SEQ ID NO:302)、YEKLLESDL(SEQ ID NO:303)、YEKLLESEI(SEQ ID NO:304)、YEKLLESEL(SEQ ID NO:305)、YEKLLESEV(SEQ ID NO:306)、YEKLVESDV(SEQ ID NO:307)、YEKLVESDI(SEQ ID NO:308)、YEKLLVESDL(SEQ ID NO:309)、YEKLVESEI(SEQ ID NO:310)、YEKLVESEL(SEQ ID NO:311)、YEKLVESEV(SEQ ID NO:312)、YEKLVDSEI(SEQ ID NO:313)、YEKLVDSEL(SEQ ID NO:314)、YEKLVDSEV(SEQ ID NO:315)、YEKLVDSDI(SEQ ID NO:316)、YEKLVDSDL(SEQ ID NO:317)、YEKLVDSDV(SEQ ID NO:318)、YEKLVETEI(SEQ ID NO:319)、YEKLVETEL(SEQ ID NO:320)、YEKLVETEV(SEQ ID NO:321)、YEKLVETDI(SEQ ID NO:322)、YEKLVETDL(SEQ ID NO:323)、YEKLVETDV(SEQ ID NO:324)、YEKILDTEI(SEQ ID NO:325)、YEKILDTEL(SEQ ID NO:326)、YEKILDTEV(SEQ ID NO:327)、YEKILDTDI(SEQ ID NO:328)、YEKILDTDL(SEQ ID NO:329)、YEKILDTDV(SEQ ID NO:330)、YEKILDSEI(SEQ ID NO:331)、YEKILDSEL(SEQID NO:332)、YEKILDSEV(SEQ ID NO:333)、YEKILDSDI(SEQ ID NO:334)、YEKILDSDL(SEQ ID NO:335)、YEKILDSDV(SEQ ID NO:336)、YEKILETEI(SEQ ID NO:337)、YEKILETEL(SEQ ID NO:338)、YEKILETEV(SEQ ID NO:339)、YEKILETDI(SEQ ID NO:340)、YEKILETDL(SEQ ID NO:341)、YEKILETDV(SEQ ID NO:342)、YEKIVDTEI(SEQ ID NO:343)、YEKIVDTEL(SEQ ID NO:344)、YEKIVDTEV(SEQ ID NO:345)、YEKIVDTDI(SEQ ID NO:346)、YEKIVDTDL(SEQ ID NO:347)、YEKIVDTDV(SEQ ID NO:348)、YEKIIDTEI(SEQ ID NO:349)、YEKIIDTEL(SEQ ID NO:350)、YEKIIDTEV(SEQ ID NO:351)、YEKIIDTDI(SEQ ID NO:352)、YEKIIDTDL(SEQ ID NO:353)、YEKIIDTDV(SEQ ID NO:354)、YEKIIETEI(SEQ ID NO:355)、YEKIIETEL(SEQ ID NO:356)、YEKIIETEV(SEQ ID NO:357)、YEKIIETDI(SEQ ID NO:358)、YEKIIETDL(SEQ ID NO:359)、YEKIIETDV(SEQ ID NO:360)、YEKIIESDV(SEQ ID NO:361)、YEKIIESDI(SEQ ID NO:362)、YEKIIESDL(SEQ ID NO:363)、YEKIIESEI(SEQ ID NO:364)、YEKIIESEL(SEQ ID NO:365)、YEKIIESEV(SEQ ID NO:366)、YEKIIDSDV(SEQ ID NO:367)、YEKIIDSDI(SEQ ID NO:368)、YEKIIDSDL(SEQ ID NO:369)、YEKIIDSEI(SEQ ID NO:370)、YEKIIDSEL(SEQ ID NO:371)、YEKIIDSEV(SEQID NO:372)、YEKILESDV(SEQ ID NO:373)、YEKILESDI(SEQ ID NO:374)、YEKILESDL(SEQ ID NO:375)、YEKILESEI(SEQ ID NO:376)、YEKILESEL(SEQ ID NO:377)、YEKILESEV(SEQ ID NO:378)、YEKIVESDV(SEQ ID NO:379)、YEKIVESDI(SEQ ID NO:380)、YEKIVESDL(SEQ ID NO:381)、YEKIVESEI(SEQ ID NO:382)、YEKIVESEL(SEQ ID NO:383)、YEKIVESEV(SEQ ID NO:384)、YEKIVDSEI(SEQ ID NO:385)、YEKIVDSEL(SEQ ID NO:386)、YEKIVDSEV(SEQ ID NO:387)、YEKIVDSDI(SEQ ID NO:388)、YEKIVDSDL(SEQ ID NO:389)、YEKIVDSDV(SEQ ID NO:390)、YEKIVETEI(SEQ ID NO:391)、YEKIVETEL(SEQ ID NO:392)、YEKIVETEV(SEQ ID NO:393)、YEKIVETDI(SEQ ID NO:394)、YEKIVETDL(SEQ ID NO:395)、YEKIVETDV(SEQ ID NO:396)、YEKVLDTEI(SEQ ID NO:397)、YEKVLDTEL(SEQ ID NO:398)、YEKVLDTEV(SEQ ID NO:399)、YEKVLDTDI(SEQ ID NO:400)、YEKVLDTDL(SEQ ID NO:401)、YEKVLDTDV(SEQ ID NO:402)、YEKVLDSEI(SEQ ID NO:403)、YEKVLDSEL(SEQ ID NO:404)、YEKVLDSEV(SEQ ID NO:405)、YEKVLDSDI(SEQ ID NO:406)、YEKVLDSDL(SEQ ID NO:407)、YEKVLDSDV(SEQ ID NO:408)、YEKVLETEI(SEQ ID NO:409)、YEKVLETEL(SEQ ID NO:410)、YEKVLETEV(SEQ ID NO:411)、YEKVLETDI(SEQID NO:412)、YEKVVLETDL(SEQ ID NO:413)、YEKVLETDV(SEQ ID NO:414)、YEKVVDTEI(SEQ ID NO:415)、YEKVVDTEL(SEQ ID NO:416)、YEKVVDTEV (SEQ ID NO:417)、YEKVVDTDI(SEQ ID NO:418)、YEKVVDTDL(SEQ ID NO:419)、YEKVVDTDV(SEQ ID NO:420)、YEKVIDTEI(SEQ ID NO:421)、YEKVIDTEL(SEQ ID NO:422)、YEKVIDTEV(SEQ ID NO:423)、YEKVIDTDI(SEQ ID NO:424)、YEKVIDTDL(SEQ ID NO:425)、YEKVIDTDV(SEQ ID NO:426)、YEKVIETEI(SEQ ID NO:427)、YEKVIETEL(SEQ ID NO:428)、YEKVIETEV(SEQ ID NO:429)、YEKVIETDI(SEQ ID NO:430)、YEKVIETDL(SEQ ID NO:431)、YEKVIETDV(SEQ ID NO:432)、YEKVIESDV(SEQ ID NO:433)、YEKVIESDI(SEQ ID NO:434)、YEKVIESDL(SEQ ID NO:435)、YEKVIESEI(SEQ ID NO:436)、YEKVIESEL(SEQ ID NO:437)、YEKVIESEV(SEQ ID NO:438)、YEKVIDSDV(SEQ ID NO:439)、YEKVIDSDI(SEQ ID NO:440)、YEKVIDSDL(SEQ ID NO:441)、YEKVIDSEI(SEQ ID NO:442)、YEKVIDSEL(SEQ ID NO:443)、YEKVIDSEV(SEQ ID NO:444)、YEKVLESDV(SEQ ID NO:445)、YEKVLESDI(SEQ ID NO:446)、YEKVLESDL(SEQ ID NO:447)、YEKVLESEI(SEQ ID NO:448)、YEKVLESEL(SEQ ID NO:449)、YEKVLESEV(SEQ ID NO:450)、YEKVVESDV(SEQ IDNO:451)、YEKVVESDI(SEQ ID NO:452)、YEKVVESDL(SEQ ID NO:453)、YEKVVESEI(SEQ ID NO:454)、YEKVVESEL(SEQ ID NO:455)、YEKVVESEV(SEQ ID NO:456)、YEKVVDSEI(SEQ ID NO:457)、YEKVVDSEL(SEQ ID NO:458)、YEKVVDSEV(SEQ ID NO:459)、YEKVVDSDI(SEQ ID NO:460)、YEKVVDSDL(SEQ ID NO:461)、YEKVVDSDV(SEQ ID NO:462)、YEKVVETEI(SEQ ID NO:463)、YEKVVETEL(SEQ ID NO:464)、YEKVVETEV(SEQ ID NO:465)、YEKVVETDI(SEQ ID NO:466)、YEKVVETDL(SEQ ID NO:467)、YEKVVETDV(SEQ ID NO:468)、YDKLLDTEI(SEQ ID NO:469)、YDKLLDTEL(SEQ ID NO:470)、YDKLLDTEV(SEQ ID NO:471)、YDKLLDTDI(SEQ ID NO:472)、YDKLLDTDL(SEQ ID NO:473)、YDKLLDTDV(SEQ ID NO:474)、YDKLLDSEI(SEQ ID NO:475)、YDKLLDSEL(SEQ ID NO:476)、YDKLLDSEV(SEQ ID NO:477)、YDKLLDSDI(SEQ ID NO:478)、YDKLLDSDL(SEQ ID NO:479)、YDKLLDSDV(SEQ ID NO:480)、YDKLLETEI(SEQ ID NO:481)、YDKLLETEL(SEQ ID NO:482)、YDKLLETEV(SEQ ID NO:483)、YDKLLETDI(SEQ ID NO:484)、YDKLLETDL(SEQ ID NO:485)、YDKLLETDV(SEQ ID NO:486)、YDKLVDTEI(SEQ ID NO:487)、YDKLVDTEL(SEQ ID NO:488)、YDKLVDTEV(SEQ ID NO:489)、YDKLVDTDI(SEQ ID NO:490)、YDKLVDTDL(SEQ IDNO:491)、YDKLVDTDV(SEQ ID NO:492)、YDKLIDTEI(SEQ ID NO:493)、YDKLIDTEL(SEQ ID NO:494)、YDKLIDTEV(SEQ ID NO:495)、YDKLIDTDI(SEQ ID NO:496)、YDKLIDTDL(SEQ ID NO:497)、YDKLIDTDV(SEQ ID NO:498)、YDKLIETEI(SEQ ID NO:499)、YDKLIETEL(SEQ ID NO:500)、YDKLIETEV(SEQ ID NO:501)、YDKLIETDI(SEQ ID NO:502)、YDKLIETDL(SEQ ID NO:503)、YDKLIETDV(SEQ ID NO:504)、YDKLIESDV(SEQ ID NO:505)、YDKLIESDI(SEQ ID NO:506)、YDKLIESDL(SEQ ID NO:507)、YDKLIESEI(SEQ ID NO:508)、YDKLIESEL(SEQ ID NO:509)、YDKLIESEV(SEQ ID NO:510)、YDKLIDSDV(SEQ ID NO:511)、YDKLIDSDI(SEQ ID NO:512)、YDKLIDSDL(SEQ ID NO:513)、YDKLIDSEI(SEQ ID NO:514)、YDKLIDSEL(SEQ ID NO:515)、YDKLIDSEV(SEQ ID NO:516)、YDKLLESDV(SEQ ID NO:517)、YDKLLESDI(SEQ ID NO:518)、YDKLLESDL(SEQ ID NO:519)、YDKLLESEI(SEQ ID NO:520)、YDKLLESEL(SEQ ID NO:521)、YDKLLESEV(SEQ ID NO:522)、YDKLVESDV(SEQ ID NO:523)、YDKLVESDI(SEQ ID NO:524)、YDKLLVESDL(SEQ ID NO:525)、YDKLVESEI(SEQ ID NO:526)、YDKLVESEL(SEQ ID NO:527)、YDKLVESEV(SEQ ID NO:528)、YDKLVDSEI(SEQ ID NO:529)、YDKLVDSEL(SEQ ID NO:530)、YDKLVDSEV(SEQ IDNO:531)、YDKLVDSDI(SEQ ID NO:532)、YDKLVDSDL(SEQ ID NO:533)、YDKLVDSDV(SEQ ID NO:534)、YDKLVETEI(SEQ ID NO:535)、YDKLVETEL(SEQ ID NO:536)、YDKLVETEV(SEQ ID NO:537)、YDKLVETDI(SEQ ID NO:538)、YDKLVETDL(SEQ ID NO:539)、YDKLVETDV(SEQ ID NO:540)、YDKILDTEI(SEQ ID NO:541)、YDKILDTEL(SEQ ID NO:542)、YDKILDTEV(SEQ ID NO:543)、YDKILDTDI(SEQ ID NO:544)、YDKILDTDL(SEQ ID NO:545)、YDKILDTDV(SEQ ID NO:546)、YDKILDSEI(SEQ ID NO:547)、YDKILDSEL(SEQ ID NO:548)、YDKILDSEV(SEQ ID NO:549)、YDKILDSDI(SEQ ID NO:550)、YDKILDSDL(SEQ ID NO:551)、YDKILDSDV(SEQ ID NO:552)、YDKILETEI(SEQ ID NO:553)、YDKILETEL(SEQ ID NO:554)、YDKILETEV(SEQ ID NO:555)、YDKILETDI(SEQ ID NO:556)、YDKILETDL(SEQ ID NO:557)、YDKILETDV(SEQ ID NO: 558)、YDKIVDTEI(SEQ ID NO:559)、YDKIVDTEL(SEQ ID NO:560)、YDKIVDTEV(SEQ ID NO:561)、YDKIVDTDI(SEQ ID NO:562)、YDKIVDTDL(SEQ ID NO:563)、YDKIVDTDV(SEQ ID NO:564)、YDKIIDTEI(SEQ ID NO:565)、YDKIIDTEL(SEQ ID NO:566)、YDKIIDTEV(SEQ ID NO:567)、YDKIIDTDI(SEQ ID NO:568)、YDKIIDTDL(SEQ ID NO:569)、YDKIIDTDV(SEQ ID NO:570)、YDKIIETEI(SEQ IDNO:571)、YDKIIETEL(SEQ ID NO:572)、YDKIIETEV(SEQ ID NO:573)、YDKIIETDI(SEQ ID NO:574)、YDKIIETDL(SEQ ID NO:575)、YDKIIETDV(SEQ ID NO:576)、YDKIIESDV(SEQ ID NO:577)、YDKIIESDI(SEQ ID NO:578)、YDKIIESDL(SEQ ID NO:579)、YDKIIESEI(SEQ ID NO:580)、YDKIIESEL(SEQ ID NO:581)、YDKIIESEV(SEQ ID NO:582)、YDKIIDSDV(SEQ ID NO:583)、YDKIIDSDI(SEQ ID NO:584)、YDKIIDSDL(SEQ ID NO:585)、YDKIIDSEI(SEQ ID NO:586)、YDKIIDSEL(SEQ ID NO:587)、YDKIIDSEV(SEQ ID NO:588)、YDKILESDV(SEQ ID NO:589)、YDKILESDI(SEQ ID NO:590)、YDKILESDL(SEQ ID NO:591)、YDKILESEI(SEQ ID NO:592)、YDKILESEL(SEQ ID NO:593)、YDKILESEV(SEQ ID NO:594)、YDKIVESDV(SEQ ID NO:595)、YDKIVESDI(SEQ ID NO:596)、YDKIVESDL(SEQ ID NO:597)、YDKIVESEI(SEQ ID NO:598)、YDKIVESEL(SEQ ID NO:599)、YDKIVESEV(SEQ ID NO:600)、YDKIVDSEI(SEQ ID NO:601)、YDKIVDSEL(SEQ ID NO:602)、YDKIVDSEV(SEQ ID NO:603)、YDKIVDSDI(SEQ ID NO:604)、YDKIVDSDL(SEQ ID NO:605)、YDKIVDSDV(SEQ ID NO:606)、YDKIVETEI(SEQ ID NO:607)、YDKIVETEL(SEQ ID NO:608)、YDKIVETEV(SEQ ID NO:609)、YDKIVETDI(SEQ ID NO:610)、YDKIVETDL(SEQ IDNO:611)、YDKIVETDV(SEQ ID NO:612)、YDKVLDTEI(SEQ ID NO:613)、YDKVLDTEL(SEQ ID NO:614)、YDKVLDTEV(SEQ ID NO:615)、YDKVLDTDI(SEQ ID NO:616)、YDKVLDTDL(SEQ ID NO:617)、YDKVLDTDV(SEQ ID NO:618)、YDKVLDSEI(SEQ ID NO:619)、YDKVLDSEL(SEQ ID NO:620)、YDKVLDSEV(SEQ ID NO:621)、YDKVLDSDI(SEQ ID NO:622)、YDKVLDSDL(SEQ ID NO:623)、YDKVLDSDV(SEQ ID NO:624)、YDKVLETEI(SEQ ID NO:625)、YDKVLETEL(SEQ ID NO:626)、YDKVLETEV(SEQ ID NO:627)、YDKVLETDI(SEQ ID NO:628)、YDKVVLETDL(SEQ ID NO:629)、YDKVLETDV(SEQ ID NO:630)、YDKVVDTEI(SEQ ID NO:631)、YDKVVDTEL(SEQ ID NO:632)、YDKVVDTEV(SEQ ID NO:633)、YDKVVDTDI(SEQ ID NO:634)、YDKVVDTDL(SEQ ID NO:635)、YDKVVDTDV(SEQ ID NO:636)、YDKVIDTEI(SEQ ID NO:637)、YDKVIDTEL(SEQ ID NO:638)、YDKVIDTEV(SEQ ID NO:639)、YDKVIDTDI(SEQ ID NO:640)、YDKVIDTDL(SEQ ID NO:641)、YDKVIDTDV(SEQ ID NO:642)、YDKVIETEI(SEQ ID NO:643)、YDKVIETEL(SEQ ID NO:644)、YDKVIETEV(SEQ ID NO:645)、YDKVIETDI(SEQ ID NO:646)、YDKVIETDL(SEQ ID NO:647)、YDKVIETDV(SEQ ID NO:648)、YDKVIESDV(SEQ ID NO:649)、YDKVIESDI(SEQ ID NO:650)、YDKVIESDL(SEQ IDNO:651), YDKVIESEI (SEQ ID NO:652), YDKVIESEL (SEQ ID NO:653), YDKVIESEV (SEQ ID NO:654), YDKVIDSDV (SEQ ID NO:655), YDKVIDSDI (SEQ ID NO:656), YDKVIDSDL (SEQ ID NO:657), YDKVIDSEI (SEQ ID NO:658), YDKVIDSEL (SEQ ID NO:659), YDKVIDSEV (SEQ ID NO:660), YDKVLESDV (SEQ ID NO:661), YDKVLESDI (SEQ ID NO:662), YDKVLESDL (SEQ ID NO:663), YDKVLESEI (SEQ ID NO:664), YDKVLESEL (SEQ ID NO:665), YDKVLESEV (SEQ ID NO:666), YDKVVESDV (SEQ ID NO:667), YDKVVESDI (SEQ ID NO:668), YDKVVESDL (SEQ ID NO:669), YDKVVESEI (SEQ ID NO:670), YDKVVESEL (SEQ ID NO:671), YDKVVESEV (SEQ ID NO:672), YDKVVDSEI (SEQ ID NO:673), YDKVVDSEL (SEQ ID NO:674), YDKVVDSEV (SEQ ID NO:675), YDKVVDSDI (SEQ ID NO:676), YDKVVDSDL (SEQ ID NO:677), YDKVVDSDV (SEQ ID NO:678), YDKVVETEI (SEQ ID NO:679), YDKVVETEL (SEQ ID NO:680), YDKVVETEV (SEQ ID NO:681), YDKVVETDI (SEQ ID NO:682), YDKVVETDL (SEQ ID NO:683) and YDKVVETDV (SEQ ID NO:684).

