CN103897033A - TfR (transferrin receptor) specific binding peptide and application thereof - Google Patents
TfR (transferrin receptor) specific binding peptide and application thereof Download PDFInfo
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Abstract
The invention discloses a TfR (transferrin receptor) specific binding peptide CPU-312-03 and an application thereof. The binding peptide sequences and nucleotide sequences of CPU-312-03 are respectively GLSRAHQ and GGGCTTTCTCGGGCTCATCAG. Vitro experiments shows that the binding peptide can be bound with cells capable of highly expressing the transferrin receptor TfR, and the coupled fluorescein isothiocyanate (FITC) can be inoculated into cells in a target mode. The binding peptide disclosed by the invention can be used in the drug targeting vector with the transferrin receptor TfR as a target site and is of great significance for the development of tumor targeting medicines, the targeted therapy of brain-derived diseases and predicting and diagnosing of the occurrence and development of tumors with transferrin receptor TfR as a target.
Description
Technical field
The invention belongs to a kind of TfR TfR antibody, particularly a kind of TfR TfR specific binding peptides and application thereof.
Background technology
Known two kinds of dissimilar TfRs are TfR 1 (TfR1) and transferrin receptor 2 (TfR2) at present.
TfR1 expresses in many cells, as red blood cell, liver cell, monocyte and hemato encephalic barrier.TfR1 is formed by two disulfide bond crosslinkings by homodimer.Each monomer is containing 760 amino acid, molecular weight is 90～95kDa, comprise large born of the same parents outer C end regions (671 amino acid), a single span diaphragm area (28 amino acid) and a short N end regions (61 amino acid).C end regions is an ectodomain, the binding site that it comprises Transferrins,iron complexes (Tf), and three N connect glycosylation site and an O connection glycosylation site, and the glycosylation in these sites is that TfR1 function is necessary.TfR1 can change conformation according to the variation of environment pH, and conformation result of variations is converted to the variation to Transferrins,iron complexes bonding force power.
TfR2 is a kind of II type transmembrane glycoprotein, it is the TfR1 homologous gene that Kawa-bata clones from Tf cell and HL-60 cell cdna library, there is 45% identical sequence with TfR1, there is 66% similarity in territory, extracellular region with TfR1, but the affinity of TfR2 and Transferrins,iron complexes is lower, lower 25 times than TfR1.TfR2 is mainly at liver expression, and its mRNA coding and non-coding region lack regulation and control iron ion composition, and this expression that just shows TfR2 is not is not regulated and controled by iron ion response protein Feedback mechanism.
The function of TfR TfR be by with the absorption of the interaction mediation iron of Transferrins,iron complexes.Under physiological pH, TfR TfR be with two Fe
3+transferrins,iron complexes avidity the highest, and be with a Fe
3+transferrins,iron complexes avidity take second place, and be not with Fe
3+transferrins,iron complexes avidity minimum, with two Fe
3+transferrins,iron complexes be 10～100 times of apotransferrin to the avidity of TfR TfR.In inclusion body, the decline of pH has promoted the change of Transferrins,iron complexes conformation, and Transferrins,iron complexes discharges Fe subsequently
3+, the avidity of apotransferrin and TfR TfR reduces.
Studies show that the Several Kinds of Malignancy cells such as nasopharyngeal carcinoma, cancer of the stomach, liver cancer, hematological system tumor are compared with their healthy tissues, TfR presents high expression level situation, and the expression of TfR TfR is usually relevant with cell proliferation activity.Serum Obtained From Advance Gastric Cancer TfR TfR level obviously increases compared with benign stomach disease patient and normal people, and the TfR TfR of III, IV phase tumour patient is also apparently higher than I, II phase tumour patient simultaneously.The expression increase that TfR TfR is described makes tumour cell obtain abnormal proliferation activity.In addition, Transferrins,iron complexes/TfR system can improve physiologic barrier as intestinal mucosa, the permeability of hemato encephalic barrier to medicine by endocytosis.It is almost completely saturated by Transferrins,iron complexes that the TfR TfR of hemato encephalic barrier is considered to, and Transferrins,iron complexes is restricted as medicine brain targeting vector.But, because TfR TfR antibody is different with the binding site of Transferrins,iron complexes and TfR from the binding site of TfR, and non-interference, thereby can adopt the antibody of TfR TfR to carry out drug transport.Coupling has the monoclonal antibody (OX26) of Chinese People's Anti-Japanese Military and Political College's mouse TfR of medicine by TfR TfR mediation endocytosis, stride across hemato encephalic barrier and transport, and OX26 to demonstrate the stronger ability that enters central nervous system.
