CN-122011155-A - Dendritic poly-L-lysine modified PACAP, and preparation method and application thereof

Abstract

The invention particularly discloses a dendritic poly-L-lysine modified PACAP and a preparation method and application thereof, and relates to the technical field of biological medicines. The PACAP-DPL provided by the invention effectively overcomes the defect of insufficient in-vivo stability of the natural PACAP under the premise of not weakening the biological function of the PACAP, provides a new technical approach for the application of the PACAP neuropeptides in Alzheimer disease, and has good research value and potential application prospect.

Inventors

• SHI JIONG
• LIU YANGZHONG
• YANG YAPING
• YU WENXIN

Assignees

• 安徽省立医院(中国科学技术大学附属第一医院)

Dates

Publication Date

20260512

Application Date

20260414

Claims (10)

1. 1. A dendritic poly-L-lysine modified PACAP having a structure according to formula (1): (1); Wherein K represents lysine; R independently represents PACAP or 。
2. 2. The dendrimeric poly-L-lysine modified PACAP according to claim 1, further comprising pharmaceutically acceptable salts, esters, hydrates, solvates, metabolites, prodrugs, stereoisomers, tautomers, polymorphs and/or isotopic derivatives thereof.
3. 3. The dendritic poly-L-lysine modified PACAP according to claim 1, wherein R represents PACAP.
4. 4. A method of preparing a dendritic poly-L-lysine modified PACAP according to any one of claims 1-3, comprising: S1, reacting EMCS with DPL to obtain DPL-MAL; S2, connecting a cysteine at the C end of the PACAP, and then reacting with the DPL-MAL to obtain the dendritic poly-L-lysine modified PACAP.
5. 5. The method of claim 4, wherein the PACAP in S2 is PACAP38.
6. 6. A pharmaceutical composition, in the form of a capsule, characterized by comprising the following steps: (1) A therapeutically effective amount of a dendrimeric poly-L-lysine modified PACAP according to any one of claims 1-3 or a dendrimeric poly-L-lysine modified PACAP obtained by the method of preparation of claim 4 or 5; (2) Pharmaceutically or immunologically acceptable carriers or excipients.
7. 7. A pharmaceutical formulation comprising the pharmaceutical composition of claim 6.
8. 8. The pharmaceutical formulation according to claim 7, wherein the route of administration of the pharmaceutical formulation is nasal and/or intraperitoneal.
9. 9. A pharmaceutical product comprising a pharmaceutical formulation according to claim 7 or 8.
10. 10. Use of a dendrimeric poly-L-lysine modified PACAP according to any one of claims 1 to 3 or a dendrimeric poly-L-lysine modified PACAP obtained by the process according to claim 4 or 5, a pharmaceutical composition according to claim 6, a pharmaceutical formulation according to claim 7 or 8 and/or a pharmaceutical product according to claim 9 for the preparation of a medicament for the prophylaxis and/or treatment of alzheimer's disease.

Description

Dendritic poly-L-lysine modified PACAP, and preparation method and application thereof Technical Field The invention relates to the technical field of biological medicine, in particular to a dendritic poly-L-lysine modified PACAP, and a preparation method and application thereof. Background A Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) is an endogenous small molecule neuropeptide consisting essentially of two natural forms, a full length form consisting of 38 amino acids (PACAP-38) and a short chain form consisting of 27 amino acids (PACAP-27). The existing research shows that PACAP has remarkable neurotrophic and neuroprotective effects in the central nervous system. PACAP-38 is the predominant form of presence in brain tissue. PACAP is capable of promoting the production of intracellular cAMP via PAC1 receptor, thereby mediating the relevant biological effects. Elevation of cAMP levels can further activate downstream signaling pathways such as Protein Kinase A (PKA) that regulate gene transcription, cell survival and functional status. Alzheimer's Disease (AD) is the most common type of dementia and there is currently no effective disease modifying treatment. Studies have shown that changes in PACAP content in cerebrospinal fluid can be used as one of the potential biomarkers of Alzheimer's disease for the assisted diagnosis of disease, and that decreased PACAP content in brain tissue has a correlation with AD pathology. Meanwhile, animal experiment results show that the exogenous administration of PACAP can improve the cognitive function of an AD model mouse to a certain extent, and the PACAP is suggested to have certain research and application value in the aspect of the intervention of Alzheimer's disease. However, PACAP, as a small-molecule polypeptide, is susceptible to degradation by various proteases in vivo, and has problems such as poor stability, short in vivo half-life, and limited duration of drug effect, resulting in low bioavailability. The literature reports that the elimination half-life of PACAP-38 in the circulatory system is usually on the order of minutes, about 5-10 minutes in humans, and that its rapid inactivation is mainly associated with degradation processes mediated by proteases (e.g., dipeptidyl peptidase 4, DPP 4) in vivo. The physicochemical and pharmaceutical properties limit the continuous exertion of the efficacy of PACAP to a certain extent, and further limit the long-term and stable application of the PACAP serving as a therapeutic drug in chronic nervous system diseases such as Alzheimer disease. Therefore, how to effectively improve the in vivo stability, prolong the half-life and improve the persistence of the drug effect of PACAP under the premise of keeping the biological activity of the PACAP is still a technical problem to be solved in the field. Disclosure of Invention (One) solving the technical problems In view of this, it is one of the primary objects of the present invention to provide a dendritic poly-L-Lysine (DPL) modified PACAP (PACAP-DPL). On the premise of not weakening the biological function of PACAP, the defect of insufficient in vivo stability of the natural PACAP is effectively overcome, a novel technical approach is provided for the application of PACAP neuropeptides in Alzheimer's disease, and the PACAP has good research value and potential application prospect. (II) technical scheme In order to achieve the above object, the present invention provides a PACAP-DPL having a structure represented by formula (1): (1); Wherein K represents lysine; R independently represents PACAP or 。 In one embodiment, the PACAP is PACAP-38. In one embodiment, pharmaceutically acceptable salts, esters, hydrates, solvates, metabolites, prodrugs, stereoisomers, tautomers, polymorphs, and/or isotopic derivatives thereof are also included. In one embodiment, the R represents PACAP. In one embodiment, the structural formula is。 The invention also provides a preparation method of the PACAP-DPL, which comprises the following steps: s1, reacting EMCS (6- (maleimide) caproic acid succinimidyl ester) with DPL to obtain DPL-MAL; s2, connecting a cysteine at the C end of the PACAP, and then reacting with the DPL-MAL to obtain the PACAP-DPL. The invention also provides PACAP-DPL obtained by the preparation method. The present invention also provides in another aspect a pharmaceutical composition comprising: (1) A therapeutically effective amount of PACAP-DPL as described above; (2) Pharmaceutically or immunologically acceptable carriers or excipients. In another aspect, the invention provides a pharmaceutical formulation comprising the pharmaceutical composition described above. In one embodiment, the dosage form of the pharmaceutical formulation includes a plaster, granule, lotion, liniment, powder, syrup, aerosol, spray, extract, elixir, solution, ointment, fluid extract, emulsion, suspension, decoction, infusion, tablet, suppository, injection, alcoholic solutio