[0081] In some embodiments of the first aspect, the conservative substitutions are further selected from substitutions between lysine (K), arginine (R) and histidine (H), and substitutions between tyrosine (Y), phenylalanine (F) and tryptophan (W).

[0082] In some specific embodiments, the variant of YEKLLDTEI can be YEKILDTEI (SEQ ID NO: 325).

[0083] As described in PCT / CN2016 / 080321, the discovery of YEKLLDTEI (SEQ ID NO: 253) is related to the following:

[0084] Some active peptides that inhibit the interaction between NMDAR and PSD-95 are based on the structure of NMDAR. For example, NMDAR2B has GenBank ID 4099612, and its C-terminal 20 amino acids are FNGSSNGHVYEKLSSLESDV (SEQ ID NO: 685) and the PL motif ESDV (SEQ ID NO: 686). Some existing active peptides select partial amino acid sequences from the C-terminus of NMDAR2B, thereby producing competitive inhibition of PSD-95 with NMDAR2B. Some studies believe that the ESDV (SEQ ID NO: 686) or LESDV (SEQ ID NO: 687) segments in these peptides play an important role in inhibiting the interaction between NMDAR and PSD-95 proteins. Without being bound by any theory, the inventors of the present application unexpectedly discovered that the active peptide YEKLLDTEI (SEQ ID NO: 253) disclosed herein, compared to the C-terminal amino acid composition of the NMDAR2B described above, does not contain the two SS residues following KL, and simultaneously adds an N-terminal YEKL amino acid sequence relative to the PL motif. The present application demonstrates that such changes can enhance the interaction of the active peptide with the PDZ1 / 2 domain. Furthermore, relative to the YEKL (SEQ ID NO: 688) motif, the C-terminal LDTEI can be varied without affecting the activity of the active peptide, or with the potential to increase its activity.

[0085] Therefore, the inventors truncated the N-terminus of YEKLLDTEI (SEQ ID NO: 253) to a certain extent and obtained the following other embodiments.

[0086] In a second aspect, the present application provides a conjugate comprising borneol and a peptide, wherein the peptide comprises LLDTEI (SEQ ID NO: 37), CLDTEI (SEQ ID NO: 689), or a variant of SEQ ID NO: 37 or 689 having one or more conservative substitutions, wherein the conservative substitutions are selected from substitutions between D and E, substitutions between L, V and I, and substitutions between T and S.

[0087] In some embodiments of the second aspect, variants of SEQ ID NO: 37 or 689 may be selected from: LLDTEL (SEQ ID NO: 38), LLDTEV (SEQ ID NO: 39), LLDTDI (SEQ ID NO: 40), LLDTDL (SEQ ID NO: 41), LLDTDV (SEQ ID NO: 42), LLDSEI (SEQ ID NO: 43), LLDSEL (SEQ ID NO: 44), LLDSEV (SEQ ID NO: 45), LLDSDI (SEQ ID NO: 46), LLDSDL (SEQ ID NO: 47), LLDSDV (SEQ ID NO: 48), LLETEI (SEQ ID NO: 49), LLETEL (SEQ ID NO: 50), LLETEV (SEQ ID NO: 51), LLETDI (SEQ ID NO: 52), LLETDL (SEQ ID NO: 53), LLETDV (SEQ ID NO: 54), LVDTEI (SEQ ID NO: 55), LVDTEL (SEQ ID NO: 56), LVDTEV (SEQ ID NO: 57), LVDTDI (SEQ ID NO: 58), LVDTDL (SEQ ID NO: 59), LVDTDV (SEQ ID NO: 60), LIDTEI (SEQ ID NO: 61), LIDTEL (SEQ ID NO: 62), LIDTEV (SEQ ID NO: 63), LIDTDI (SEQ ID NO: 64), LIDTDL (SEQ ID NO: 65), LIDTDV (SEQ ID NO: 66), LIETEI (SEQ ID NO: 67), LIETEL (SEQ ID NO: 68), LIETEV (SEQ ID NO: 69), LIETDI (SEQ ID NO: 70), LIETDL (SEQ ID NO: 71), LIETDV (SEQ ID NO: 72), LIESDV (SEQ ID NO: 73), LIESDI (SEQ ID NO: 74), LIESDL (SEQ ID NO: 75), LIESEI (SEQ ID NO: 76), LIESEL (SEQ ID NO: 77), LIESEV (SEQ ID NO: 78), LIDSDV (SEQ ID NO: 79), LIDSDI (SEQ ID NO: 80), LIDSDL (SEQ ID NO: 81), LIDSEI (SEQ ID NO: 82), LIDSEL (SEQNO:83)、LIDSEV(SEQ ID NO:84)、LLESDV(SEQ ID NO:85)、LLESDI(SEQ ID NO:86)、LLESDL(SEQ ID NO:87)、LLESEI(SEQ ID NO:88)、LLESEL(SEQ ID NO:89)、LLESEV(SEQ ID NO:90)、LVESDV(SEQ ID NO:91)、LVESDI(SEQ ID NO:92)、LLVESDL(SEQ ID NO:93)、LVESEI(SEQ ID NO:94)、LVESEL(SEQ ID NO:95)、LVESEV(SEQ ID NO:96)、LVDSEI(SEQ ID NO:97)、LVDSEL(SEQ ID NO:98)、LVDSEV(SEQ ID NO:99)、LVDSDI(SEQ ID NO:100)、LVDSDL(SEQ ID NO:101)、LVDSDV(SEQ ID NO:102)、LVETEI(SEQ ID NO:103)、LVETEL(SEQ ID NO:104)、LVETEV(SEQ ID NO:105)、LVETDI(SEQ ID NO:106)、LVETDL(SEQ ID NO:107)、LVETDV(SEQ ID NO:108)、ILDTEI(SEQ ID NO:109)、ILDTEL(SEQ ID NO:110)、ILDTEV(SEQ ID NO:111)、ILDTDI(SEQ ID NO:112)、ILDTDL(SEQ ID NO:113)、ILDTDV(SEQ ID NO:114)、ILDSEI(SEQ ID NO:115)、ILDSEL(SEQ ID NO:116)、ILDSEV(SEQ ID NO:117)、ILDSDI(SEQ ID NO:118)、ILDSDL(SEQ ID NO:119)、ILDSDV(SEQ ID NO:120)、ILETEI(SEQ ID NO:121)、ILETEL(SEQ ID NO:122)、ILETEV(SEQ ID NO:123)、ILETDI(SEQ ID NO:124)、ILETDL(SEQ ID NO:125)、ILETDV(SEQ ID NO:126)、IVDTEI(SEQ ID NO:127)、IVDTEL(SEQ ID NO:128)、IVDTEV(SEQ IDNO:129)、IVDTDI(SEQ ID NO:130)、IVDTDL(SEQ ID NO:131)、IVDTDV(SEQ ID NO:132)、IIDTEI(SEQ ID NO:133)、IIDTEL(SEQ ID NO:134)、IIDTEV(SEQ ID NO:135)、IIDTDI(SEQ ID NO:136)、IIDTDL(SEQ ID NO:137)、IIDTDV(SEQ ID NO:138)、IIETEI(SEQ ID NO:139)、IIETEL(SEQ ID NO:140)、IIETEV(SEQ ID NO:141)、IIETDI(SEQ ID NO:142)、IIETDL(SEQ ID NO:143)、IIETDV(SEQ ID NO:144)、IIESDV(SEQ ID NO:145)、IIESDI(SEQ ID NO:146)、IIETDL(SEQ ID NO:143) NO:147), IIESEI(SEQ ID NO:148), IIESEL(SEQ ID NO:149), IIESEV(SEQ ID NO:150), IIDSDV(SEQ ID NO:151), IIDSDI(SEQ ID NO:152), IIDSDL(SEQ ID NO:153), IIDSEI(SEQ ID NO:154), IIDSEL(SEQ ID NO:155), IIDSEV(SEQ ID NO:156), ILESDV(SEQ ID NO:157), ILESDI(SEQ ID NO:158), ILESDL(SEQ ID NO:159), ILESEI(SEQ ID NO:160), ILESEL(SEQ ID NO:161), ILESEV(SEQ ID NO:162), IVESDV(SEQ ID NO:163), IVESDI(SEQ ID NO:164), IVESDL(SEQ ID NO:165), IVESEI(SEQ ID NO:166)、IVESEL(SEQ ID NO:167)、IVESEV(SEQ ID NO:168)、IVDSEI(SEQ ID NO:169)、IVDSEL(SEQ ID NO:170)、IVDSEV(SEQ ID NO:171)、IVDSDI(SEQ ID NO:172)、IVDSDL(SEQ ID NO:173)、IVDSDV(SEQ ID NO:171)NO:174)、IVETEI(SEQ ID NO:175)、IVETEL(SEQ ID NO:176)、IVETEV(SEQ ID NO:177)、IVETDI(SEQ ID NO:178)、IVETDL(SEQ ID NO:179)、IVETDV(SEQ ID NO:180)、VLDTEI(SEQ ID NO:181)、VLDTEL(SEQ ID NO:182)、VLDTEV(SEQ ID NO:183)、VLDTDI(SEQ ID NO:184)、VLDTDL(SEQ ID NO:185)、VLDTDV(SEQ ID NO:186)、VLDSEI(SEQ ID NO:187)、VLDSEL(SEQ ID NO:188)、VLDSEV(SEQ ID NO:189)、VLDSDI(SEQ ID NO:190)、VLDSDL(SEQ ID NO:191)、VLDSDV(SEQ ID NO:192)、VLETEI(SEQ ID NO:193)、VLETEL(SEQ ID NO:194)、VLETEV(SEQ ID NO:195)、VLETDI(SEQ ID NO:196)、VVLETDL(SEQ ID NO:197)、VLETDV(SEQ ID NO:198)、VVDTEI(SEQ ID NO:199)、VVDTEL(SEQ ID NO:200)、VVDTEV(SEQ ID NO:201)、VVDTDI(SEQ ID NO:202)、VVDTDL(SEQ ID NO:203)、VVDTDV(SEQ ID NO:204)、VIDTEI(SEQ ID NO:205)、VIDTEL(SEQ ID NO:206)、VIDTEV(SEQ ID NO:207)、VIDTDI(SEQ ID NO:208)、VIDTDL(SEQ ID NO:209)、VIDTDV(SEQ ID NO:210)、VIETEI(SEQ ID NO:211)、VIETEL(SEQ ID NO:212)、VIETEV(SEQ ID NO:213)、VIETDI(SEQ ID NO:214)、VIETDL(SEQ ID NO:215)、VIETDV(SEQ ID NO:216)、VIESDV(SEQ ID NO:217)、VIESDI(SEQ ID NO:218)、VIESDL(SEQ IDNO:219)、VIESEI(SEQ ID NO:220)、VIESEL(SEQ ID NO:221)、VIESEV(SEQ ID NO:222)、VIDSDV(SEQ ID NO:223)、VIDSDI(SEQ ID NO:224)、VIDSDL(SEQ ID NO:225)、VIDSEI(SEQ ID NO:226)、VIDSEL(SEQ ID NO:227)、VIDSEV(SEQ ID NO:228)、VLESDV(SEQ ID NO:229)、VLESDI(SEQ ID NO:230)、VLESDL(SEQ ID NO:231)、VLESEI(SEQ ID NO:232)、VLESEL(SEQ ID NO:233)、VLESEV(SEQ ID NO:234)、VVESDV(SEQ ID NO:235)、VVESDI(SEQ ID NO:236)、VVESDL(SEQ ID NO:237)、VVESEI(SEQ ID NO:238)、VVESEL(SEQ ID NO:239)、VVESEV(SEQ ID NO:240)、VVDSEI(SEQ ID NO:241)、VVDSEL(SEQ ID NO:242)、VVDSEV(SEQ ID NO:243)、VVDSDI(SEQ ID NO:244)、VVDSDL(SEQ ID NO:245)、VVDSDV(SEQ ID NO:246)、VVETEI(SEQ ID NO:247)、VVETEL(SEQ ID NO:248)、VVETEV(SEQ ID NO:249)、VVETDI(SEQ ID NO:250)、VVETDL(SEQ ID NO:251)、VVETDV(SEQ ID NO:252)、CLDTEL(SEQ ID NO:690)、CLDTEV(SEQ ID NO:691)、CLDTDI(SEQ ID NO:692)、CLDTDL(SEQ ID NO:693)、CLDTDV(SEQ ID NO:694)、CLDSEI(SEQ ID NO:695)、CLDSEL(SEQ ID NO:696)、CLDSEV(SEQ ID NO:697)、CLDSDI(SEQ ID NO:698)、CLDSDL(SEQ ID NO:699)、CLDSDV(SEQ ID NO:700)、CLETEI(SEQ IDNO:701), CLETEL (SEQ ID NO:702), CLETEV (SEQ ID NO:703), CLETDI (SEQ ID NO:704), CLETDL (SEQ ID NO:705), CLETDV (SEQ ID NO:706), CVDTEI (SEQ ID NO:707), CVDTEL (SEQ ID NO:708), CVDTEV (SEQ ID NO:709), CVDTDI (SEQ ID NO:710), CVDTDL (SEQ ID NO:711), CVDTDV (SEQ ID NO:712), CIDTEI (SEQ ID NO:713), CIDTEL (SEQ ID NO:714), CIDTEV (SEQ ID NO:715), CIDTDI (SEQ ID NO:716), CIDTDL (SEQ ID NO:717), CIDTDV (SEQ ID NO:718), CIETEI (SEQ ID NO:719), CIETEL (SEQ ID NO:720), CIETEV (SEQ ID NO:721), CIETDI (SEQ ID NO:722), CIETDL (SEQ ID NO:723) and CIETDV (SEQ ID NO:724).

