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TPP-1 Sale

目录号 : GC61946

TPP-1 是 PD-1/PD-L1 相互作用的有效抑制剂。TPP-1 与 PD-L1 特异性高亲和力结合 (KD=95 nM)。动物模型中,TPP-1 通过再激活 T 细胞功能抑制肿瘤生长。

TPP-1 Chemical Structure

Cas No.:2426685-25-6

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25 mg
¥5,400.00
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产品描述

TPP-1 is a potent inhibitor of the PD-1/PD-L1 interaction. TPP-1 binds specifically to PD-L1 with a high affinity (KD=95 nM). TPP-1 inhibits human tumor growth in vivo via reactivating T-cell function[1].

TPP-1 binds to PD-L1 with high affinity and blocks PD-1/PD-L1 interaction. The KD value of PD-L1 with TPP-1 peptide is about 95 nmol/L (around five times less than that with PD-1), The binding site of TPP-1 to PD-L1 is close to the interactive site of PD-1 and PD-L1[1].TPP-1 (4 µM) reactivates T-cell functions, it induces IFNγ release significantly higher than control and SPP-1, and the TPP-1 group shows similar outcomes for cell proliferation[1].

TPP-1 (subcutaneous injection; 4 mg/kg; every other day eight times; 32 days) inhibits tumor growth (compared with SPP-1 and control). The growth rate in TPP-1-treated mice is 56%. And when administered in the absence of T cells (control group), TPP-1 has no effect on the growth of the H460-luc tumors[1].

References:
[1]. Chunlin Li, et al. Peptide Blocking of PD-1/PD-L1 Interaction for Cancer Immunotherapy. Cancer Immunol Res. 2018 Feb;6(2):178-188.

Chemical Properties

Cas No. 2426685-25-6 SDF
分子式 C107H150N34O32S2 分子量 2488.67
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1 mM 0.4018 mL 2.0091 mL 4.0182 mL
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Research Update

Peptide Blocking of PD-1/PD-L1 Interaction for Cancer Immunotherapy

Cancer Immunol Res 2018 Feb;6(2):178-188.PMID:29217732DOI:10.1158/2326-6066.CIR-17-0035.

Immunotherapy has become a promising alternative therapeutic approach for cancer patients. Interruption of immune checkpoints, such as CTLA-4 and PD-1, has been verified to be a successful means for cancer therapy in clinical trials. mAb targeting PD-L1 has been approved to treat urothelial carcinoma, non-small cell lung cancer, or Merkel cell carcinoma by the FDA. However, the high cost of the antibody can limit its application. In our study, targeting PD-L1 peptide (TPP-1), which specifically binds to PD-L1 with high affinity, was identified through bacterial surface display methods. Using a T-cell activation assay and mixed lymphocyte reaction, TPP-1 was verified to interfere with the interaction of PD-1/PD-L1. To examine the inhibitory effect of TPP-1 on tumor growth in vivo, a xenograft mouse model using H460 cells was established. The growth rate of tumor masses in TPP-1 or PD-L1 antibody-treated mice was 56% or 71% lower than that in control peptide-treated mice, respectively, indicating that TPP-1 inhibits, or at least retards, tumor growth. IHC of the tumors showed that IFNγ and granzyme B expression increased in the TPP-1 or PD-L1 antibody-treated groups, indicating that TPP-1 attenuates the inhibitory effect of PD-L1 on T cells and that T cells may get reactivated. On the basis of our data, TPP-1 peptide could work as an alternative to antibodies for tumor immunotherapy. Cancer Immunol Res; 6(2); 178-88. ©2017 AACR.

Polysaccharide extracted from Taraxacum platycarpum root exerts immunomodulatory activity via MAPK and NF-κB pathways in RAW264.7 cells

J Ethnopharmacol 2021 Dec 5;281:114519.PMID:34390795DOI:10.1016/j.jep.2021.114519.