Display technique of bacteriophage is created in 1985 by Smith, taking the phage that changes structure as carrier, the directed gene fragment to be selected bacteriophage coat protein plasmagene district that inserts, make allogenic polypeptide or protein expression and be showed in phage surface, and then expressing by affine concentration method the phage that has special peptide or protein.It is set up based on 3 points: (1) inserts foreign gene at the N of pIII and pVIII capsid protein end, the expressing fusion protein forming is on the surface of phage particle, do not affect and disturb the life cycle of phage, keep foreign gene native conformation simultaneously, also can be identified by corresponding antibody or acceptor; (2) utilize target molecule fixing and solid support, adopt suitable elutriation method, wash away the phage of non-specific binding, filter out object phage; (3) allogenic polypeptide or protein expression be on the surface of phage, and its encoding gene can be derived by the single stranded DNA order-checking of secretor type phage as the part in viral genome.This technology has realized the conversion of genotype and phenotype, more and more widely for the analysis of Characterization of antigenic epitopes, protein one protein-protein interaction sites analysis, zymolyte, the simulating peptide that searching has the albumen of biological function, discovery, separation and qualification disease specific epitope mimic peptide, screening cell and organ specificity binding peptide, Study on Protein and nucleic acid binding characteristic, the signal for locating transduction pathway etc. of lead compound.
Micromolecule polypeptide is simple in structure, and to penetrate the ability of tumor tissues strong, and be difficult for being repelled by immunity system, therefore has very large potentiality as good drug targeting carrier.Long-actingization of polypeptide means become increasingly abundant simultaneously, make polypeptide stability increase in vivo, Increased Plasma Half-life.
Summary of the invention
Primary and foremost purpose of the present invention is that the shortcoming that overcomes prior art, with not enough, provides a kind of TfR TfR specific binding peptides.Another object of invention is to provide the application of described TfR TfR specific binding peptides.
Object of the present invention is achieved through the following technical solutions: a kind of TfR TfR specific binding peptides, and its aminoacid sequence is Gly Leu Ser Arg Aal His Gln, i.e. GLSRAHQ;
The nucleotide sequence of described TfR TfR specific binding peptides is as follows: GGGCTTTCTCGGGCTCATCAG; A kind of TfR TfR specific binding peptides, is characterized in that: the aminoacid sequence of described binding peptide is as Seq NO.1.
Described TfR TfR specific binding peptides is in the application of drug targeting tumour.
The application of described TfR TfR specific binding peptides in drug targeting tumour, is characterized in that tumor surface high expression level TfR TfR.Selected tumour is liver cancer or mammary cancer.
The application of described TfR TfR specific binding peptides in saturating hemato encephalic barrier medicine.
The application of described TfR TfR specific binding peptides in TfR TfR detects.
The present invention has following advantage and effect with respect to prior art: TfR TfR specific binding peptides of the present invention obtains by display technique of bacteriophage, is brand-new sequence.Be easy to by biology and the synthetic structure of chemical process.Bioinformatics technique shows that this is combined with TfR TfR in conjunction with Toplink, experiment in vitro shows this Cell binding in conjunction with Toplink and high expression level TfR TfR, and the fluorescein isothiocyanate being coupled (FITC) can be proceeded in born of the same parents, can be used as the detection of pharmaceutical carrier and TfR TfR.Therefore binding peptide of the present invention can be used for the exploitation of the tumor-targeting drug taking TfR TfR as target spot, the targeted therapy of brain-borne disease, and prediction to the tumor development taking TfR TfR as target, diagnose significant.
Brief description of the drawings
Fig. 1 is the mixture model that TfR TfR and binding peptide form
Fig. 2 is TfR TfR and the interactional amino-acid residue of binding peptide
Fig. 3 fluorescence microplate reader detects HepG2 cell to being coupled the picked-up experiment of FITC binding peptide and FITC
Fig. 4 fluorescence microplate reader detects LO2 cell to being coupled the picked-up experiment of FITC binding peptide and FITC
Fig. 5 is that fluorescence microscope HepG2 cell is to being coupled the experiment of engulfing of FITC binding peptide
Fig. 6 is the engulf experiment of fluorescence microscope HepG2 cell to FITC
Fig. 7 is that fluorescence microscope LO2 cell is to being coupled the experiment of engulfing of FITC binding peptide
Embodiment
Following examples material therefor and plant and instrument are:
Implement material: intestinal bacteria ER2738 (New England Biolabs company of the U.S.), phage display random 7 peptide library (New England Biolabs company of the U.S.), TfR (German CalBiochem company), HRP-M13 antibody (GE Healthcare company), RPMI-1640 (Gibco company), calf serum (Gibco company), trypsin Gibco company).