[0088] In some specific embodiments of the second aspect, the variant of SEQ ID NO: 37 can be ILDTEI (SEQ ID NO: 109).

[0089] In a third aspect, the present application provides a conjugate comprising borneol and a peptide, wherein the peptide comprises LDTEI (SEQ ID NO: 1) or a variant of SEQ ID NO: 1 in which one or more conservative substitutions occur, wherein the conservative substitutions are selected from substitutions between D and E, substitutions between L, V and I, and substitutions between T and S.

[0090] In some embodiments of the third aspect, a variant of SEQ ID NO: 1 can be selected from the group consisting of: LDTEL (SEQ ID NO: 2), LDTEV (SEQ ID NO: 3), LDTDI (SEQ ID NO: 4), LDTDL (SEQ ID NO: 5), LDTDV (SEQ ID NO: 6), LDSEI (SEQ ID NO: 7), LDSEL (SEQ ID NO: 8), LDSEV (SEQ ID NO: 9), LDSDI (SEQ ID NO: 10), LDSDL (SEQ ID NO: 11), LDSDV (SEQ ID NO: 12), LETEI (SEQ ID NO: 13), LETEL (SEQ ID NO: 14), LETEV (SEQ ID NO: 15), LETDI (SEQ ID NO: 16), LETDL (SEQ ID NO: 17), LETDV (SEQ ID NO: 18), VDTEI (SEQ ID NO: 19), VDTEL (SEQ ID NO: 20), VDTEV (SEQ ID NO: 21), VDTDI (SEQ ID NO: 22), VDTDL (SEQ ID NO: 23), ID NO:23), VDTDV (SEQ ID NO:24), IDTEI (SEQ ID NO:25), IDTEL (SEQ ID NO:26), IDTEV (SEQ ID NO:27), IDTDI (SEQ ID NO:28), IDTDL (SEQ ID NO:29), IDTDV (SEQ ID NO:30), IETEI (SEQ ID NO:31), IETEL (SEQ ID NO:32), IETEV (SEQ ID NO:33), IETDI (SEQ ID NO:34), IETDL (SEQ ID NO:35) and IETDV (SEQ ID NO:36).

[0091] In some embodiments of any of the foregoing aspects, borneol is located on the N-terminal side of the peptide.

[0092] In some embodiments of any of the foregoing aspects, in a single conjugate molecule, the molar ratio of borneol to the peptide is 1:1.

[0093] In some embodiments of any of the foregoing aspects, borneol is linked to the peptide via a linker.

[0094] In some embodiments of any of the above aspects, the linker includes, but is not limited to, glycine, non-peptidyl polymers such as polyethylene glycol (PEG) or fatty acid chains of varying lengths (e.g., stearoyl, palmitoyl, octanoyl, etc.); homopolymeric amino acids (e.g., polyhistidine, polyarginine, polylysine, or polyalanine) or heteropolymeric amino acids; and small molecule groups (e.g., carbonyl, alkylene (e.g., C 1-6 The polymer may be linear or branched.

[0095] In some embodiments of any of the foregoing aspects, the linker is selected from the group consisting of:

[0096] In some embodiments of any of the above aspects, one end of the linker can be connected to the N-terminus, C-terminus or side chain of an amino acid residue (such as lysine, aspartic acid, glutamic acid, etc. in the polypeptide) of the peptide.

[0097] In some embodiments of any of the aforementioned aspects, one end of the linker is connected to the N-terminus of the peptide.

[0098] In some embodiments of any of the above aspects, the other end of the linker is connected to the O atom of borneol.

[0099] In some embodiments of any of the aforementioned aspects, the peptide can bind to the PDZ1 / 2 domain of postsynaptic density protein 95 (PSD-95) and inhibit the interaction between N-methyl-D-aspartate receptor (NMDAR) and PSD-95.

[0100] In a fourth aspect, the present application provides a pharmaceutical composition comprising the conjugate described in any one of the above aspects and a pharmaceutically acceptable carrier.

[0101] In some embodiments of the fourth aspect, the pharmaceutical composition can be manufactured by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing methods.

[0102] In some embodiments of the fourth aspect, the pharmaceutical composition can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or adjuvants that facilitate processing of the conjugate into a pharmaceutically acceptable preparation. Appropriate formulation depends on the chosen route of administration.

[0103] In some embodiments of the fourth aspect, administration can be parenteral, intravenous, oral, subcutaneous, intraarterial, intracranial, intrathecal, intraperitoneal, topical, intranasal, or intramuscular. Intravenous administration is preferred.

[0104] In some embodiments of the fourth aspect, the pharmaceutical composition for parenteral administration is preferably sterile and substantially isotonic. For injection, the conjugate can be formulated into an aqueous solution, preferably a physiologically compatible buffer such as Hank's solution, Ringer's solution, or normal saline or acetate buffer (to reduce discomfort at the injection site). The solution can contain a preparatant such as a suspending agent, a stabilizer, and / or a dispersant. Alternatively, the conjugate can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0105] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. This route of administration can be used to deliver the conjugate to the nasal cavity or for sublingual administration.

[0106] In some embodiments of the fourth aspect, for oral administration, the conjugate can be formulated with a pharmaceutically acceptable carrier as a tablet, pill, lozenge, capsule, liquid, gel, syrup, slurry, suspension, etc. for oral ingestion by the patient being treated. For oral solid formulations such as powders, capsules, and tablets, suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, carboxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvidone (PVP); granulating agents and binders. If necessary, a disintegrant such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, can be added. If necessary, the solid dosage form can be sugar-coated or enteric-coated using standard techniques. For oral liquid formulations such as suspensions, elixirs, and solutions, suitable carriers, excipients, or diluents include water, glycerol, oils, and alcohols. In addition, flavoring agents, preservatives, coloring agents and the like may be added.

[0107] In addition to the formulations described previously, the conjugates may also be formulated as depot preparations. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound may be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, e.g., as a sparingly soluble salt.

[0108] Alternatively, other drug delivery systems can be used. Liposomes and emulsions can be used to deliver the conjugate. Certain organic solvents such as dimethyl sulfoxide can also be used. In addition, sustained-release systems (e.g., semipermeable matrices of solid polymers containing the therapeutic agent) can be used to deliver the conjugate.

[0109] Depending on its chemical nature, sustained-release capsules can release the conjugate for several weeks up to over 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, other strategies for protein stabilization can be used.

[0110] In some embodiments of the fourth aspect, because the conjugates disclosed herein may contain charged side chains or termini, they can be included in any of the above-described formulations as free acids or bases or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts that substantially retain the biological activity of the free bases and are prepared by reaction with inorganic acids. Pharmaceutical salts tend to be more soluble in water and other protic solvents than the corresponding free base forms.

[0111] The conjugate is used in an amount effective to achieve the intended purpose (e.g., to reduce the damaging effects of traumatic stroke and related conditions). A therapeutically effective amount means an amount of the conjugate sufficient to significantly reduce the damage caused by stroke in a patient (or animal model population) treated with the conjugate disclosed herein relative to the central nervous system damage in a control population of patients (or animal models) not treated with the conjugate disclosed herein. If an individual treated patient achieves a better output (as measured by infarct volume) than the mean output in a comparable control population of patients not treated by the methods disclosed herein, the amount is also considered therapeutically effective. If an individual treated patient shows a disability of 2 or less on the Rankin scale and 75 or more on the Barthel scale, the amount is also considered therapeutically effective. If the treated patient population shows a distribution of scores on the disability scale that is significantly improved (i.e., less disabled) compared to a comparable untreated population, the dose is also considered therapeutically effective, see Lees et al., N Engl J Med 2006; 354: 588-600. A therapeutically effective regimen refers to a combination of therapeutically effective doses and frequency of administration required to achieve the above-mentioned intended purpose. Usually a single administration is sufficient.

[0112] In some embodiments of the fourth aspect, the amount of the conjugate administered depends on the subject being treated, the subject's weight, the severity of the affliction, the mode of administration, and the discretion of the prescribing physician. Treatment may be repeated when symptoms are detectable or even when they are not detectable. Treatment may be provided alone or in combination with other drugs.

[0113] In some embodiments of the fourth aspect, a therapeutically effective dose of the conjugate disclosed herein can provide therapeutic benefit without causing significant toxicity. The toxicity of the peptides linked to borneol can be determined by standard pharmaceutical procedures in cell culture or experimental animals, for example, by determining the LD50 (dose lethal to 50% of the population) or LD100 (dose lethal to 100% of the population). The dose ratio of toxic and therapeutic effects is the therapeutic index. Conjugates that exhibit a high therapeutic index are preferred (see, for example, Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Chapter 1, page 1).

[0114] In some embodiments of the fourth aspect, the pharmaceutical composition is used to treat, improve or prevent damage to the nervous system of a mammal or a disease or pain caused by the damage, a neurodegenerative disease, anxiety or epilepsy, or is used as a neuroprotective agent.

[0115] In some embodiments of the fourth aspect, the disease is stroke or nervous system damage caused by stroke.

[0116] In some embodiments of the fourth aspect, the nervous system injury is nervous system injury caused by excitotoxicity, wherein the injury is located in the peripheral nervous system or the central nervous system.

[0117] In some embodiments of the fourth aspect, the nervous system damage caused by excitotoxicity includes damage selected from stroke or spinal cord injury, ischemic or traumatic injury to the brain or spinal cord, and damage to central nervous system (CNS) neurons, including acute CNS injury, ischemic stroke or spinal cord injury, and damage caused by hypoxia, ischemia, mechanical injury and neurodegenerative diseases, anxiety, epilepsy, and stroke.

[0118] In some embodiments of the fourth aspect, the cerebral stroke includes ischemic stroke, hemorrhagic stroke, and hemorrhagic stroke converted from ischemic stroke.

[0119] In some embodiments of the fourth aspect, the pharmaceutical composition is used to treat, improve or prevent nervous system damage caused by ischemic stroke.

[0120] Cerebral stroke is a disease caused by impaired blood flow in the CNS. Possible causes include embolism, hemorrhage and thrombosis. Some neuronal cells die immediately due to impaired blood flow. These cells release their component molecules (including glutamate), which then activate NMDA receptors, which increase intracellular calcium levels and intracellular enzyme levels, leading to more neuronal cell death (excitatory neurotoxicity cascade). The death of CNS tissue is referred to as infarction. Infarct volume (i.e., the volume of dead neuronal cells caused by stroke in the brain) can be used as an index of the pathological damage caused by stroke. Symptomatic effects depend not only on infarct volume, but also on where the infarction is located in the brain. Disability index can be used as a measure of symptomatic damage, such as the Rankin Stroke Outcome Scale (Rankin, Scott Med J; 2: 200-15 (1957)) and the Barthel Index (Barthel Index). The Rankin scale is based on the following direct evaluation of the patient's global symptoms:

[0121] 0 - No symptoms at all.

[0122] 1-No significant disability despite symptoms; able to perform all daily tasks and activities.

[0123] 2 - Mild disability; unable to perform all previous activities, but able to take care of own affairs without assistance.

[0124] 3-Moderate disability requiring some assistance, but able to walk without assistance.