Ethnopharmacological relevance: Taraxacum platycarpum Dahlst. (Korean dandelion) is a medicinal herb used in traditional medicine in Korea to treat various disease such as furuncles, mammitis, hepatitis, jaundice. Moreover, a decoction prepared from T. platycarpum leaves and stems is an effective treatment for cancer, glycosuria, liver disease, pleurodynia, and stomach problems. Aim of the study: The main objective of this work was to study the composition and structural properties of polysaccharides (TPP) from Taraxacum platycarpum Dahlst. root and investigate the immunostimulatory activity on RAW264.7 cells. Materials and methods: TPP was extracted from T. platycarpum using hot water extraction, ethanol precipitation method and its fractionated using DEAE-Sepharose fast flow column. The composition, molecular weight, and structural characterization of TPP and its fractions were evaluated by various techniques. Further, the immunostimulatory activity of polysaccharides was tested on murine macrophage cell line RAW264.7 by various in vitro assays. The structure effect of TPP on RAW264.7 cells was studied by the removal of sulfate (desulfation) and protein (deproteinization) contents from TPP. Results: We obtained three fractions namely TPP-1, TPP-2, and TPP-3 which mainly consisted of carbohydrates (75.55, 52.71, and 48.41%), sulfate (8.42, 15.19, and 27.67%), uronic acid (1.27, 6.56, and 4.39%), and protein (8.15, 24.85, and 9.73%). The average molecular weight of the fractions was 56.7, 108.2, and 132.3 × 103 g/mol, respectively. The polysaccharides activate the RAW264.7 cell to produce a significant amount of NO and upregulate the various mRNA expression by the activation of MAPK and NF-κB pathways via TLR4, TLR2, and CR3 receptors. The structurally modified deproteinated derivative (DP-TPP-2) more effectively decreases the NO production which means the protein content of TPP-2 mainly contributes to the RAW264.7 cells activation. The structure of DP-TPP-2 primarily consists of 1 → 2)-Galp, 1 → 6)-Glup, 1 → 2) - Rhap, and 1 → 5) - Arap glycosidic linkages. Conclusions: The present study demonstrated that the polysaccharide isolated from T. platycarpum shows admirable immunostimulatory by the activation of MAPK and NF-κB pathways through TLR4, TLR2, and CR3 receptors. The protein content of polysaccharides mainly contributes to the RAW264.7 cells activation. Our study results could be useful for developing a new immunostimulant agent.

Tumor cell membrane-based peptide delivery system targeting the tumor microenvironment for cancer immunotherapy and diagnosis

Acta Biomater 2021 Jun;127:266-275.PMID:33813091DOI:10.1016/j.actbio.2021.03.056.

The development of an effective delivery system for peptides targeting the tumor microenvironment has always been a hot topic of research in the field of cancer diagnosis and therapy. In this study, superparamagnetic iron oxide nanoparticles (SPIO NPs) were encapsulated with H460 lung cancer cell membranes (SPIO NP@M), and two peptides, namely PD-L1 inhibitory peptide (TPP1) and MMP2 substrate peptide (PLGLLG), were conjugated to the H460 membrane (SPIO NP@M-P). Homologous targeting, cytotoxicity, and pharmacokinetics of SPIO NP@M-P were evaluated. The TPP1 peptide was delivered and released to the tumor microenvironment through the homotypic effect of tumor cell membrane and specific digestion by the tumor-specific enzyme MMP2. The newly developed delivery system (SPIO NP@M-P) for the PD-L1 inhibitory peptide could effectively extend the half-life of the peptides (60 times longer than that for peptides alone) and could maintain the ability to reactivate T cells and inhibit the tumor growth both in vitro and in vivo. Furthermore, SPIO NPs in the system could be used as a tumor imaging agent and thus show the effect of peptide treatment. The SPIO NP@M might serve as a promising theranostic platform for therapeutic application of peptides in cancer therapy. STATEMENT OF SIGNIFICANCE: A multifunctional delivery system (SPIO NP@M) was constructed for effectively delivering therapeutic peptides into the tumor microenvironment for cancer diagnosis and therapy. In this paper, the TPP-1 peptide inhibiting the binding of PD-L1 and PD-1 was delivered and released into the tumor microenvironment by the homotypic targeting of H460 cell membrane and specific digestion by the MMP2 enzyme. SPIO NPs in this system were aggregated effectively at the tumor sites and were used for magnetic resonance imaging of tumors. The SPIO NP@M-P delivery system could effectively extend the half-life of the TPP-1 peptide (60 times longer than that of the free peptide) and could maintain the ability to re-activate T cells and inhibit tumor growth in vitro and in vivo. In conclusion, the SPIO NP@M system coated with lung cancer cell membrane and loaded with the PD-L1-blocking TPP-1 peptide could be a promising integrated platform for tumor diagnosis and treatment.