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited to this.
Embodiment 1
By the method for phage display, obtain TfR TfR specific binding peptides CPU-312-03:
(1), by the screening of phage random peptide library, obtain the nucleotide sequence of TfR TfR specific binding peptides CPU-312-03:
A. the Biopanning of phage display random 7 peptide library: with coating buffer (0.1M NaHCO3, pH8.6) TfR TfR is diluted to 100 μ g/ml, adds 150ul to a hole of enzyme plate, rotation is until surface is completely moistening repeatedly, keep moisture state, 4 DEG C are spent the night.Outwell coating buffer, clappers are removed raffinate, fill it up with confining liquid (0.1M NaHCO3, pH8.6,5mg/ml BSA), and 4 DEG C at least act on one hour.Pour out confining liquid, with 0.1%TBST[TBS+0.1% (v/v) Tween-20] wash clappers at every turn 6 times.Dilute the original phage peptide library of 10 μ l with 100 μ l TBST, add with in the coated hole of TfR TfR, room temperature incubation 1 hour, topples over unconjugated phage, rinses 10 times clappers at every turn with 0.1%TBST.Then add 100 μ l elutriants [0.2M Glycine-HCl (ph2.2), 1mg/mLBSA] room temperature slightly to shake 15min, sucking-off elutriant, then use in the 1M Tris-HCL of 15 μ l and above-mentioned elutriant.Draw the elutriant mensuration titre that 1 μ l has neutralized, all the other liquid add 20mlLB substratum (containing the bacterium liquid of 20 μ l tsiklomitsin+200 μ l incubated overnight), and 37 DEG C, 225rpm cultivates 5 hours; Centrifugal amplification phage, 4 DEG C, centrifugal 10 minutes of 12000g, proceeds in a new centrifuge tube 80% of supernatant, adds the PEG8000/NaCl of 1/6 volume, allows 4 DEG C of precipitations of phage spend the night; Centrifugal phage, 12000g, 15 minutes, 4 DEG C.Outwell supernatant, draw residual solution.Add the resuspended precipitation of 1ml TBS, proceed in Eppendorf tube.4 DEG C, 14000rpm makes residual cells precipitation for centrifugal 5 minutes.Supernatant proceeds in another Eppendorf tube, adds the PEG8000/Nacl of 1/6 volume, ice bath 1h.4 DEG C, centrifugal 10 minutes of 14000rpm, abandons supernatant, precipitates resuspended with 200 μ lTBS.Any undissolvable material of centrifugal 1min precipitation, supernatant proceeds in a new Eppendorf tube, this phage of increasing.Undertaken the 2nd by above step, 3 take turns screening, and the coated concentration that reduces TfR TfR is taken turns in every screening one, changes 50 μ g/ml and 30 μ g/ml into, in conjunction with time add 2 × 10
11last round of wash-out amplified material, when wash-out,, use 5%TBST instead and wash in conjunction with phage with free TfR TfR molecule (100g μ g/ml is dissolved in TBS) competitive elution, improve screening specificity.
B. phage titre is measured: with LB substratum dilution phage, phage dilution range does not increase: 10
1-10
4, phage dilution range after amplification: 10
8-10
11.Get the phage of the above-mentioned dilution of 10 μ l, add in 200 μ l mid-log phase ER2738, act on 2 minutes, the infection thalline obtaining is added in 3ml liquid top-layer agar and mixed, uniform spreading is on the IPTG/Xgal/Tet of preheating flat board, be inverted lucifuge for 37 DEG C and spend the night, calculate the blue plaque quantity on flat board, extension rate is multiplied by plaque quantity and is phage titre.