[0125] 4 - Moderate to severe disability, unable to walk without assistance and unable to care for own physical needs without assistance.

[0126] 5 - Severe disability; bedridden, incontinent, and requiring constant care and attention.

[0127] The Barthel Index is based on a series of questions about a patient's ability to perform 10 basic activities of daily living, which yield a score between 0 and 100, with lower scores indicating more disability (Mahoney et al., Maryland State Medical Journal 14:56-61 (1965)).

[0128] Alternatively, stroke severity / outcome can be measured using the NIH Stroke Scale, which is available on the World Wide Web at ninds.nih.gov / doctors / NIH_Stroke_Scale_Booklet.pdf. This scale is based on the patient's ability to perform 11 functions that assess the patient's level of consciousness, movement, perception, and language function.

[0129] In some embodiments of the fourth aspect, the stroke is ischemic stroke.

[0130] Ischemic stroke more specifically refers to a type of stroke caused by blockage of blood flow to the brain. The most common underlying condition for this type of blockage is the development of fatty deposits along the blood vessel walls. This condition is called atherosclerosis. These fatty deposits can cause two types of obstruction. Cerebral thrombosis refers to a thrombus (blood clot) that forms in the blocked part of a blood vessel. "Cerebral embolism" usually refers to various emboli in the blood (such as mural thrombi in the heart, atherosclerotic plaques, fat, tumor cells, fibrocartilage or air, etc.) that enter the cerebral artery with the blood flow and block the blood vessel. When the collateral circulation cannot compensate, it causes ischemic necrosis of the brain tissue in the arterial blood supply area, resulting in focal neurological deficits. The second important cause of embolism is irregular heartbeat, called arterial myocardial fibrillation. It causes the following conditions, in which blood clots can form in the heart, move and metastasize to the brain. Other potential causes of ischemic stroke are hemorrhage, thrombosis, cutting of an artery or vein, cardiac arrest, shock from any cause (including hemorrhage), and iatrogenic causes such as direct surgical injury to a cerebral blood vessel or a blood vessel leading to the brain or heart surgery. Ischemic stroke accounts for approximately 83% of all stroke cases.

[0131] Several other neurological conditions can also cause nerve death through the excitatory neurotoxicity mediated by NDMAR. These conditions include neurodegenerative diseases, anxiety, epilepsy, anoxia, trauma to CNS unrelated to stroke such as traumatic brain injury and spinal cord injury. Therefore, in some embodiments, pharmaceutical composition is used to treat, improve or prevent neurodegenerative diseases, anxiety or epilepsy, wherein the neurodegenerative disease includes Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease or Huntington's disease.

[0132] In a fifth aspect, the present application provides the use of the conjugate described in any one of the first to third aspects or the pharmaceutical composition described in the fourth aspect in the preparation of a drug or neuroprotectant for treating, improving or preventing the following diseases in mammals: nervous system damage and diseases or pain related to the damage, neurodegenerative diseases, anxiety or epilepsy.

[0133] In some embodiments of the fifth aspect, the disease is stroke or nervous system damage caused by stroke.

[0134] In some embodiments of the fifth aspect, the cerebral stroke includes ischemic stroke, hemorrhagic stroke, and hemorrhagic stroke converted from ischemic stroke.

[0135] In some specific embodiments of the fifth aspect, the stroke is ischemic stroke.

[0136] In some embodiments of the fifth aspect, the nervous system injury is nervous system injury caused by excitotoxicity.

[0137] In some embodiments of the fifth aspect, the nervous system damage caused by excitotoxicity includes damage selected from stroke or spinal cord injury, ischemic or traumatic injury to the brain or spinal cord, and damage to central nervous system (CNS) neurons, including acute CNS injury, ischemic stroke or spinal cord injury, and damage caused by hypoxia, ischemia, mechanical injury and neurodegenerative diseases, anxiety, epilepsy, and stroke.

[0138] In some embodiments of the fifth aspect, the injury or pain is located in the peripheral nervous system or the central nervous system.

[0139] In some embodiments of the fifth aspect, the neurodegenerative disease comprises Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, or Huntington's disease.

[0140] In some embodiments of the fifth aspect, the medicament is used to treat, improve or prevent nervous system damage caused by ischemic stroke.

[0141] In a sixth aspect, the present application also provides a method for treating, ameliorating or preventing the following diseases in mammals: nervous system damage and diseases or pain associated with the damage, neurodegenerative diseases, anxiety or epilepsy, which comprises administering the conjugate described in any one of the first to third aspects, or the pharmaceutical composition described in the fourth aspect, to an individual in need.

[0142] In some embodiments of the sixth aspect, the nervous system damage caused by excitotoxicity includes damage selected from stroke or spinal cord injury, ischemic or traumatic injury of the brain or spinal cord, and damage to central nervous system (CNS) neurons, including acute CNS injury, ischemic stroke or spinal cord injury, and damage caused by hypoxia, ischemia, mechanical injury and neurodegenerative diseases, anxiety, epilepsy, and stroke.

[0143] In some embodiments of the sixth aspect, the neurodegenerative disease comprises Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, or Huntington's disease.

[0144] In some embodiments of the sixth aspect, the individual is an individual who has experienced ischemic stroke. In some embodiments, administering the conjugate of any one of the first to third aspects of the present application, or the pharmaceutical composition of the fourth aspect, can reduce the volume of the cerebral infarction caused by cerebral ischemia.

[0145] It should be understood that the above detailed description is only for the purpose of enabling those skilled in the art to more clearly understand the content of the present application and is not intended to limit the present invention in any respect. Those skilled in the art can make various modifications and variations to the embodiments described. Example

[0146] The following examples are provided merely to illustrate some embodiments of the present application and are not intended to be limiting in any way.

[0147] The detailed information of experimental animals, reagents, and materials used in this application are as follows:

[0148] SD rats, male, 230-250 g, 16-18 days pregnant, SPF grade, were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd., license number: SCXK (Beijing) 2019-0010.

[0149] Reagents and materials: suture (L3400, Guangzhou Jialing), N-methyl-D-aspartic acid (NMDA, M3262, Sigma), conjugate containing borneol and peptide, chimeric peptide, hemin chloride (Hemin) (H9039, Sigma), papain (P5306, Sigma), DNA enzyme (D8071, Solebio Biotechnology Co., Ltd.), DMEM high glucose medium (812003, Gibco), Neurobasal TM Culture medium (21103049, Gibco), B-27 TM Plus supplement (50×) (A3582801, Gibco), L-glutamine, premium fetal bovine serum (Gibco), streptomycin and penicillin double antibody for cell culture (P1400, Solebio Biotechnology Co., Ltd.), mammalian cell LIVE / DEAD TM Cell viability / cytotoxicity kit (L3224, ThermoFisher), L-polylysine (Sigma), Laminin (2070487, Natural), D-PBS (14040, ThermoFisher).

[0150] The Chinese explanations of the abbreviations or English full names used in this application are shown in the following table:

[0151] The specific information of the conjugates containing borneol and peptides and the chimeric peptides prepared in this application are shown in Table 1 (-CO- as a linker or a part thereof is omitted in the names and abbreviations):

[0152] Table 1

[0153] TAT-9-mer, TAT-6-mer, and TAT-5-mer were all synthesized using conventional peptide solid-phase synthesis. TAT-9-mer was provided by Chengdu Shengnuo Biotechnology Co., Ltd., and TAT-6-mer and TAT-5-mer were provided by Beijing Zhongke Yaguang Biotechnology Co., Ltd. TAT-9-mer: Lyophilized powder is acetate salt with 99.77% purity, 82.66% peptide content, and a pure peptide molecular weight of 2665.1; TAT-6-mer: Lyophilized powder is trifluoroacetate salt with 98% purity, 71.1% peptide content, and a pure peptide molecular weight of 2244.7; TAT-5-mer: Lyophilized powder is trifluoroacetate salt with 98% purity, 70.0% peptide content, and a pure peptide molecular weight of 2131.5.

[0154] The drug concentration of the conjugate or chimeric peptide is calculated based on the molecular weight and content of the pure conjugate or chimeric peptide, and is prepared into a 1 mM stock solution, which is diluted to the target concentration with neuronal maintenance culture medium when used.

[0155] 100 mM NMDA stock solution: Weigh 14.7 mg of NMDA and dissolve it in 1 mL of PBS.

[0156] In animal experiments, each conjugate or chimeric peptide was formulated into 2 mg / mL and administered at a dose of 5 ml / kg, ultimately reaching a drug dose of 10 mg / kg.

[0157] Example 1. Synthesis of B-YEKLLDTEI

[0158] 1.1 Synthesis of 4-nitrophenyl ((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl) carbonate

[0159] The reaction equation is as follows:

[0160] Procedure: Weigh 9.65 g (48 mmol) of phenyl 4-nitrochloroformate and 6.16 g (40 mmol) of borneol into a 250 ml flask, add appropriate amount of dichloromethane to dissolve, add 5.5 mL (40 mmol) of triethylamine dropwise in an ice bath, and react for 3 h after naturally warming to room temperature.

[0161] Post-treatment: After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, an appropriate amount of petroleum ether was added, the sample was stirred with silica gel, and column chromatography was performed to purify 4-nitrophenyl ((1S,2S,4R)-1,7,7-trimethylbicyclo [2.2.1] heptane-2-yl) carbonate 9.31 g (yield 73%), [M+H] + :319.08.

[0162] 4-Nitrophenyl ((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) carbonate (B-linker) 1 H NMR spectroscopy ( 1 H-NMR) diagram is shown in Figure 1, 1 The H-NMR analysis is shown in Table 2.

[0163] Table 2. Target 4-nitrophenyl ((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl) carbonate 1 H-NMR analysis

[0164] 1.2 Synthesis of B-YEKLLDTEI

[0165] Support: Fmoc-Ile-Wang resin, substitution constant: 0.5 mmol / g.

[0166] 1) Synthesis of Fmoc-Glu(OtBu)-Ile-Wang resin

[0167] Weigh 1.0 g of Fmoc-Ile-Wang resin into a reactor and add 10 ml of DMF to swell for 1 hour. Filter and remove the N-terminal Fmoc group from the resin with 25% 4-methylpiperidine / DMF (volume ratio). React for 30 minutes. Remove the solvent and wash the resin five times with DMF. Weigh 1.70 g (4 mmol) of Fmoc-Glu(OtBu)-OH and 1.52 g (4 mmol) of HBTU to the resin and dissolve in DMF. Then, add NMM to initiate the reaction. The reaction endpoint is determined by ninhydrin test. If the test results indicate the reaction is complete, the reaction solution is removed and the resin is washed three times with DMF.

[0168] 2) Synthesis of Fmoc-Tyr(TBu)-Glu(TBu)-Lys(Boc)-Leu-Leu-Asp(TBu)-Thr(TBu)-Glu(TBu)-Ile-Wang resin

[0169] 25% 4-methylpiperidine / DMF (volume ratio) was added to the resin to remove the Fmoc group at the N-terminus of the resin. Then, Fmoc-Thr(tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Glu(OtBu)-OH, and Fmoc-Tyr(TBu)-OH were connected in sequence according to the same method as above. After the reaction, the resin was washed with DMF three times.

[0170] 3) Synthesis of Borneol-CO-Tyr(TBu)-Glu(TBu)-Lys(Boc)-Leu-Leu-Asp(TBu)-Thr(TBu)-Glu(TBu)-Ile-Wang Resin

[0171] 25% 4-methylpiperidine / DMF (volume ratio) was added to the resin to remove the Fmoc group at the N-terminus of the resin, and then the weighed 4-nitrophenyl ((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl) carbonate was added to the resin, an appropriate amount of DCM was added to dissolve it, and then triethylamine was added to start the reaction. After the reaction was complete (ninhydrin detection end point), the reaction liquid was removed, and the resin was washed with DMF 3 times, methanol 2 times, DCM 2 times, and methanol 2 times in sequence, and then vacuum-dried to obtain the peptide resin.

[0172] 4) Synthesis of borneol-CO-Tyr-Glu-Lys-Leu-Leu-Asp-Thr-Glu-Ile

[0173] The drained peptide resin was added to the reactor, and the lysis solution (TFA:TIS:H2O=95:2.5:2.5) was added, 10 ml per gram of peptide resin, and the reaction was stirred at room temperature for 2.5 hours. The mixture after the reaction was filtered, the filtrate was collected, and the resin was washed twice with a small amount of TFA; a centrifuge tube was prepared, ice ether was added, and then the collected filtrate was poured into the ether and stirred until the polypeptide precipitated. The centrifuge tube was then placed in a centrifuge and centrifuged. The supernatant was poured out, and the white object at the bottom of the centrifuge tube was washed twice with ether, and then placed in a vacuum desiccator and dried for more than 12 hours to obtain a crude product.

[0174] 5) Purification of borneol-CO-Tyr-Glu-Lys-Leu-Leu-Asp-Thr-Glu-Ile

[0175] The crude product was dissolved in acetonitrile and water, and the solution was loaded onto a reverse-phase HPLC column for gradient elution. The location of the product was confirmed by MS. The correct product fractions were collected and lyophilized to obtain the final product. The product purity was 99.91% (HPLC, 220 nm, C18, linear gradient) (Figure 2); [M+H] + :1303.37, [M+Na] + :1326.27.

[0176] B-YEKLLDTEI's 1 H NMR spectroscopy ( 1 H-NMR) diagram is shown in Figure 3, 1 The H-NMR spectrum is shown in Table 3.

[0177] Table 3. B-YEKLLDTEI 1 H-NMR analysis

[0178] B-YEKLLDTEI's 13 C NMR spectroscopy ( 13 C-NMR) diagram is shown in Figure 4, 13 The analysis of C-NMR spectra is shown in Table 4.

[0179] Table 4. B-YEKLLDTEI 13 C-NMR analysis

[0180] Example 2. Synthesis of B-YEKILDTEI

[0181] B-YEKILDTEI was synthesized by a method similar to that in Example 1 (B-YEKLLDTEI). Mass spectrum [M+H] + :1303.7.

[0182] Example 3. Synthesis of B-ILDTEI

[0183] B-ILDTEI was synthesized by a method similar to that of Example 1 (B-YEKLLDTEI). Mass spectrum [M+H] + :883.5.

[0184] Example 4. Synthesis of B-LDTEI

[0185] Support: Fmoc-Ile-Wang resin, substitution constant: 0.5 mmol / g.

[0186] 1) Synthesis of Fmoc-Glu(OtBu)-Ile-Wang resin

[0187] Weigh 1.0 g of Fmoc-Ile-Wang resin into a reactor and add 30 mL of DMF to swell for 30 minutes. Filter and remove the N-terminal Fmoc group from the resin with 33% 4-methylpiperidine / DMF (volume ratio). Each reaction lasts 10 minutes, for a total of two reactions. Remove the solvent and wash the resin five times with DMF. Weigh 1.7 g of Fmoc-Glu(OtBu)-OH and 1.52 g of HBTU and add them to the resin. Dissolve the resin in DMF, then add DIEA to initiate the reaction. Determine the endpoint of the reaction using the ninhydrin test. If the reaction is complete, remove the reaction solution and wash the resin five times with DMF.

