CN112724197A - 7 peptide for blocking PDL1 in immunotherapy - Google Patents
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- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 49
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 title claims abstract description 44
- 230000000903 blocking effect Effects 0.000 title claims abstract description 17
- 238000009169 immunotherapy Methods 0.000 title claims abstract description 17
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 title claims abstract 8
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- 229920001184 polypeptide Polymers 0.000 claims abstract description 25
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 25
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- 238000002360 preparation method Methods 0.000 claims description 2
- 108010021462 proto-oncogene protein pp60(c-Src) (140-157) Proteins 0.000 claims description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
The application belongs to the technical field of biological medicines, and particularly relates to a 7 peptide for blocking PDL1 in immunotherapy. The polypeptide is named as L1W7 peptide, has a 7-peptide structure, has an amino acid sequence shown as SEQ ID No.1, and specifically comprises the following components: LFWIKFW. In the application, an inventor utilizes MOE software to construct a D-type 7 peptide library, virtually screens PDL1 (PDB: 3 BIK) of a human in an immunodetection site, preliminarily screens and determines a D-type 7 peptide structure with the highest binding energy by utilizing a protein-protein docking technical principle and taking an amino acid site interacted between PDL1 and PD1 as a polypeptide docking site, names the peptide as L1W7 with an energy value of-51.6342, has the capacity of blocking the binding of PD1 and PDL1 (affinity or blocking property), and has a potential anti-tumor application effect.
Description
Technical Field
The application belongs to the technical field of biological medicines, and particularly relates to a 7 peptide for blocking PDL1 in immunotherapy.
Background
Immune checkpoints refer to a series of molecules expressed on immune cells and regulating the degree of immune activation, which play an important role in preventing the development of autoimmune (abnormal immune function, attack on normal cells) effects, especially in the immunotherapy of tumors. On the other hand, the immune function of the human body is activated when being stimulated, but is not usually over-activated, and the main reason is that one of the important functions of the "immune checkpoint molecule" is to "brake" like the brake system of the automobile, so that the activation of the immune system can be kept within the normal range when the immune system is activated.
The expression and the function abnormality of the immune checkpoint molecules are one of the important reasons for the occurrence of a plurality of diseases, for example, the immune checkpoint molecules are over-expressed or over-functional, the immune function is inhibited, the immunity of the organism is low, and the human body is easy to have diseases such as tumors and the like; conversely, if the immunosuppressive function of the immune checkpoint molecule is too poor, the immune function of the body will be abnormal.
In tumor cells, the tumor cells express some special substances to activate immune check points, and once the immune check points are activated, the 'brake' is pressed, so that antigens cannot be presented to T cells, the process of presenting the antigens in the tumor immune loop is blocked, the immune function of the T cells is inhibited, and the tumor cells can escape monitoring and survive. In the prior art, commonly used immune checkpoint molecules have been found to be: CTLA-4 (cytotoxic T lymphocyte-associated antigen-4), PDL1 (programmed cell death protein receptor 1, programmed death-Ligand 1), and the like. Based on the deep research of the immune checkpoint molecules, a better theoretical basis is laid for the design of related molecular drugs.
The screening and design of polypeptide drugs are an important technical idea in the immunotherapy of tumors, and certain progress is made in the immunotherapy of part of tumors. However, most of polypeptide drugs are small molecular substances which are easily degraded in vivo, and the half-life period is usually several seconds or several minutes, so that the practical technical effect is limited. Therefore, designing new polypeptide drugs with longer half-life is of great technical significance for improving the treatment method of immunotherapy.
Disclosure of Invention
By utilizing the related peptide library, the application aims at providing the 7 peptide for blocking PDL1 in immunotherapy, thereby laying a certain technical foundation for related tumor prevention and treatment and immunotherapy.
The technical solution adopted in the present application is detailed as follows.
A7 peptide for blocking PDL1 in immunotherapy, which is named as L1W7 peptide, has a 7-peptide structure (with 7 amino acid residues), and has an amino acid sequence shown as SEQ ID No.1, specifically (from N end to C end): LFWIKFW (leucine-phenylalanine-tryptophan-isoleucine-lysine-phenylalanine-tryptophan);
each amino acid is an L-type amino acid or a D-type amino acid.