C. the amplification of plaque: measure the phage titre that third round does not increase, 300 μ l overnight culture, 30 μ l Tet, after mixing, 30mlLB liquid nutrient medium is divided in 30 test tubes, each test tube 1ml, locus coeruleus of each test tube picking adds, and 37 DEG C of shaking tables are cultivated 5 hours, culture proceeds in Eppendorf tube, centrifugal 30 seconds, supernatant proceeded in new centrifuge tube centrifugal again, and 80% supernatant is proceeded in new centrifuge tube, this is the phage storage liquid of amplification, 4 DEG C of storages.
D.ELISA identifies positive phage clones: the phage storage liquid of getting gained in 5 μ l step C, add 20mlLB substratum (containing 20 μ l tsiklomitsins, the bacterium liquid of 200 μ l incubated overnight) in, cultivate 4.5 hours for 37 DEG C, centrifugal amplification phage, centrifugal 10 minutes of 4 DEG C of 12000g, proceed in a new centrifuge tube 80% of supernatant, add the PEG8000/NaCl of 1/6 volume, allow 4 DEG C of precipitations of phage spend the night; Centrifugal phage, 12000g, 15min, 4 DEG C.Outwell supernatant, draw residual solution.Add the resuspended precipitation of 1ml TBS, proceed in Eppendorf tube.Centrifugal, 4 DEG C, 14000rpm, 5min makes residual cells precipitation.Supernatant proceeds in another Eppendorf tube, adds the PEG8000/NaCl of 1/6 volume, ice bath 1h.Centrifugal, 4 DEG C, 14000rpm, 10min, abandons supernatant, and precipitation is resuspended in 50 μ l TBS, and this is the phage storage liquid of amplification, measures titre, prepares to carry out ELISA qualification.
The TfR TfR molecule of preparing 100 μ g/ml (is dissolved in 0.1M NaHCO
3, PH8.6).For 30 phages to be identified, 4 phage gradients are set, 3 holes of each gradient, and the not coated negative contrast of blank well is set, the enzyme plate being coated with is placed 4 DEG C and is spent the night.The unnecessary target molecule solution of sucking-off, adds the liquid of blockading, and 4 DEG C act on 1 hour, and negative control seals equally.Throw away the liquid of blockading, wash plate 6 times with 0.5%TBST, get the phage of increasing in step C, dilute four quantity gradients and (be respectively 10
9, 10
10, 10
11, 10
12pfu), add in the hole being coated with room temperature effect 1 hour.Wash plate 6 times with 0.5%TBST, add 1: 5000 dilution HRP-M13 antibody, act on 1 hour.Wash plate 6 times with 0.5%TBST, add OPD nitrite ion, develop the color and add 2M H after 30 minutes
2sO
4termination reaction.Select 490nm wavelength, on enzyme-linked immunosorbent assay instrument, measure each hole absorption value, record result.Using OD value higher than 2.1 times of negative controls as positive colony.
E. the extraction of positive bacteriophage single stranded DNA and order-checking: get the above-mentioned phage storage of 500 μ l liquid, adding 200 μ lPEG8000/NaCl places 10 minutes, centrifugal 10 minutes of 14000rpm, abandons supernatant, and precipitation is resuspended in 100 μ l iodide damping fluids, add 250 μ l ethanol, room temperature effect 10 minutes, centrifugal 10 minutes of 14000rpm, abandons supernatant, wash precipitation, of short duration vacuum-drying with 70% ethanol.Precipitation is resuspended in 30 μ l TE (10mMTris-HCl, 1mMEDTA), gets above-mentioned solution order-checking.This order-checking is completed by Jin Wei intelligence bio tech ltd.
(2) by the sequencing result translation obtaining, choose the positive value of Elisa high by (0.834,0.717) and the consistent sequence of nucleotide sequence obtain binding peptide CPU-312-03, and deliver to the biochemical company limited of Ningbo health shellfish and synthesize and mark fluorescent probe, its nucleotides sequence is classified Seq NO.2 as, and aminoacid sequence is Seq NO.1.
Combination with computer simulation TfR TfR and binding peptide:
Set up out the model of TfR TfR and binding peptide with zDock docking software, then use the combination situation of discovery studio2.5 (DS2.5) software simulation TfR TfR and binding peptide, the mixture model that TfR TfR and binding peptide form is as Fig. 1, wherein bar shaped part represents TfR TfR, and spherical part represents binding peptide.Fig. 2 is the TfR TfR and the interactional amino-acid residue of binding peptide that go out with software simulation.Result shows that binding peptide is wrapped in the calmodulin binding domain CaM of being combined with TfR TfR, wherein 533 of TfR TfR, 559 L-glutamic acid (GLU533, GLU559), 538,560,562 aspartic acids (ASP538, ASP560, ASP562), with the arginine (ARG4) of binding peptide, between Histidine (HIS6), closely interact.