[0188] 2) Synthesis of Fmoc-Leu-Asp(OTBu)-Thr(TBu)-Glu(OTBu)-Ile-Wang resin

[0189] 33% 4-methylpiperidine / DMF (volume ratio) was added to the resin to remove the Fmoc group at the N-terminus of the resin. After the reaction, the resin was washed with DMF until ninhydrin was no longer colorable to ensure that the 4-methylpiperidine was completely washed away. Then, Fmoc-Thr(tBu)-OH, Fmoc-Asp(OtBu)-OH, and Fmoc-Leu-OH were connected in sequence according to the same method as above. After the reaction, the resin was washed with DMF 5 times.

[0190] 3) Synthesis of Borneol-CO-Leu-Asp(OTBu)-Thr(TBu)-Glu(OTBu)-Ile-Wang Resin

[0191] Preparation of chloroformic acid bornyl ester intermediate:

[0192] 2 g of borneol was weighed and dissolved in about 40 mL of dichloromethane in a 100 mL eggplant-shaped flask. 2 g of triphosgene and 1.7 g of triethylamine were added and stirred at room temperature for three hours. The solvent was evaporated and vacuum-dried to obtain a crude product, which was directly used in the related peptide synthesis reaction at a volume of three equivalents.

[0193] 25% 4-methylpiperidine / DMF (volume ratio) was added to the resin to remove the Fmoc group at the N-terminus of the resin. The weighed borneol chloroformate intermediate was then added to the resin, an appropriate amount of DCM was added to dissolve it, and DIEA was added to start the reaction. After the reaction was complete (ninhydrin detection end point), the reaction liquid was removed, and the resin was washed with DMF 3 times, methanol 2 times, DCM 2 times, and methanol 2 times in sequence, and then vacuum-dried to obtain the peptide resin.

[0194] 4) Synthesis of borneol-CO-Leu-Asp-Thr-Glu-Ile-OH

[0195] The drained peptide resin was added to the reactor, and a lysis solution (TFA:TIS:H2O=95:2.5:2.5) was added, 10 mL per gram of peptide resin, and the reaction was stirred at room temperature for 2.5 hours. The mixture after the reaction was filtered, the filtrate was collected, and the resin was washed twice with a small amount of TFA; a centrifuge tube was prepared, methyl tert-butyl ether was added, and then the collected filtrate was poured into methyl tert-butyl ether and stirred until the polypeptide was precipitated. The centrifuge tube was then placed in a centrifuge and centrifuged. The supernatant was discarded, and the white object at the bottom of the centrifuge tube was washed twice with methyl tert-butyl ether, and then placed in a vacuum desiccator and dried for more than 12 hours to obtain a crude product.

[0196] 5) Purification of borneol-CO-Leu-Asp-Thr-Glu-Ile-OH

[0197] The obtained crude product was dissolved in acetonitrile and water, and the solution was loaded onto a reverse-phase high-performance liquid chromatography column for gradient elution. The location of the product was confirmed by MS detection; the correct product components were collected and freeze-dried to obtain the final product.

[0198] Purity of target product: 98.71% (HPLC, 220 nm, C18, linear gradient) (Figure 5);

[0199] Mass spectrum of target product [M+H] + :769.4;

[0200] m / z(ESI)M + +H:770.4;

[0201] B-LDTEI 1 H NMR spectroscopy ( 1 H-NMR) diagram is shown in Figure 6, 1 The H-NMR analysis is shown in Table 5.

[0202] Table 5. B-LDTEI 1 H-NMR analysis

[0203] B-LDTEI 13 C NMR spectroscopy ( 13 C-NMR) diagram is shown in Figure 7, 13 The analysis of the C-NMR spectrum is shown in Table 6.

[0204] Table 6. B-LDTEI 13 C-NMR analysis

[0205] Example 5. Synthesis of B-EACA-LDTEI

[0206] B-EACA-LDTEI was synthesized by a method similar to that in Example 4. Before the connection of borneol, Fmoc-6-aminohexanoic acid (CAS: 88574-06-5) was connected to the polypeptide as an amino acid unit. The mass spectrum [M+H] + :883.5.

[0207] Example 6. Synthesis of B-AEEP-LDTEI

[0208] B-AEEP-LDTEI was synthesized by a method similar to that in Example 4. Before the connection of borneol, Fmoc-9-amino-4,7-dioxonanoic acid (CAS: 872679-70-4) was connected to the peptide as an amino acid unit. The mass spectrum [M+H] + :929.5.

[0209] Example 7. Synthesis of B-Ac-LDTEI

[0210] Support: Fmoc-Ile-Wang resin, substitution constant: 0.5 mmol / g.

[0211] Synthesis route of borneol acetic acid:

[0212] The intermediate tert-butyl borneol acetate was synthesized as follows: (+)-borneol (1.0 g, 1.0 eq) was weighed into a 50 mL single-necked flask, 20 mL of solvent (50% NaOH / toluene (1:1)) was added, followed by tert-butyl bromoacetate (2.53 g, 2.0 eq) and TBAB (0.42 g, 0.2 eq), and the mixture was stirred at room temperature for 16 h. TLC (PE:EA = 6:1) indicated the reaction was complete. The reaction solution was diluted with 10 mL of water and extracted with EA (20 × 3 mL). The organic phase was separated and washed with saturated NaCl (10 × 3 mL). The combined organic phases were dried and purified on a silica gel column (pure PE can purify the product). The product was determined using a phosphomolybdic acid fumigation plate to yield 1.2 g of a white solid, with a yield of 70%. LC-MS: 269 [M+1] + ,tR=3.148min.

[0213] Borneol acetic acid was synthesized as follows: 1.2 g of tert-butyl borneol acetate was dissolved in 24 mL of a 1:1 TFA / DCM solution and stirred at room temperature for 2 h. TLC (DCM:MeOH = 10:1) indicated the reaction was complete. The mixture was then dried under vacuum, dissolved in ethyl acetate, and then mixed with silica gel. The sample was purified on a silica gel column (first using PE / PE = 3:1 to flush out impurities, then using pure EA to flush out the product). 0.64 g of a white solid was obtained, with a yield of 68%. LC-MS: 213 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.47(s,1H),4.05-3.88(m,2H),3.69-3.61(m,1H),2.09-2.05(m,1H),1.99-1. 88(m,1H),1.63-1.59(m,2H),1.19-1.11(m,2H),0.98-0.97(m,1H),0.85(s,3H),0.81(d,J=3.2Hz,6H).

[0214] B-Ac-LTDEI was synthesized using a method similar to Example 4, except that bornyl acetic acid and condensing agent HATU were used instead of bornyl chloroformate.

[0215] Purity of target product: 98.52% (HPLC, 220 nm, C18, linear gradient);

[0216] Mass spectrum of target product [M+H] + : 783.4; and

[0217] m / z(ESI)M + +H:784.4.

[0218] Example 8. Protective effect of a conjugate comprising borneol and a peptide on damaged primary neuronal cells

[0219] 8.1 Isolation and culture of primary neuronal cells

[0220] Preparation and configuration of the solutions required for the experiment: Surgical instruments were disinfected by soaking in 75% alcohol; 6-well plates and 35 mm dishes were coated with 100 μg / L poly-lysine at 37°C for 1 h, washed three times with PBS, then coated with 3 μg / mL laminin at 37°C for 2 h, and coated at 4°C overnight. Before use the next day, each well was rinsed twice with sterile PBS and set aside.

[0221] Fetal Mouse Dissection: After dissection, the fetus is quickly placed in ice-cold DMEM high-glucose medium. Carefully separate the cortical tissue and transfer it to a 35mm dish containing ice-cold DMEM high-glucose medium. Carefully remove the cortical vascular tissue and pia mater (the entire process is performed on a cold ice pack). The cerebral cortex is then transferred to another dish containing pre-chilled DMEM high-glucose medium. Under sterile conditions, mince the brain tissue using ophthalmic forceps. Add 2mL of papain (containing 1.5mg / mL DNase) and digest for 36 minutes (gently shaking the dish every 5 minutes). After digestion, terminate the reaction with 1mL of fetal bovine serum. Place the digested dish on ice to cool and let it rest for 2-3 minutes. Carefully remove the supernatant liquid, retaining the digested tissue pieces. Using the step-by-step pipetting method, add 1mL of neuronal cell culture medium, gently pipette 10 times, let it stand for 2 minutes, and draw the free single cells above into a 15mL centrifuge tube (cooled on ice). Add 1mL of fresh culture medium to the cell mass below, repeat the gentle pipetting, standing, and transfer for a total of 3 times. The collected single cell suspension was filtered through a 200-mesh microporous filter, centrifuged at 900rpm for 5 minutes, the supernatant was discarded, and the cells were resuspended with the neuronal cell culture medium and counted. 3-7×10 5 Cells were seeded into 100 cells / well of a poly-lysine + laminin-coated six-well plate or 35mm dish, shaken, and incubated at 37°C for 4-5 hours. The cells were then replaced with neuronal maintenance medium for continued culture. Cells from two 35mm dishes were used for neuronal identification, while cells from the remaining six-well plate were used for experimental processing. All steps except animal disinfection were performed in a cleanroom.

[0222] 8.2 Protective Effects of Conjugates Comprising Borneol and Peptides on NMDA-Induced Primary Neuronal Cell Damage

[0223] Control group 1 was primary neuronal cells cultured normally, control group 2 was primary neuronal cells treated with 100 μM NMDA and then cultured normally in culture medium, and treatment groups 1-7 were primary neuronal cells treated with 100 μM NMDA and then treated with the conjugates containing borneol and peptides and chimeric peptides shown in Table 1, all at a concentration of 100 nM. The primary neuronal cells in treatment groups 1-7 were incubated with 100 μM NMDA for 1 hour, and then the supernatant was aspirated. After washing the cells with PBS buffer, the conjugates containing borneol and peptides or chimeric peptides shown in Table 1 were added and incubated for 1 hour. The supernatant was aspirated, and after washing the cells with PBS buffer, culture medium was added and cultured for 20 hours before using mammalian cell LIVE / DEAD. TM Cell viability / cytotoxicity assay was performed using a cell viability / cytotoxicity kit.

[0224] The results are shown in Figure 8: The cell death rate in control group 1 was close to 20%, and the cell death rate in control group 2 was approximately 50%. The results of treatment groups 2-3 showed that the administration of 100 nM B-9-mer-1 or B-9-mer-2 after NMDA treatment had a significant protective effect against NMDA-induced cell damage, which was comparable to the protective effect of TAT-9-mer in treatment group 1. Further truncation of the amino acid sequences of the B-9-mer-1 and B-9-mer-2 conjugates, retaining the C-terminal 5-6 amino acids, to form B-5-mer and B-6-mer conjugates, still retained the neuroprotective effects of these peptides. However, the neuroprotective effect was reduced after the TAT transmembrane guide peptide was added to these short peptides.

[0225] 8.3 Protective Effects of Conjugates of Camphene and Peptides Containing Different Linkers on NMDA-Induced Primary Neuronal Cell Damage

[0226] Control group 1 was a normal culture of primary neuronal cells, control group 2 was a normal culture of primary neuronal cells after being treated with 100 μM NMDA and then using culture medium, and treatment groups 1-4 were groups treated with 100 μM NMDA and then treated with the conjugates containing borneol and peptides numbered 5 and 8-10 shown in Table 1, all at a concentration of 100 nM. The primary neuronal cells of treatment groups 1-4 were incubated with 100 μM NMDA for 1 hour, and then the supernatant was aspirated. After washing the cells with PBS buffer, the conjugates containing borneol and peptides numbered 5 and 8-10 shown in Table 1 were added and incubated for 1 hour, and then the supernatant was aspirated. After washing the cells with PBS buffer, culture medium was added and cultured for 20 hours before using mammalian cell LIVE / DEAD. TM Cell viability / cytotoxicity assay was performed using a cell viability / cytotoxicity kit.

[0227] The results are shown in Figure 9: the cell death rate of control group 1 was 21%, and the cell death rate of control group 2 was 48%. The results of treatment groups 1-4 showed that administration of 100 nM B-5-mer, B-EACA-5-mer, B-AEEP-5-mer or B-Ac-5-mer after NMDA treatment had a significant protective effect on NMDA-induced cell damage. The protective effect of treatment groups 2, 3 and 4 was equivalent to that of treatment group 1 B-5-mer.

[0228] 8.4 Protective Effects of Conjugates Comprising Borneol and Peptides on Hemin-Induced Primary Neuronal Cell Injury

[0229] Treatment of primary cortical neurons with hemin can induce cell death. Hemin was dissolved in 0.1 M NaOH to prepare a stock solution, which was diluted to 80 μM before use; the conjugates or chimeric peptides containing borneol and peptides shown in Table 1 were used at a concentration of 100 nM. Control group 1 consisted of normally cultured primary neuronal cells, control group 2 consisted of primary neuronal cells treated with 80 μM hemin and then cultured normally in culture medium, and treatment groups 1-7 consisted of primary neuronal cells treated with 80 μM hemin and then treated with the conjugates or chimeric peptides containing borneol and peptides numbered 1-7 shown in Table 1. For neuroprotection studies, cells were treated with the conjugates or chimeric peptides containing borneol and peptides shown in Table 1 for 16 hours before cell viability analysis. The protective effect of the conjugates or chimeric peptides against hemin-induced cell death was verified by calcein-AM / ethidium homodimer 1 staining in D-PBS (live / dead assay, Thermo Fisher Scientific).

[0230] The results are shown in Figure 10: The cell death rate in control group 1 was close to 20%, and the cell death rate in control group 2 was around 50%. The results of treatment groups 2-3 showed that the administration of 100nM B-9-mer-1 or B-9-mer-2 after hemin treatment had a significant protective effect against hemin-induced cell damage, which was comparable to the protective effect of TAT-9-mer in treatment group 1. Further truncation of the amino acid sequence in the B-9-mer-2 conjugate to retain the C-terminal 5 (LDTEI) or 6 amino acids (ILDTEI) still retained the neuroprotective effects of these peptides. However, the neuroprotective effect was reduced after the TAT transmembrane guide peptide was added in front of this short peptide.

[0231] Example 9. Protective effect of a conjugate comprising borneol and a peptide on rats with ischemia-reperfusion

[0232] Before the experiment, the rats were kept in a quiet environment for 2-3 days and were free to eat and drink during the feeding period. The preparation of the focal cerebral ischemia-reperfusion model was based on the reversible middle cerebral artery occlusion (MCAO) suture method proposed by Longa, and was improved according to the rat brain anatomical structure diagram to prepare a focal cerebral ischemia-reperfusion model. After 1 hour of cerebral ischemia, the suture was withdrawn to form reperfusion, and at the same time, 10 mg / kg body weight (5 ml / kg body weight) of the conjugate or chimeric peptide containing borneol and peptide shown in Table 1 was injected into the tail vein. The model control group was not treated with peptides. TTC staining was performed 24 hours after the ischemia-reperfusion animal model was established.