When each amino acid is an L-type amino acid, the further amino acid sequence is shown as (shown in SEQ ID No. 1),
l type: Leu-Phe-Trp-Ile-Lys-Phe-Trp;
when each amino acid is a D-type amino acid, the further amino acid sequence is shown as (shown in SEQ ID No. 2),
type D: DLE-DPN-DTR-DIL-DLY-DPN-DTR.
The application of the 7 peptide for blocking PDL1 in the immunotherapy in preparing an anti-tumor agent.
The polypeptide drug has good application prospect in immunotherapy, but in practical application, the configuration determined by the polypeptide sequence is the basic premise for ensuring the application effect, so that the screening of related polypeptide sequences is still the most important and basic research and development work foundation of the polypeptide drug. On the other hand, because natural L-amino acids have the defect of short half-life, how to prolong the half-life of polypeptide drugs is also a key direction for the research and development of the existing polypeptide drugs. Aiming at the defects, the prior art further improves the curative effect of the polypeptide medicament fundamentally through sequence modification on one hand, and prolongs the half life period of the polypeptide medicament through modifying the structure of the existing polypeptide sequence on the other hand, thereby improving the application effect of the polypeptide medicament.
For the modification of polypeptide sequence structure, the prior art, on one hand, reduces the biodegradation rate by modifying a single or multiple amino acids at a specific site (for example, coupling a certain group), and on the other hand, the modification of a part of polypeptide structure by using D-type amino acid is also a more common modification. However, due to different polypeptide structure sequences, the polypeptide effect after modification can be determined only after further experiments.
Limited by the technical difficulty of the existing artificial synthesis of protein sequences, the synthesis cost and other influences, the existing artificial synthesis of more than 50 amino acid sequence proteins still has great difficulty, so the screening and research work of small molecule polypeptides is still carried out in the prior art. Based on the actual situation of the prior art and combined with the factors for preventing degradation, in the application, the inventor utilizes Molecular Operating Environment (MOE) software to construct a D-type 7 peptide library, virtually screens PDL1 (PDB: 3 BIK) of a human in an immunodetection site, and in the screening process, utilizes the principle of protein-protein Docking technology, takes an amino acid site of interaction between PDL1 and PD1 as a Docking site of polypeptide (A, B, C and D4 sites are Docking sites), primarily screens and determines a D-type 7 peptide structure with the highest binding energy, and names the peptide L1W7 with an energy value of-51.6342, has the capacity of blocking the binding of PD1 and PDL1 (affinity or blocking performance), and has a potential anti-tumor application effect.
Drawings
FIG. 1 is a design process of D-type 7 peptide library, wherein: a, D-amino acid interface; b, a D-type peptide library operation interface; c, obtaining a D-type 7 peptide library;
fig. 2 is a schematic diagram of the 3BIK crystal structure, wherein: a, PD1 and PDL1 structures (homo PDL1 in red in color view); b, optimally setting the structure of homo PDL1 by QuickPrep Panel in the MOE; c, optimized homo PDL 1;
FIG. 3 is a diagram of the interaction pattern of PDL1 with L1W7, in which: a, PDL1 interacts with the L1W7 interface and important interactions; b, interaction pattern between L1W7 and PDL1 amino acid residues.
Detailed Description
The present application is further illustrated by the following examples.
Example 1
It should be noted that the polypeptides claimed in the present application are obtained by screening using related software and databases, and therefore the present embodiment is briefly described below with respect to the related software, databases, and other background situations.
Screening software: MOE software (Molecular Operating Environment), purchased from the data center of the shanghai database, version number: MOE 2016.0802.
Construction of virtual 7-peptide library: in MOE software, D-type amino acid of ACDEFGH is selected (mainly for avoiding repetition) under a Protein Builder module to construct a 3D structure; then selecting a resource Scan under a Protein design module, setting Display options as All resources, selecting 20D-type amino acids at each Site, setting Site Limit as 7, carrying out multi-Site simultaneous mutation, simultaneously checking the options of Properties, and calculating the stability of each polypeptide; finally, after the polypeptide library is generated, repeated heptapeptides are removed, and D-type 7 peptide libraries with the library capacity of 43989 are constructed.