Fluorescence microplate reader detects cell to being coupled the picked-up experiment of FITC binding peptide and FITC:
The HepG2 cell (liver cancer cell) of taking the logarithm vegetative period, with appropriate 0.25% pancreatin solution digestion, jog makes Digestive system stepless action in cell, when the contracting of cell in blocks circle, while being individual cells state, add rapidly the appropriate RPMI-1640 substratum containing 10% calf serum, blow and beat gently and make into single cell suspension with suction pipe; Every hole adds 8 × 10
4individual cell, in 24 orifice plates, and adds 500 μ l containing the RPMI-1640 substratum of 10% serum, in 37 DEG C, containing 5%CO
2constant incubator in cultivate 24 hours to monolayer cell state; 1h before detecting, 2h, 3h, 4h adds respectively 500 μ l to be coupled the RPMI-1640 substratum of FITC binding peptide containing 10% calf serum, 50um, and 3 multiple holes of each time point, are placed in 37 DEG C, 5%CO
2in constant incubator, cultivate; Simultaneously using FITC and LO2 cell (normal liver cell) as negative control, detect fluorescence (λ ex=485nm, λ em=528nm) with fluorescence microplate reader.The above-mentioned substratum of sucking-off while detecting fluorescence, with PBS washing 2 times.Experimental result as shown in Figure 3 and Figure 4, in Fig. 3, CPU-312-03-FITC is serial for HepG2 cellular uptake is coupled time (h)-fluorescence intensity level (AU) curve that FITC binding peptide records, time (h)-fluorescence intensity level (AU) curve that FITC series records for HepG2 cellular uptake FITC.As can be seen from Figure 3 the former fluorescence intensity is higher than the latter, after illustrating that FITC and polypeptide are coupled, can pass through the endocytosis of Mediated by Transferrin Receptor cell to CPU-312-03-FITC, to compared with nonspecific endocytosis of FITC, intake improves greatly with cell.In Fig. 4, HepG2 series is coupled time (h)-fluorescence intensity level (AU) curve that FITC binding peptide records for HepG2 cellular uptake, LO2 series is coupled time (h)-fluorescence intensity level (AU) curve that FITC binding peptide records for LO2 cellular uptake, after 2h, the HepG2 cell fluorescence intensity value of high expression level TfR TfR is apparently higher than the LO2 cell fluorescence intensity value of low expression TfR TfR, TfR TfR expression level improves can improve the picked-up of cell to binding peptide, illustrate that this small peptide has and the target bonding force of high expression level TfR TfR tumour cell, and can be by fluorescein isothiocyanate (FITC) targeted cells.
Embodiment 4
Fluorescence microscope cell is to being coupled the experiment of engulfing of FITC binding peptide and FITC:
The HepG2 cell (liver cancer cell) of taking the logarithm vegetative period, with appropriate 0.25% pancreatin solution digestion, jog makes Digestive system stepless action in cell, when the contracting of cell in blocks circle, while being individual cells state, add rapidly the appropriate RPMI-1640 substratum containing 10% calf serum, blow and beat gently and make into single cell suspension with suction pipe, every hole adds 8 × 10
4individual cell, in 24 orifice plates, and adds 500 μ l containing the RPMI-1640 substratum of 10% serum, in 37 DEG C, containing 5%CO
2constant incubator in cultivate 24 hours to monolayer cell state, every hole adds 500 μ l to be coupled the RPMI-1640 substratum of FITC binding peptide containing 10% calf serum, 50um, 3 multiple holes, are placed in 37 DEG C, 5%CO
2in constant incubator, cultivate; Simultaneously using FITC and LO2 cell (normal liver cell) as negative control.The above-mentioned substratum of sucking-off after 4h, with PBS washing 2 times, with fluorescence microscope and take pictures.Experimental result is as shown in Fig. 5, Fig. 6, Fig. 7, Fig. 5 is that HepG2 cell is to being coupled the situation of engulfing of FITC binding peptide, Fig. 6 is the engulf situation of HepG2 cell to FITC, Fig. 7 is that LO2 cell is to being coupled the situation of engulfing of FITC binding peptide, illustrate the in the situation that of same time same concentrations, be coupled FITC binding peptide more easily by HepG2 cellular uptake, this is in conjunction with Toplink and TfR TfR interacts and make cytophagic FITC more.