Serine-Carboxyl Peptidases, Sedolisins: From Discovery to Evolution

Biochemistry 2022 Aug 16;61(16):1643-1664.PMID:35862020DOI:10.1021/acs.biochem.2c00239.

Sedolisin is a proteolytic enzyme, listed in the peptidase database MEROPS as a founding member of clan SB, family S53. This enzyme, although active at low pH, was originally shown not to be inhibited by an aspartic peptidase specific inhibitor, S-PI (pepstatin Ac). In this Perspective, the S53 family is described from the moment of original identification to evolution. The representative enzymes of the family are sedolisin, kumamolisin, and TPP-1. They exhibit the following unique features. (1) The fold of the molecule is similar to that of subtilisin, but the catalytic residues consist of a triad, Ser/Glu/Asp, that is unlike the Ser/His/Asp triad of subtilisin. (2) The molecule is expressed as a pro-form composed of the amino-terminal prosegment and the active domain. Additionally, some members of this family have an additional, carboxy-terminal prosegment. (3) Their optimum pH for activity is in the acidic region, not in the neutral to alkaline region where subtilisin is active. (4) Their distribution in nature is very broad across the three kingdoms of life. (5) Some of these enzymes from fungi and bacteria are pathogens to plants. (6) Some of them have significant potential applications for industry. (7) The lack of a TPP-1 gene in human brain is the cause of incurable juvenile neuronal ceroid lipofuscinosis (Batten's disease).

Different molecular mechanisms involved in spontaneous and oxidative stress-induced mitochondrial fragmentation in tripeptidyl peptidase-1 (TPP-1)-deficient fibroblasts

Biosci Rep 2013 Feb 7;33(2):e00023.PMID:23249249DOI:10.1042/BSR20120104.

NCLs (neuronal ceroid lipofuscinoses) form a group of eight inherited autosomal recessive diseases characterized by the intralysosomal accumulation of autofluorescent pigments, called ceroids. Recent data suggest that the pathogenesis of NCL is associated with the appearance of fragmented mitochondria with altered functions. However, even if an impairement in the autophagic pathway has often been evoked, the molecular mechanisms leading to mitochondrial fragmentation in response to a lysosomal dysfunction are still poorly understood. In this study, we show that fibroblasts that are deficient for the TPP-1 (tripeptidyl peptidase-1), a lysosomal hydrolase encoded by the gene mutated in the LINCL (late infantile NCL, CLN2 form) also exhibit a fragmented mitochondrial network. This morphological alteration is accompanied by an increase in the expression of the protein BNIP3 (Bcl2/adenovirus E1B 19 kDa interacting protein 3) as well as a decrease in the abundance of mitofusins 1 and 2, two proteins involved in mitochondrial fusion. Using RNAi (RNA interference) and quantitative analysis of the mitochondrial morphology, we show that the inhibition of BNIP3 expression does not result in an increase in the reticulation of the mitochondrial population in LINCL cells. However, this protein seems to play a key role in cell response to mitochondrial oxidative stress as it sensitizes mitochondria to antimycin A-induced fragmentation. To our knowledge, our results bring the first evidence of a mechanism that links TPP-1 deficiency and oxidative stress-induced changes in mitochondrial morphology.