[0233] The results are shown in Figures 11 and 12: The percentages of cerebral infarction volume in rats treated with the conjugates or chimeric peptides comprising borneol and a peptide, numbered 1-7 as shown in Table 1, were 26.18±16.0%, 39.66±17.43%, 23.09±12.89%, 42.91±6.26%, 52.73±14.17%, 32.14±11.77% and 36.10±9.21%, respectively. Among them, the percentages of infarction volume in rats treated with TAT-9-mer and B-9-mer-1 were statistically significantly different from those in the model control group (45.82±12.94%) (p<0.01), and the percentages of infarction volume in rats treated with truncated amino acid sequences, B-5-mer and B-6-mer, were statistically significantly different from those in the model control group (45.53±8.66%) (p<0.05).

[0234] Example 10. Preliminary evaluation of the safety of the conjugate containing borneol and peptide by rat skin allergy test

[0235] A modified Miles assay was performed in rats. The procedure was as follows: The rats were shaved on the back and sides of the spine, and injected intravenously with 0.5% EB in saline at a dose of 2 mL / kg body weight. Ten minutes after the intravenous injection of EB, the rats were anesthetized with chloral hydrate via intraperitoneal injection. Conjugates or chimeric peptides containing borneol and peptides (numbered 1-7) listed in Table 1 were injected intradermally at different sites along the spine from the cranial to the caudal region. Each peptide was injected at two sites, with 50 μL injected into each site. Each peptide was diluted with saline to the same concentration (10 mg / mL) and injected in equal volumes. Compound 48 / 80 (C48 / 80) was used as a positive control drug in the experiment, inducing intradermal blue plaques in rats; a control group was injected with saline. Twenty minutes later, the formation of blue plaques in the skin was observed, and their size and color intensity were measured using Image J software.

[0236] The results are shown in Figures 13-15: The size of the blue spots produced by B-9-mer-1, B-9-mer-2, B-5-mer and B-6-mer in rat skin was not significantly different from that in the normal saline group, indicating good safety.

[0237] All publications and patent documents cited in this specification are incorporated herein by reference, as if each publication or patent was expressly indicated to be incorporated herein by reference. Without departing from the true idea and scope of the present disclosure, various changes and equivalents may be made to each embodiment disclosed in the present application. Unless otherwise indicated in the context, any feature, step or embodiment of the embodiment of the present disclosure may be used in combination with any other feature, step or embodiment.

Claims

1. A conjugate comprising borneol and a peptide, wherein The peptide comprises LDTEI (SEQ ID NO: 1) or a variant of SEQ ID NO: 1 having one or more conservative substitutions, wherein the conservative substitutions are selected from the group consisting of substitutions between aspartic acid (D) and glutamic acid (E), substitutions between leucine (L), valine (V) and isoleucine (I), and substitutions between threonine (T) and serine (S); Optionally, borneol is located on the N-terminal side of the peptide.

2. The conjugate of claim 1 , wherein a variant of SEQ ID NO: 1 is selected from the group consisting of: LDTEL (SEQ ID NO: 2), LDTEV (SEQ ID NO: 3), LDTDI (SEQ ID NO: 4), LDTDL (SEQ ID NO: 5), LDTDV (SEQ ID NO: 6), LDSEI (SEQ ID NO: 7), LDSEL (SEQ ID NO: 8), LDSEV (SEQ ID NO: 9), LDSDI (SEQ ID NO: 10), LDSDL (SEQ ID NO: 11), LDSDV (SEQ ID NO: 12), LETEI (SEQ ID NO: 13), LETEL (SEQ ID NO: 14), LETEV (SEQ ID NO: 15), LETDI (SEQ ID NO: 16), LETDL (SEQ ID NO: 17), LETDV (SEQ ID NO: 18), VDTEI (SEQ ID NO: 19), VDTEL (SEQ ID NO: 20), VDTEV (SEQ ID NO: 21), VDTDI (SEQ ID NO: 22). NO:22), VDTDL (SEQ ID NO:23), VDTDV (SEQ ID NO:24), IDTEI (SEQ ID NO:25), IDTEL (SEQ ID NO:26), IDTEV (SEQ ID NO:27), IDTDI (SEQ ID NO:28), IDTDL (SEQ ID NO:29), IDTDV (SEQ ID NO:30), IETEI (SEQ and / or The borneol is dextrorotatory borneol, racemic borneol or levorotatory borneol; preferably, the borneol is dextrorotatory borneol.

3. A conjugate comprising borneol and a peptide, wherein The peptide comprises LLDTEI (SEQ ID NO: 37), CLDTEI (SEQ ID NO: 689), or a variant of SEQ ID NO: 37 or 689 having one or more conservative substitutions, wherein the conservative substitutions are selected from substitutions between D and E, substitutions between L, V and I, and substitutions between T and S; Optionally, borneol is located on the N-terminal side of the peptide.

4. The conjugate according to claim 3, wherein the variant of SEQ ID NO: 37 or 689 is selected from: LLDTEL (SEQ ID NO: 38), LLDTEV (SEQ ID NO: 39), LLDTDI (SEQ ID NO: 40), LLDTDL (SEQ ID NO: 41), LLDTDV (SEQ ID NO: 42), LLDSEI (SEQ ID NO: 43), LLDSEL (SEQ ID NO: 44), LLDSEV (SEQ ID NO: 45), LLDSDI (SEQ ID NO: 46), LLDSDL (SEQ ID NO: 47), LLDSDV (SEQ ID NO: 48), LLETEI (SEQ ID NO: 49), LLETEL (SEQ ID NO: 50), LLETEV (SEQ ID NO: 51), LLETDI (SEQ ID NO: 52), LLETDL (SEQ ID NO: 53), LLETDV (SEQ ID NO: 54), LVDTEI (SEQ ID NO: 55), LVDTEL (SEQ ID NO: 56), LVDTEV (SEQ ID NO: 57), LVDTDI (SEQ ID NO: 58), LVDTDL (SEQ ID NO: 59), LVDTDV (SEQ ID NO: 60), LIDTEI (SEQ ID NO: 61), LIDTEL (SEQ ID NO: 62), LIDTEV (SEQ ID NO: 63), LIDTDI (SEQ ID NO: 64), LIDTDL (SEQ ID NO: 65), LIDTDV (SEQ ID NO: 66), LIETEI (SEQ ID NO: 67), LIETEL (SEQ ID NO: 68), LIETEV (SEQ ID NO: 69), LIETDI (SEQ ID NO: 70), LIETDL (SEQ ID NO: 71), LIETDV (SEQ ID NO: 72), LIESDV (SEQ ID NO: 73), LIESDI (SEQ ID NO: 74), LIESDL (SEQ ID NO: 75), LIESEI (SEQ ID NO: 76), LIESEL (SEQ ID NO: 77), LIESEV (SEQ ID NO: 78), LIDSDV (SEQ ID NO: 79), LIDSDI (SEQ ID NO: 80), LIDSDL (SEQ ID NO: 81), LIDSEI (SEQ ID NO: 82), LIDSEL (SEQ IDNO:83)、LIDSEV(SEQ ID NO:84)、LLESDV(SEQ ID NO:85)、LLESDI(SEQ ID NO:86)、LLESDL(SEQ ID NO:87)、LLESEI(SEQ ID NO:88)、LLESEL(SEQ ID NO:89)、LLESEV(SEQ ID NO:90)、LVESDV(SEQ ID NO:91)、LVESDI(SEQ ID NO:92)、LLVESDL(SEQ ID NO:93)、LVESEI(SEQ ID NO:94)、LVESEL(SEQ ID NO:95)、LVESEV(SEQ ID NO:96)、LVDSEI(SEQ ID NO:97)、LVDSEL(SEQ ID NO:98)、LVDSEV(SEQ ID NO:99)、LVDSDI(SEQ ID NO:100)、LVDSDL(SEQ ID NO:101)、LVDSDV(SEQ ID NO:102)、LVETEI(SEQ ID NO:103)、LVETEL(SEQ ID NO:104)、LVETEV(SEQ ID NO:105)、LVETDI(SEQ ID NO:106)、LVETDL(SEQ ID NO:107)、LVETDV(SEQ ID NO:108)、ILDTEI(SEQ ID NO:109)、ILDTEL(SEQ ID NO:110)、ILDTEV(SEQ ID NO:111)、ILDTDI(SEQ ID NO:112)、ILDTDL(SEQ ID NO:113)、ILDTDV(SEQ ID NO:114)、ILDSEI(SEQ ID NO:115)、ILDSEL(SEQ ID NO:116)、ILDSEV(SEQ ID NO:117)、ILDSDI(SEQ ID NO:118)、ILDSDL(SEQ ID NO:119)、ILDSDV(SEQ ID NO:120)、ILETEI(SEQ ID NO:121)、ILETEL(SEQ ID NO:122)、ILETEV(SEQ ID NO:123)、ILETDI(SEQ ID NO:124)、ILETDL(SEQ ID NO:125)、ILETDV(SEQ ID NO:126)、IVDTEI(SEQ ID NO:127)、IVDTEL(SEQ ID NO:128)、IVDTEV(SEQ IDNO:129)、IVDTDI(SEQ ID NO:130)、IVDTDL(SEQ ID NO:131)、IVDTDV(SEQ ID NO:132)、IIDTEI(SEQ ID NO:133)、IIDTEL(SEQ ID NO:134)、IIDTEV(SEQ ID NO:135)、IIDTDI(SEQ ID NO:136)、IIDTDL(SEQ ID NO:137)、IIDTDV(SEQ ID NO:138)、IIETEI(SEQ ID NO:139)、IIETEL(SEQ ID NO:140)、IIETEV(SEQ ID NO:141)、IIETDI(SEQ ID NO:142)、IIETDL(SEQ ID NO:143)、IIETDV(SEQ ID NO:144)、IIESDV(SEQ ID NO:145)、IIESDI(SEQ ID NO:146)、IIETDL(SEQ ID NO:143) NO:147), IIESEI(SEQ ID NO:148), IIESEL(SEQ ID NO:149), IIESEV(SEQ ID NO:150), IIDSDV(SEQ ID NO:151), IIDSDI(SEQ ID NO:152), IIDSDL(SEQ ID NO:153), IIDSEI(SEQ ID NO:154), IIDSEL(SEQ ID NO:155), IIDSEV(SEQ ID NO:156), ILESDV(SEQ ID NO:157), ILESDI(SEQ ID NO:158), ILESDL(SEQ ID NO:159), ILESEI(SEQ ID NO:160), ILESEL(SEQ ID NO:161), ILESEV(SEQ ID NO:162), IVESDV(SEQ ID NO:163), IVESDI(SEQ ID NO:164), IVESDL(SEQ ID NO:165), IVESEI(SEQ ID NO:166)、IVESEL(SEQ ID NO:167)、IVESEV(SEQ ID NO:168)、IVDSEI(SEQ ID NO:169)、IVDSEL(SEQ ID NO:170)、IVDSEV(SEQ ID NO:171)、IVDSDI(SEQ ID NO:172)、IVDSDL(SEQ ID NO:173)、IVDSDV(SEQ ID NO:171)NO:174)、IVETEI(SEQ ID NO:175)、IVETEL(SEQ ID NO:176)、IVETEV(SEQ ID NO:177)、IVETDI(SEQ ID NO:178)、IVETDL(SEQ ID NO:179)、IVETDV(SEQ ID NO:180)、VLDTEI(SEQ ID NO:181)、VLDTEL(SEQ ID NO:182)、VLDTEV(SEQ ID NO:183)、VLDTDI(SEQ ID NO:184)、VLDTDL(SEQ ID NO:185)、VLDTDV(SEQ ID NO:186)、VLDSEI(SEQ ID NO:187)、VLDSEL(SEQ ID NO:188)、VLDSEV(SEQ ID NO:189)、VLDSDI(SEQ ID NO:190)、VLDSDL(SEQ ID NO:191)、VLDSDV(SEQ ID NO:192)、VLETEI(SEQ ID NO:193)、VLETEL(SEQ ID NO:194)、VLETEV(SEQ ID NO:195)、VLETDI(SEQ ID NO:196)、VVLETDL(SEQ ID NO:197)、VLETDV(SEQ ID NO:198)、VVDTEI(SEQ ID NO:199)、VVDTEL(SEQ ID NO:200)、VVDTEV(SEQ ID NO:201)、VVDTDI(SEQ ID NO:202)、VVDTDL(SEQ ID NO:203)、VVDTDV(SEQ ID NO:204)、VIDTEI(SEQ ID NO:205)、VIDTEL(SEQ ID NO:206)、VIDTEV(SEQ ID NO:207)、VIDTDI(SEQ ID NO:208)、VIDTDL(SEQ ID NO:209)、VIDTDV(SEQ ID NO:210)、VIETEI(SEQ ID NO:211)、VIETEL(SEQ ID NO:212)、VIETEV(SEQ ID NO:213)、VIETDI(SEQ ID NO:214)、VIETDL(SEQ ID NO:215)、VIETDV(SEQ ID NO:216)、VIESDV(SEQ ID NO:217)、VIESDI(SEQ ID NO:218)、VIESDL(SEQ IDNO:219)、VIESEI(SEQ ID NO:220)、VIESEL(SEQ ID NO:221)、VIESEV(SEQ ID NO:222)、VIDSDV(SEQ ID NO:223)、VIDSDI(SEQ ID NO:224)、VIDSDL(SEQ ID NO:225)、VIDSEI(SEQ ID NO:226)、VIDSEL(SEQ ID NO:227)、VIDSEV(SEQ ID NO:228)、VLESDV(SEQ ID NO:229)、VLESDI(SEQ ID NO:230)、VLESDL(SEQ ID NO:231)、VLESEI(SEQ ID NO:232)、VLESEL(SEQ ID NO:233)、VLESEV(SEQ ID NO:234)、VVESDV(SEQ ID NO:235)、VVESDI(SEQ ID NO:236)、VVESDL(SEQ ID NO:237)、VVESEI(SEQ ID NO:238)、VVESEL(SEQ ID NO:239)、VVESEV(SEQ ID NO:240)、VVDSEI(SEQ ID NO:241)、VVDSEL(SEQ ID NO:242)、VVDSEV(SEQ ID NO:243)、VVDSDI(SEQ ID NO:244)、VVDSDL(SEQ ID NO:245)、VVDSDV(SEQ ID NO:246)、VVETEI(SEQ ID NO:247)、VVETEL(SEQ ID NO:248)、VVETEV(SEQ ID NO:249)、VVETDI(SEQ ID NO:250)、VVETDL(SEQ ID NO:251)、VVETDV(SEQ ID NO:252)、CLDTEL(SEQ ID NO:690)、CLDTEV(SEQ ID NO:691)、CLDTDI(SEQ ID NO:692)、CLDTDL(SEQ ID NO:693)、CLDTDV(SEQ ID NO:694)、CLDSEI(SEQ ID NO:695)、CLDSEL(SEQ ID NO:696)、CLDSEV(SEQ ID NO:697)、CLDSDI(SEQ ID NO:698)、CLDSDL(SEQ ID NO:699)、CLDSDV(SEQ ID NO:700)、CLETEI(SEQ IDNO:701), CLETEL (SEQ ID NO:702), CLETEV (SEQ ID NO:703), CLETDI (SEQ ID NO:704), CLETDL (SEQ ID NO:705), CLETDV (SEQ ID NO:706), CVDTEI (SEQ ID NO:707), CVDTEL (SEQ ID NO:708), CVDTEV (SEQ ID NO:709), CVDTDI (SEQ ID NO:710), CVDTDL (SEQ ID NO:711), CVDTDV (SEQ ID NO:712), CIDTEI (SEQ ID NO:713), CIDTEL (SEQ ID NO:714), CIDTEV (SEQ ID NO:715), CIDTDI (SEQ ID NO:716), CIDTDL (SEQ ID NO:717), CIDTDV (SEQ ID NO:718), CIETEI (SEQ ID NO:719), CIETEL (SEQ ID NO:720), CIETEV (SEQ ID NO:721), CIETDI (SEQ ID NO:722), CIETDL (SEQ ID NO:723) and CIETDV (SEQ ID NO:724); and / or The borneol is dextrorotatory borneol, racemic borneol or levorotatory borneol; preferably, the borneol is dextrorotatory borneol.