Above experimental result shows, TfR TfR specific binding peptides CPU-312-03 of the present invention, can with the Cell binding of TfR TfR and high expression level TfR TfR, and can be by FITC targeted cells, have the ability of transhipment material targeted cells.To the exploitation of the tumor-targeting drug taking TfR TfR as target spot, the prediction of the targeted therapy of brain-borne disease and the tumor development taking TfR as target, diagnose significant.
Above-mentioned is exemplary embodiment; but embodiments of the present invention are not restricted to the described embodiments; any change, modification that does not deviate from the various forms done under spirit of the present invention and principle and details that the research of this area and technician should be appreciated that other, substitute, combination, simplify; all should be equivalent substitute mode, within being included in protection scope of the present invention.
Claims (6)
1. a TfR TfR specific binding peptides, is characterized in that: the aminoacid sequence of described binding peptide is as Seq NO.1.
2. a kind of TfR TfR specific binding peptides as claimed in claim 1, is characterized in that: the nucleotide sequence of described binding peptide is as Seq NO.2.
3. TfR TfR specific binding peptides as claimed in claim 1 is in the application of preparing in target tumor medicine.
4. TfR TfR specific binding peptides as claimed in claim 3, in the application of preparing in target tumor medicine, is characterized in that described TfR TfR is tumor surface high expression level TfR TfR.
5. the application of TfR TfR specific binding peptides as claimed in claim 1 in the saturating hemato encephalic barrier medicine of preparation.
6. the application of TfR TfR specific binding peptides as claimed in claim 1 in TfR TfR detects.
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| CN107250158A (en) * | 2014-11-19 | 2017-10-13 | 基因泰克公司 | Anti-rotation Human Placental Ferritin Receptor/anti-BACE1 multi-specificity antibodies and application method |
| CN110382526A (en) * | 2017-02-17 | 2019-10-25 | 戴纳立制药公司 | TfR transgenic models |
| CN112243953A (en) * | 2020-07-15 | 2021-01-22 | 吉林医药学院 | TfR1 lung tissue specific knockout mouse model and construction method and application thereof |
| CN113329758A (en) * | 2018-12-14 | 2021-08-31 | 弗莱德哈钦森癌症研究中心 | Transferrin receptor targeting peptides |
| WO2023022234A1 (en) * | 2021-08-19 | 2023-02-23 | ペプチドリーム株式会社 | Human transferrin receptor–binding peptide |
| US11612150B2 (en) | 2017-02-17 | 2023-03-28 | Denali Therapeutics Inc. | Transferrin receptor transgenic models |
| US11732023B2 (en) | 2017-02-17 | 2023-08-22 | Denali Therapeutics Inc. | Engineered polypeptides |
| WO2024114306A1 (en) * | 2022-11-29 | 2024-06-06 | Vacino Biotech Co., Ltd. | Transporter peptides and application thereof |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107250158A (en) * | 2014-11-19 | 2017-10-13 | 基因泰克公司 | Anti-rotation Human Placental Ferritin Receptor/anti-BACE1 multi-specificity antibodies and application method |
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| CN110382526A (en) * | 2017-02-17 | 2019-10-25 | 戴纳立制药公司 | TfR transgenic models |
| US11612150B2 (en) | 2017-02-17 | 2023-03-28 | Denali Therapeutics Inc. | Transferrin receptor transgenic models |
| US11732023B2 (en) | 2017-02-17 | 2023-08-22 | Denali Therapeutics Inc. | Engineered polypeptides |
| CN110382526B (en) * | 2017-02-17 | 2023-12-26 | 戴纳立制药公司 | Transferrin receptor transgene model |
| CN113329758A (en) * | 2018-12-14 | 2021-08-31 | 弗莱德哈钦森癌症研究中心 | Transferrin receptor targeting peptides |
| CN112243953A (en) * | 2020-07-15 | 2021-01-22 | 吉林医药学院 | TfR1 lung tissue specific knockout mouse model and construction method and application thereof |
| WO2023022234A1 (en) * | 2021-08-19 | 2023-02-23 | ペプチドリーム株式会社 | Human transferrin receptor–binding peptide |
| WO2024114306A1 (en) * | 2022-11-29 | 2024-06-06 | Vacino Biotech Co., Ltd. | Transporter peptides and application thereof |
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