The specific MOE software operation condition and the constructed 7-peptide library operation screenshot are shown in FIG. 1. In general, the constructed D-type 7 peptide library has large library capacity and good stability, so that the method can be used for subsequent virtual screening.
Screening for subjects: the homo PDL1 amino acid sequence was obtained based on the prior art as follows (290 amino acid sequences):
MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET。
it is to be explained that the homo PDL1 amino acid in this example was derived from the resolution of the crystal structure of a 3BIK structure, which is a 3 mer complex of mus PD1 and homo PDL1 (1 PD1 and homologous 2 PDL1, as shown in FIG. 2A). Based on the crystal structure, for the convenience of subsequent screening application, the structure is optimized by deleting the PD1 sequence and water molecules in the structure (namely, only the PDL1 structure is reserved).
Example 2
Based on the 7 peptide library and homo PDL1 amino acid sequence in example 1, the inventors performed further screening using the principle of protein-protein docking, specifically:
firstly, a structure preparation is completed on the optimized PDL1 structure in the embodiment 1 by utilizing a Quickprep Panel module in MOE software (the process and the result are shown in FIGS. 2B and 2C);
then, according to the fact that PDL1 and PD1 interact with each other, the site is used as a binding site of D-type polypeptide (PDL 1 Docking site, (A) 1-10 AFTVTVPKDL, (B) 36-42 LIVYWEM, (C) 44-53 KNIIQEVHG, (D) 95-110 YRCMISYGGADYKRIT), and inhibitors of the D-type 7 peptide are screened;
and finally, docking, setting the Pre-plan in the position: 1000, plan: 100, Refinement: 1.
in the screening, binding sites of PD1 and PDL1 were used as the Docking sites, which are shown above. The D-type polypeptide of PDL1 was screened by Protein-Protein gating pattern, the screening results were ranked according to S-value (energy value), and the Top10 ranked D peptide (Top10) results were selected as candidate sequences, and the specific results are shown in Table 1 below.
TABLE 1 PDL1 blocking 7 peptide docking Top10 results
Based on the screening results, the 7 peptide with the strongest affinity was identified by S value result analysis and named L1W7, and the sequence is as follows: n terminal-DLE-DPN-DTR-DIL-DLY-DPN-DTR-C terminal (D type single amino acid sequence: N terminal-LFWIKFW-C terminal, amino terminal-leucine-phenylalanine-tryptophan-isoleucine-lysine-phenylalanine-tryptophan-carboxyl terminal).
As can be seen from the structural and interaction pattern diagrams, 4 molecular bonds in the L1W7 peptide of the present application are involved in the interaction with PDL1, namely van der waals forces, ionic bonds, hydrogen bonds and pi-pi conjugation (table 2 and fig. 3). The specific action results are shown in table 2 below and fig. 3.
TABLE 2 results of the interaction of PDL1 with L1W7 peptide
Note: d (distance) represents van der Waals force, I (ionic) denotes ionic bonds, H (Hbond) denotes hydrogen bonds, and A (arene) denotes pi-pi conjugation.
For specific analysis: all amino acids of L1W7 participated in generating van der Waals forces (D) with partial amino acids of PDL 1; the Arg113 and Arg125 sites in DRT7 and PDL1 form hydrogen bonds and ionic bonds, have the strongest interaction capacity, bond energies of-17.33 and-15.67, respectively, and have intermolecular distances of 3.77 a and 3.65 a, respectively. DTR3 formed a pi-pi conjugation with an Asn63 site in PDL1, with an energy value of-3.43 and an intermolecular distance of 3.65 a. Asp61 in DLY5 and PDL1 formed hydrogen bonds with a bond energy of-3.15 and an intermolecular distance of 4.05A. The Tyr123 position in DPN6 and PDL1 formed pi-pi conjugation with a bond energy of-1.35 and an intermolecular distance of 4.06 a. The L1W7 peptide and PDL1 form strong force, and have the potential capability of blocking the combination of PDL1 and PD1, thereby achieving the anti-tumor effect.
It should be added that for the sake of checking, the abbreviations of related amino acid sequences in the art are indicated below.