5. A conjugate comprising borneol and a peptide, wherein The peptide comprises YEKLLDTEI (SEQ ID NO: 253) or a variant of SEQ ID NO: 253 having one or more conservative substitutions, wherein the conservative substitutions are selected from substitutions between D and E, substitutions between L, V and I, and substitutions between T and S; Preferably, variants of SEQ ID NO:253 are selected from: YEKLLDTEL (SEQ ID NO:254), YEKLLDTEV (SEQ ID NO:255), YEKLLDTDI (SEQ ID NO:256), YEKLLDTDL (SEQ ID NO:257), YEKLLDTDV (SEQ ID NO:258), YEKLLDSEI (SEQ ID NO:259), YEKLLDSEL (SEQ ID NO:260), YEKLLDSEV (SEQ ID NO:261), YEKLLDSDI (SEQ ID NO:262), YEKLLDSDL (SEQ ID NO:263), YEKLLDSDV (SEQ ID NO:264), YEKLLETEI (SEQ ID NO:265), YEKLLETEL (SEQ ID NO:266), YEKLLETEV (SEQ ID NO:267), YEKLLETDI (SEQ ID NO:268), YEKLLETDL (SEQ ID NO:269), YEKLLETDV (SEQ ID NO:270), YEKLVDTEI (SEQ ID NO:271), YEKLVDTEL (SEQ ID NO:272), YEKLVDTEV (SEQ ID NO:273), YEKLVDTDI (SEQ ID NO:274), YEKLVDTDL (SEQ ID NO:275), YEKLVDTDV (SEQ ID NO:276), YEKLIDTEI (SEQ ID NO:277), YEKLIDTEL (SEQ ID NO:278), YEKLIDTEV (SEQ ID NO:279), YEKLIDTDI (SEQ ID NO:280), YEKLIDTDL (SEQ ID NO:281), YEKLIDTDV (SEQ ID NO:282), YEKLIETEI (SEQ ID NO:283), YEKLIETEL (SEQ ID NO:284), YEKLIETEV (SEQ ID NO:285), YEKLIETDI (SEQ ID NO:286), YEKLIETDL (SEQ ID NO:287), YEKLIETDV (SEQ ID NO:288), YEKLIESDV (SEQ ID NO:289), YEKLIESDI (SEQ ID NO:290), YEKLIESDL (SEQ ID NO:291), YEKLIESEI (SEQ ID<h2 style=";text-align:left;direction:ltr">NO:292)、YEKLIESEL(SEQ ID NO:293)、YEKLIESEV(SEQ ID NO:294)、YEKLIDSDV(SEQ ID NO:295)、YEKLIDSDI(SEQ ID NO:296)、YEKLIDSDL(SEQ ID NO:297)、YEKLIDSEI(SEQ ID NO:298)、YEKLIDSEL(SEQ ID NO:299)、YEKLIDSEV(SEQ ID NO:300)、YEKLLESDV(SEQ ID NO:301)、YEKLLESDI(SEQ ID NO:302)、YEKLLESDL(SEQ ID NO:303)、YEKLLESEI(SEQ ID NO:304)、YEKLLESEL(SEQ ID NO:305)、YEKLLESEV(SEQ ID NO:306)、YEKLVESDV(SEQ ID NO:307)、YEKLVESDI(SEQ ID NO:308)、YEKLLVESDL(SEQ ID NO:309)、YEKLVESEI(SEQ ID NO:310)、YEKLVESEL(SEQ ID NO:311)、YEKLVESEV(SEQ ID NO:312)、YEKLVDSEI(SEQ ID NO:313)、YEKLVDSEL(SEQ ID NO:314)、YEKLVDSEV(SEQ ID NO:315)、YEKLVDSDI(SEQ ID NO:316)、YEKLVDSDL(SEQ ID NO:317)、YEKLVDSDV(SEQ ID NO:318)、YEKLVETEI(SEQ ID NO:319)、YEKLVETEL(SEQ ID NO:320)、YEKLVETEV(SEQ ID NO:321)、YEKLVETDI(SEQ ID NO:322)、YEKLVETDL(SEQ ID NO:323)、YEKLVETDV(SEQ ID NO:324)、YEKILDTEI(SEQ ID NO:325)、YEKILDTEL(SEQ ID NO:326)、YEKILDTEV(SEQ ID NO:327)、YEKILDTDI(SEQ ID NO:328)、YEKILDTDL(SEQ ID NO:329)、YEKILDTDV(SEQ ID NO:330)、YEKILDSEI(SEQ ID NO:331)、YEKILDSEL(SEQ IDNO:332)、YEKILDSEV(SEQ ID NO:333)、YEKILDSDI(SEQ ID NO:334)、YEKILDSDL(SEQ ID NO:335)、YEKILDSDV(SEQ ID NO:336)、YEKILETEI(SEQ ID NO:337)、YEKILETEL(SEQ ID NO:338)、YEKILETEV(SEQ ID NO:339)、YEKILETDI(SEQ ID NO:340)、YEKILETDL(SEQ ID NO:341)、YEKILETDV(SEQ ID NO:342)、YEKIVDTEI(SEQ ID NO:343)、YEKIVDTEL(SEQ ID NO:344)、YEKIVDTEV(SEQ ID NO:345)、YEKIVDTDI(SEQ ID NO:346)、YEKIVDTDL(SEQ ID NO:347)、YEKIVDTDV(SEQ ID NO:348)、YEKIIDTEI(SEQ ID NO:349)、YEKIIDTEL(SEQ ID NO:350)、YEKIIDTEV(SEQ ID NO:351)、YEKIIDTDI(SEQ ID NO:352)、YEKIIDTDL(SEQ ID NO:353)、YEKIIDTDV(SEQ ID NO:354)、YEKIIETEI(SEQ ID NO:355)、YEKIIETEL(SEQ ID NO:356)、YEKIIETEV(SEQ ID NO:357)、YEKIIETDI(SEQ ID NO:358)、YEKIIETDL(SEQ ID NO:359)、YEKIIETDV(SEQ ID NO:360)、YEKIIESDV(SEQ ID NO:361)、YEKIIESDI(SEQ ID NO:362)、YEKIIESDL(SEQ ID NO:363)、YEKIIESEI(SEQ ID NO:364)、YEKIIESEL(SEQ ID NO:365)、YEKIIESEV(SEQ ID NO:366)、YEKIIDSDV(SEQ ID NO:367)、YEKIIDSDI(SEQ ID NO:368)、YEKIIDSDL(SEQ ID NO:369)、YEKIIDSEI(SEQ ID NO:370)、YEKIIDSEL(SEQ ID NO:371)、YEKIIDSEV(SEQ IDNO:372)、YEKILESDV(SEQ ID NO:373)、 YEKILESDI(SEQ ID NO:374)、YEKILESDL(SEQ ID NO:375)、YEKILESEI(SEQ ID NO:376)、YEKILESEL(SEQ ID NO:377)、YEKILESEV(SEQ ID NO:378)、YEKIVESDV(SEQ ID NO:379)、YEKIVESDI(SEQ ID NO:380)、YEKIVESDL(SEQ ID NO:381)、YEKIVESEI(SEQ ID NO:382)、YEKIVESEL(SEQ ID NO:383)、YEKIVESEV(SEQ ID NO:384)、YEKIVDSEI(SEQ ID NO:385)、YEKIVDSEL(SEQ ID NO:386)、YEKIVDSEV(SEQ ID NO:387)、YEKIVDSDI(SEQ ID NO:388)、YEKIVDSDL(SEQ ID NO:389)、YEKIVDSDV(SEQ ID NO:390)、YEKIVETEI(SEQ ID NO:391)、YEKIVETEL(SEQ ID NO:392)、YEKIVETEV(SEQ ID NO:393)、YEKIVETDI(SEQ ID NO:394)、YEKIVETDL(SEQ ID NO:395)、YEKIVETDV(SEQ ID NO:396)、YEKVLDTEI(SEQ ID NO:397)、YEKVLDTEL(SEQ ID NO:398)、YEKVLDTEV(SEQ ID NO:399)、YEKVLDTDI(SEQ ID NO:400)、YEKVLDTDL(SEQ ID NO:401)、YEKVLDTDV(SEQ ID NO:402)、YEKVLDSEI(SEQ ID NO:403)、YEKVLDSEL(SEQ ID NO:404)、YEKVLDSEV(SEQ ID NO:405)、YEKVLDSDI(SEQ ID NO:406)、YEKVLDSDL(SEQ ID NO:407)、YEKVLDSDV(SEQ ID NO:408)、YEKVLETEI(SEQ ID NO:409)、YEKVLETEL(SEQ ID NO:410)、YEKVLETEV(SEQ ID NO:411)、YEKVLETDI(SEQ ID NO:412)、YEKVVLETDL(SEQ IDNO:413)、YEKVLETDV(SEQ ID NO:414)、YEKVVDTEI(SEQ ID NO:415)、YEKVVDTEL(SEQ ID NO:416)、YEKVVDTEV(SEQ ID NO:417)、YEKVVDTDI(SEQ ID NO:418)、YEKVVDTDL(SEQ ID NO:419)、YEKVVDTDV(SEQ ID NO:420)、YEKVIDTEI(SEQ ID NO:421)、YEKVIDTEL(SEQ ID NO:422)、YEKVIDTEV(SEQ ID NO:423)、YEKVIDTDI(SEQ ID NO:424)、YEKVIDTDL(SEQ ID NO:425)、YEKVIDTDV(SEQ ID NO:426)、YEKVIETEI(SEQ ID NO:427)、YEKVIETEL(SEQ ID NO:428)、YEKVIETEV(SEQ ID NO:429)、YEKVIETDI(SEQ ID NO:430)、YEKVIETDL(SEQ ID NO:431)、YEKVIETDV(SEQ ID NO:432)、YEKVIESDV(SEQ ID NO:433)、YEKVIESDI(SEQ ID NO:434)、YEKVIESDL(SEQ ID NO:435)、YEKVIESEI(SEQ ID NO:436)、YEKVIESEL(SEQ ID NO:437)、YEKVIESEV(SEQ ID NO:438)、YEKVIDSDV(SEQ ID NO:439)、YEKVIDSDI(SEQ ID NO:440)、YEKVIDSDL(SEQ ID NO:441)、YEKVIDSEI(SEQ ID NO:442)、YEKVIDSEL(SEQ ID NO:443)、YEKVIDSEV(SEQ ID NO:444)、YEKVLESDV(SEQ ID NO:445)、YEKVLESDI(SEQ ID NO:446)、YEKVLESDL(SEQ ID NO:447)、YEKVLESEI(SEQ ID NO:448)、YEKVLESEL(SEQ ID NO:449)、YEKVLESEV(SEQ ID NO:450)、YEKVVESDV(SEQ ID NO:451)、YEKVVESDI(SEQ ID NO:452)、YEKVVESDL(SEQ IDNO:453)、YEKVVESEI(SEQ ID NO:454)、YEKVVESEL(SEQ ID NO:455)、YEKVVESEV(SEQ ID NO:456)、YEKVVDSEI(SEQ ID NO:457)、YEKVVDSEL(SEQ ID NO:458)、YEKVVDSEV(SEQ ID NO:459)、YEKVVDSDI(SEQ ID NO:460)、YEKVVDSDL(SEQ ID NO:461)、YEKVVDSDV(SEQ ID NO:462)、YEKVVETEI(SEQ ID NO:463)、YEKVVETEL(SEQ ID NO:464)、YEKVVETEV(SEQ ID NO:465)、YEKVVETDI(SEQ ID NO:466)、YEKVVETDL(SEQ ID NO:467)、YEKVVETDV(SEQ ID NO:468)、YDKLLDTEI(SEQ ID NO:469)、YDKLLDTEL(SEQ ID NO:470)、YDKLLDTEV(SEQ ID NO:471)、YDKLLDTDI(SEQ ID NO:472)、YDKLLDTDL(SEQ ID NO:473)、YDKLLDTDV(SEQ ID NO:474)、YDKLLDSEI(SEQ ID NO:475)、YDKLLDSEL(SEQ ID NO:476)、YDKLLDSEV(SEQ ID NO:477)、YDKLLDSDI(SEQ ID NO:478)、YDKLLDSDL(SEQ ID NO:479)、YDKLLDSDV(SEQ ID NO:480)、YDKLLETEI(SEQ ID NO:481)、YDKLLETEL(SEQ ID NO:482)、YDKLLETEV(SEQ ID NO:483)、YDKLLETDI(SEQ ID NO:484)、YDKLLETDL(SEQ ID NO:485)、YDKLLETDV(SEQ ID NO:486)、YDKLVDTEI(SEQ ID NO:487)、YDKLVDTEL(SEQ ID NO:488)、YDKLVDTEV(SEQ ID NO:489)、YDKLVDTDI(SEQ ID NO:490)、YDKLVDTDL(SEQ ID NO:491)、YDKLVDTDV(SEQ ID NO:492)、YDKLIDTEI(SEQ IDNO:493)、YDKLIDTEL(SEQ ID NO:494)、YDKLIDTEV(SEQ ID NO:495)、YDKLIDTDI(SEQ ID NO:496)、YDKLIDTDL(SEQ ID NO:497)、YDKLIDTDV(SEQ ID NO:498)、YDKLIETEI(SEQ ID NO:499)、YDKLIETEL(SEQ ID NO:500)、YDKLIETEV(SEQ ID NO:501)、YDKLIETDI(SEQ ID NO:502)、YDKLIETDL(SEQ ID NO:503)、YDKLIETDV(SEQ ID NO:504)、YDKLIESDV(SEQ ID NO:505)、YDKLIESDI(SEQ ID NO:506)、YDKLIESDL(SEQ ID NO:507)、YDKLIESEI(SEQ ID NO:508)、YDKLIESEL(SEQ ID NO:509)、YDKLIESEV(SEQ ID NO:510)、YDKLIDSDV(SEQ ID NO:511)、YDKLIDSDI(SEQ ID NO:512)、YDKLIDSDL(SEQ ID NO:513)、YDKLIDSEI(SEQ ID NO:514)、YDKLIDSEL(SEQ ID NO:515)、YDKLIDSEV(SEQ ID NO:516)、YDKLLESDV(SEQ ID NO:517)、YDKLLESDI(SEQ ID NO:518)、YDKLLESDL(SEQ ID NO:519)、YDKLLESEI(SEQ ID NO:520)、YDKLLESEL(SEQ ID NO:521)、YDKLLESEV(SEQ ID NO:522)、YDKLVESDV(SEQ ID NO:523)、YDKLVESDI(SEQ ID NO:524)、YDKLLVESDL(SEQ ID NO:525)、YDKLVESEI(SEQ ID NO:526)、YDKLVESEL(SEQ ID NO:527)、YDKLVESEV(SEQ ID NO:528)、YDKLVDSEI(SEQ ID NO:529)、YDKLVDSEL(SEQ ID NO:530)、YDKLVDSEV(SEQ ID NO:531)、YDKLVDSDI(SEQ ID NO:532)、YDKLVDSDL(SEQ ID NO:533)、YDKLVDSDV(SEQ ID NO:534)、YDKLVETEI(SEQ ID NO:535)、YDKLVETEL(SEQ ID NO:536)、YDKLVETEV(SEQ ID NO:537)、YDKLVETDI(SEQ ID NO:538)、YDKLVETDL(SEQ ID NO:539)、YDKLVETDV(SEQ ID NO:540)、YDKILDTEI(SEQ ID NO:541)、YDKILDTEL(SEQ ID NO:542)、YDKILDTEV(SEQ ID NO:543)、YDKILDTDI(SEQ ID NO:544)、YDKILDTDL(SEQ ID NO:545)、YDKILDTDV(SEQ ID NO:546)、YDKILDSEI(SEQ ID NO:547)、YDKILDSEL(SEQ ID NO:548)、YDKILDSEV(SEQ ID NO:549)、YDKILDSDI(SEQ ID NO:550)、YDKILDSDL(SEQ ID NO:551)、YDKILDSDV(SEQ ID NO:552)、YDKILETEI(SEQ ID NO:553)、YDKILETEL(SEQ ID NO:554)、YDKILETEV(SEQID NO:555)、YDKILETDI(SEQ ID NO:556)、YDKILETDL(SEQ ID NO:557)、YDKILETDV(SEQ ID NO:558)、YDKIVDTEI(SEQ ID NO:559)、YDKIVDTEL(SEQ ID NO:560)、YDKIVDTEV(SEQ ID NO:561)、YDKIVDTDI(SEQ ID NO:562)、YDKIVDTDL(SEQ ID NO:563)、YDKIVDTDV(SEQ ID NO:564)、YDKIIDTEI(SEQ ID NO:565)、YDKIIDTEL(SEQ ID NO:566)、YDKIIDTEV(SEQ ID NO:567)、YDKIIDTDI(SEQ ID NO:568)、YDKIIDTDL(SEQ ID NO:569)、YDKIIDTDV(SEQ ID NO:570)、YDKIIETEI(SEQ ID NO:571)、YDKIIETEL(SEQ ID NO:572)、YDKIIETEV(SEQ ID NO:573)、YDKIIETDI(SEQ ID NO:574)、YDKIIETDL(SEQ ID NO:575)、YDKIIETDV(SEQ ID NO:576)、YDKIIESDV(SEQ ID NO:577)、YDKIIESDI(SEQ ID NO:578)、YDKIIESDL(SEQ ID NO:579)、YDKIIESEI(SEQ ID NO:580)、YDKIIESEL(SEQ ID NO:581)、YDKIIESEV(SEQ ID NO:582)、YDKIIDSDV(SEQ ID NO:583)、YDKIIDSDI(SEQ ID NO:584)、YDKIIDSDL(SEQ ID NO:585)、YDKIIDSEI(SEQ ID NO:586)、YDKIIDSEL(SEQ ID NO:587)、YDKIIDSEV(SEQ ID NO:588)、YDKILESDV(SEQ ID NO:589)、YDKILESDI(SEQ ID NO:590)、YDKILESDL(SEQ ID NO:591)、YDKILESEI(SEQ ID NO:592)、YDKILESEL(SEQ ID NO:593)、YDKILESEV(SEQ ID NO:594)、YDKIVESDV(SEQID NO:595)、YDKIVESDI(SEQ ID NO:596)、YDKIVESDL(SEQ ID NO:597)、YDKIVESEI(SEQ ID NO:598)、YDKIVESEL(SEQ ID NO:599)、YDKIVESEV(SEQ ID NO:600)、YDKIVDSEI(SEQ ID NO:601)、YDKIVDSEL(SEQ ID NO:602)、YDKIVDSEV(SEQ ID NO:603)、YDKIVDSDI(SEQ ID NO:604)、YDKIVDSDL(SEQ ID NO:605)、YDKIVDSDV(SEQ ID NO:606)、YDKIVETEI(SEQ ID NO:607)、YDKIVETEL(SEQ ID NO:608)、YDKIVETEV(SEQ ID NO:609)、YDKIVETDI(SEQ ID NO:610)、YDKIVETDL(SEQ ID NO:611)、YDKIVETDV(SEQ ID NO:612)、YDKVLDTEI(SEQ ID NO:613)、YDKVLDTEL(SEQ ID NO:614)、YDKVLDTEV(SEQ ID NO:615)、YDKVLDTDI(SEQ ID NO:616)、YDKVLDTDL(SEQ ID NO:617)、YDKVLDTDV(SEQ ID NO:618)、YDKVLDSEI(SEQ ID NO:619)、YDKVLDSEL(SEQ ID NO:620)、YDKVLDSEV(SEQ ID NO:621)、YDKVLDSDI(SEQ ID NO:622)、YDKVLDSDL(SEQ ID NO:623)、YDKVLDSDV(SEQ ID NO:624)、YDKVLETEI(SEQ ID NO:625)、YDKVLETEL(SEQ ID NO:626)、YDKVLETEV(SEQ ID NO:627)、YDKVLETDI(SEQ ID NO:628)、YDKVVLETDL(SEQ ID NO:629)、YDKVLETDV(SEQ ID NO:630)、YDKVVDTEI(SEQ ID NO:631)、YDKVVDTEL(SEQ ID NO:632)、YDKVVDTEV(SEQ ID NO:633)、YDKVVDTDI(SEQ ID NO:634)、YDKVVDTDL(SEQID NO:635)、YDKVVDTDV(SEQ ID NO:636)、YDKVIDTEI(SEQ ID NO:637)、YDKVIDTEL(SEQ ID NO:638)、YDKVIDTEV(SEQ ID NO:639)、YDKVIDTDI(SEQ ID NO:640)、YDKVIDTDL(SEQ ID NO:641)、YDKVIDTDV(SEQ ID NO:642)、YDKVIETEI(SEQ ID NO:643)、YDKVIETEL(SEQ ID NO:644)、YDKVIETEV(SEQ ID NO:645)、YDKVIETDI(SEQ ID NO:646)、YDKVIETDL(SEQ ID NO:647)、YDKVIETDV(SEQ ID NO:648)、YDKVIESDV(SEQ ID NO:649)、YDKVIESDI(SEQ ID NO:650)、YDKVIESDL(SEQ ID NO:651)、YDKVIESEI(SEQ ID NO:652)、YDKVIESEL(SEQ ID NO:653)、YDKVIESEV(SEQ ID NO:654)、YDKVIDSDV(SEQ ID NO:655)、YDKVIDSDI(SEQ ID NO:656)、YDKVIDSDL(SEQ ID NO:657), YDKVIDSEI (SEQ ID NO:658), YDKVIDSEL (SEQ ID NO:659), YDKVIDSEV (SEQ ID NO:660), YDKVLESDV (SEQ ID NO:661), YDKVLESDI (SEQ ID NO:662), YDKVLESDL (SEQ ID NO:663), YDKVLESEI (SEQ ID NO:664), YDKVLESEL (SEQ ID NO:665), YDKVLESEV (SEQ ID NO:666), YDKVVESDV (SEQ ID NO:667), YDKVVESDI (SEQ ID NO:668), YDKVVESDL (SEQ ID NO:669), YDKVVESEI (SEQ ID NO:670), YDKVVESEL (SEQ ID NO:671), YDKVVESEV (SEQ ID NO:672), YDKVVDSEI (SEQ ID NO:673), YDKVVDSEL (SEQ ID NO:674), YDKVVDSEV (SEQ ID NO:675), YDKVVDSDI (SEQ ID NO:676), YDKVVDSDL (SEQ ID NO:677), YDKVVDSDV (SEQ ID NO:678), YDKVVETEI (SEQ ID NO:679), YDKVVETEL (SEQ ID NO:680), YDKVVETEV (SEQ ID NO:681), YDKVVETDI (SEQ ID NO:682), YDKVVETDL (SEQ ID NO:683) and YDKVVETDV (SEQ ID NO:684); and / or The borneol is dextrorotatory borneol, racemic borneol or levorotatory borneol; preferably, the borneol is dextrorotatory borneol; Optionally, borneol is located at the N-terminal side of the peptide; and / or The conservative substitutions are further selected from substitutions between lysine (K), arginine (R) and histidine (H), and substitutions between tyrosine (Y), phenylalanine (F) and tryptophan (W).