Note: the/stands for no D-form amino acid, i.e.no chirality. Definition of amino acids in D and L forms: according to the Fisher projection formula (optical rotation), the carboxyl group is on the top, the amino group is L-form on the left side, the amino group is D-form on the right side, the natural amino acids (constituting the protein) are all L-form, and the D-form is synthesized substantially.
SEQUENCE LISTING
<110> university of Henan
<120> 7 peptide for blocking PDL1 in immunotherapy
<130> none
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 7
<212> PRT
<213> Artificial design
<400> 1
Leu Phe Trp Ile Lys Phe Trp
1 5
<210> 2
<211> 7
<212> PRT
<213> Artificial design
<400> 2
DLE DPN DTR DIL DLY DPN DTR
1 5
Claims (3)
1. A7 peptide for blocking PDL1 in immunotherapy, wherein the polypeptide is named as L1W7 peptide, and has a 7 peptide structure, and the amino acid sequence is as follows: leucine-phenylalanine-tryptophan-isoleucine-lysine-phenylalanine-tryptophan;
each amino acid is an L-type amino acid or a D-type amino acid.
2. The 7 peptide for blocking PDL1 in immunotherapy according to claim 1, wherein when each amino acid is an L-type amino acid, the amino acid sequence is as shown in SEQ ID No.1, and specifically:
l type: Leu-Phe-Trp-Ile-Lys-Phe-Trp;
when all amino acids are D-type amino acids, the amino acid sequence is shown as SEQ ID No.2, and specifically comprises the following steps:
type D: DLE-DPN-DTR-DIL-DLY-DPN-DTR.
3. Use of the 7 peptide for blocking PDL1 in immunotherapy according to claim 1 or 2 for the preparation of an anti-tumor agent.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098651A (en) * | 2014-06-30 | 2014-10-15 | 郑州大学 | PD-L1 IgV affinity peptide with antineoplastic activity, and preparation method and application of thereof |
| US20180339044A1 (en) * | 2017-05-25 | 2018-11-29 | Leidos, Inc. | PD-1 and CTLA-4 Dual Inhibitor Peptides |
| CN111153961A (en) * | 2020-01-08 | 2020-05-15 | 郑州大学 | Peptide with affinity to PD-1 and application thereof |
| CN112028968A (en) * | 2019-06-04 | 2020-12-04 | 国家纳米科学中心 | Polypeptide targeting PD-L1 and application thereof |
-
2021
- 2021-02-03 CN CN202110145088.6A patent/CN112724197A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098651A (en) * | 2014-06-30 | 2014-10-15 | 郑州大学 | PD-L1 IgV affinity peptide with antineoplastic activity, and preparation method and application of thereof |
| US20180339044A1 (en) * | 2017-05-25 | 2018-11-29 | Leidos, Inc. | PD-1 and CTLA-4 Dual Inhibitor Peptides |
| CN112028968A (en) * | 2019-06-04 | 2020-12-04 | 国家纳米科学中心 | Polypeptide targeting PD-L1 and application thereof |
| CN111153961A (en) * | 2020-01-08 | 2020-05-15 | 郑州大学 | Peptide with affinity to PD-1 and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| CHUNLIN LI ET AL.: "Peptide Blocking of PD-1/PD-L1 Interaction for Cancer Immunotherapy", 《CANCER IMMUNOLOGY RESEARCH》, vol. 6, no. 2, 7 December 2017 (2017-12-07), pages 178 - 188, XP055669439, DOI: 10.1158/2326-6066.CIR-17-0035 * |
| HAO-NAN CHANG ET AL.: "Blocking of the PD-1/PD-L1 Interaction by a d-Peptide Antagonist for Cancer Immunotherapy", 《ANGEW. CHEM. INT. ED.》, vol. 54, 10 August 2015 (2015-08-10), pages 11760 - 1764, XP055247320, DOI: 10.1002/anie.201506225 * |
| 王佳其等: "免疫检查点PD-1/PD-L1阻断剂耐药机制的研究进展", 《现代肿瘤医学》, vol. 27, no. 18, 30 September 2019 (2019-09-30), pages 3345 - 3349 * |
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Application publication date: 20210430 |
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