6. The conjugate according to any one of claims 1 to 5, wherein In a single conjugate molecule, the molar ratio of borneol to the peptide is 1:1; and / or Borneol is connected to the peptide via a linker; Preferably, the linker is selected from the group consisting of: glycine, non-peptidyl polymers such as polyethylene glycol (PEG) or fatty acid chains of varying lengths (e.g., stearoyl, palmitoyl, octanoyl, etc.); homopolymeric amino acids (e.g., polyhistidine, polyarginine, polylysine, or polyalanine) or heteropolymeric amino acids; and chemical groups (e.g., carbonyl, alkylene (e.g., C 1-6 alkylene), constrained alkylene (e.g., branched alkylene, cyclic alkylene, fused alkylene, adamantylene), alkyleneoxy, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylenyl, aryl, heteroaryl, or heterocyclic group); Optionally, one end of the linker is connected to the side chain of the N-terminal amino acid residue, the C-terminal amino acid residue or the middle amino acid residue (such as lysine, aspartic acid, glutamic acid, etc.) of the peptide; preferably, one end of the linker is connected to the N-terminus of the peptide; and / or The other end of the linker is connected to the O atom of borneol.

7. The conjugate of any one of claims 1 to 6, wherein the peptide can bind to the PDZ1 / 2 domain of postsynaptic density protein 95 (PSD-95) and inhibit the interaction between N-methyl-D-aspartate receptor (NMDAR) and PSD-95.

8. A pharmaceutical composition comprising the conjugate according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier; Optionally, the pharmaceutical composition is used to treat, improve or prevent damage to the nervous system of a mammal or a disease or pain caused by the damage, a neurodegenerative disease, anxiety or epilepsy, or as a neuroprotective agent; Optionally, the disease is stroke or nervous system damage caused by stroke; Preferably, the cerebral stroke includes ischemic stroke, hemorrhagic stroke and hemorrhagic stroke transformed from ischemic stroke; more preferably, the cerebral stroke is ischemic stroke; and / or Preferably, the nervous system damage is a nervous system damage caused by excitotoxicity; more preferably, the nervous system damage caused by excitotoxicity is selected from cerebral stroke or spinal cord injury, ischemic or traumatic injury of the brain or spinal cord, and damage to central nervous system (CNS) neurons, including acute CNS injury, ischemic stroke or spinal cord injury, and damage caused by hypoxia, ischemia, mechanical injury and neurodegenerative diseases, anxiety, epilepsy, and stroke; Optionally, the injury or pain is in the peripheral nervous system or the central nervous system; and / or Optionally, the neurodegenerative disease comprises Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease or Huntington's disease.

9. Use of the conjugate according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament or neuroprotective agent for treating, ameliorating or preventing the following diseases or neuron-protective agents in mammals: nervous system damage and diseases or pain associated with such damage, neurodegenerative diseases, anxiety or epilepsy; Optionally, the disease is stroke or nervous system damage caused by stroke; Preferably, the cerebral stroke includes ischemic stroke, hemorrhagic stroke and hemorrhagic stroke transformed from ischemic stroke; more preferably, the cerebral stroke is ischemic stroke; and / or Preferably, the nervous system damage is a nervous system damage caused by excitotoxicity; more preferably, the nervous system damage caused by excitotoxicity is selected from cerebral stroke or spinal cord injury, ischemic or traumatic injury of the brain or spinal cord, and damage to central nervous system (CNS) neurons, including acute CNS injury, ischemic stroke or spinal cord injury, and damage caused by hypoxia, ischemia, mechanical injury and neurodegenerative diseases, anxiety, epilepsy, and stroke; Optionally, the injury or pain is in the peripheral nervous system or the central nervous system; and / or Optionally, the neurodegenerative disease comprises Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease or Huntington's disease.

10. A method for treating, ameliorating or preventing the following diseases in mammals: nervous system damage and diseases or pain associated with the damage, neurodegenerative diseases, anxiety or epilepsy, comprising administering the conjugate according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 to an individual in need thereof; Optionally, the disease is stroke or nervous system damage caused by stroke; Preferably, the cerebral stroke includes ischemic stroke, hemorrhagic stroke and hemorrhagic stroke transformed from ischemic stroke; more preferably, the cerebral stroke is ischemic stroke; and / or Preferably, the nervous system damage is a nervous system damage caused by excitotoxicity; more preferably, the nervous system damage caused by excitotoxicity is selected from cerebral stroke or spinal cord injury, ischemic or traumatic injury of the brain or spinal cord, and damage to central nervous system (CNS) neurons, including acute CNS injury, ischemic stroke or spinal cord injury, and damage caused by hypoxia, ischemia, mechanical injury and neurodegenerative diseases, anxiety, epilepsy, and stroke; Optionally, the injury or pain is in the peripheral nervous system or the central nervous system; and / or Optionally, the neurodegenerative disease comprises Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease or Huntington's disease.