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细胞穿膜肽TAT(48-60)、HIV-1 TAT (48-60),H2N-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Pro-Gln-COOH,H2N-GRKKRRQRRRPPQ-OH,杭州专肽生物的产品

细胞穿膜肽TAT(48-60)、HIV-1 TAT (48-60)

源自人免疫缺陷病毒 (HIV)-1蛋白残基48-60,可渗透细胞的多肽。它已被用于以不中断的方式将外源性大分子递送到细胞中。

编号:179948

CAS号:

单字母:H2N-GRKKRRQRRRPPQ-OH

纠错
  • 编号:179948
    中文名称:细胞穿膜肽TAT(48-60)、HIV-1 TAT (48-60)
    英文名:TAT(48-60)、HIV-1 TAT (48-60)
    单字母:H2N-GRKKRRQRRRPPQ-OH
    三字母:H2N

    N端氨基

    -Gly

    甘氨酸

    -Arg

    精氨酸

    -Lys

    赖氨酸

    -Lys

    赖氨酸

    -Arg

    精氨酸

    -Arg

    精氨酸

    -Gln

    谷氨酰胺

    -Arg

    精氨酸

    -Arg

    精氨酸

    -Arg

    精氨酸

    -Pro

    脯氨酸

    -Pro

    脯氨酸

    -Gln

    谷氨酰胺

    -OH

    C端羧基

    氨基酸个数:13
    分子式:C70H131N35O16
    平均分子量:1719.01
    精确分子量:1718.05
    等电点(PI):-
    pH=7.0时的净电荷数:8.97
    平均亲水性:2.44
    疏水性值:-3.49
    外观与性状:粉末状固体
    消光系数:-
    来源:人工化学合成,仅限科学研究使用,不得用于人体。
    纯度:95%、98%
    盐体系:可选TFA、HAc、HCl或其它
    生成周期:2-3周
    储存条件:负80℃至负20℃
    标签:细胞穿膜肽(Cell permeable peptides, CPPs)    人类免疫缺陷病(HIV)肽   

  • HIV-1 TAT (48-60) 是源自人免疫缺陷病毒 (HIV)-1蛋白残基48-60,可渗透细胞的多肽。它已被用于以不中断的方式将外源性大分子递送到细胞中。

    HIV-1 TAT (48-60) is a cell-penetrating peptide derived from the human immunodeficient virus (HIV)-1 Tat protein residue 48-60. It has been used to deliver exogenous macromolecules into cells in a non-disruptive way.

    细胞穿膜肽-说明
          穿透细胞膜进入细胞内是许多作用靶点在细胞内的生物大分子发挥作用的先决条件,然而生物膜的生物屏障作用阻止了许多高分子物质进入细胞内,从而很大程度地限制了这些物质在治疗领域的应用。因此,如何引导这些物质穿透细胞膜是一个迫切需要解决的问题,目前介导生物大分子穿透细胞膜的方法主要包括细胞穿透肽(cell penetrating peptides,CPPs)、脂质体、腺病毒、纳米颗粒、影细胞等,而CPPs是一类以非受体依赖方式,非经典内吞方式直接穿过细胞膜进入细胞的多肽,它们的长度一般不超过30个氨基酸且富含碱性氨基酸,氨基酸序列通常带正电荷。
          1型人免疫缺陷病毒转录激活因子TAT(human immunodeficiency virus-1 transcription activator, HIV-1 TAT)是第一个被发现的细胞穿透肽,它凭借一种无毒的、高效的方式进入细胞。
          细胞穿透肽(cell penetrating peptides,CPPs)的一个重要特点是可以携带多种不同大小和性质的生物活性物质进入细胞,包括小分子化合物、染料、多肽、多肽核酸(peptide nucleo acid, PNA)、蛋白质、质粒DNA、siRNA、200nm的脂质体、噬菌体颗粒和超顺磁性粒子等,这一性质为其成为靶向药物的良好载体提供了可能。
          CPPs作为载体的优势在于低毒性和无细胞类型的限制,尽管CPPs可输送不同类型的物质进入细胞,但其实际应用多集中于寡肽、蛋白质、寡聚核苷(oligonucleotides,ONs)或类似物的细胞转运。

    跨膜机理
    不同的细胞穿透肽(CPP)跨膜机制不同,一个细胞穿透肽(CPP)的具体机制有赖于几个参数,如分子大小(携带物质)、温度、细胞类型和细胞内外的稳定性等。细胞穿透肽(CPP)进入细胞的具体机制目前还不清楚,比较流行的推测包括以下三种:
    A: 倒置胶粒模型(inverted micelle model),CPPs通过细胞膜上磷脂分子的移动形成倒置胶粒结构,而进入胞浆。
    B: 直接穿透,即孔隙结构模型 (pore formation model),CPPs在细胞膜上组成跨膜的孔隙结构而进入胞浆 。
    C: 内吞方式进行细胞摄取。
    来源: Cell-penetrating peptides and their therapeutic applications, Victoria Sebbage, BioscienceHorizons, Volume 2, Number 1, March 2009.


    细胞穿透肽 HIV TAT
          细胞穿透肽(如HIV TAT)可以以直接穿透和内吞两种方式进入细胞。HIV TAT或者简单的多聚精氨酸可被设计作为有效的药物载体,但CPP(如HIV TAT)是如何实现胞膜转运,目前仍不清楚。
    简单的HIV TAT是如何促进象直接穿透和内吞作用的入胞机制的呢?来自Gerard Wong实验室的研究人员研究了在不同的条件下,HIV TAT是如何与细胞质膜、细胞骨架、特异的胞膜受体相互作用,从而诱导了多重转运途径。

          有趣的是,TAT在不同条件下可与同一序列发生多种不同的反应,因而与胞膜、细胞骨架、特异受体相互作用可产生多种转运途径。
          CPP的跨膜机制与多肽序列存在很敏感的关系,如果在一个纯亲水性的CPP中增加一个疏水残基,就能彻底地改变其转运机制,例如,最简单的CPP原型-多聚精氨基(polyR),可以诱导细胞膜上形成跨膜的孔隙结构。疏水氨基酸通过插入胞膜来形成正曲率,精氨酸可同时形成正曲率和负曲率,赖氨酸只能沿一个方向形成负曲率,这就意味着在精氨酸与赖氨酸/疏水物之间存在补偿关系。
          如果疏水性有助于形成负高斯曲率(Gaussian curvature),那为什么TAT肽中的疏水含量相对较低呢?其原因是CPPs都是利用尽可能少的疏水基去形成saddle-splay curvature。序列上的差异很可能只会在膜上诱导短暂的类似孔隙的跨膜结构,从而形成对CPP来说更短的孔隙寿命。由于CPP的氨基酸组成不同,TAT肽在有或无受体情况下都可以介导细胞内吞作用。

         专肽生物提供各类细胞穿膜肽序列,部分由现货,例如TAT,R8,R4等,具体可咨询销售人员。

    Definition

    Cell permeable peptides (CPPs) are carriers with small peptide domains that can freely cross cell membranes.  They are mainly used as carriers of proteins and nucleic acids into the cell1.

    Discovery

    The first CPP was discovered independently by two laboratories in 1988 when it was found that the trans-activating transcriptional activator (Tat) from Human Immunodeficiency Virus 1 (HIV-1) could be efficiently taken up from the surrounding media by numerous cell types in culture2. 

    Structural Characteristics

    CPPs typically have an amino acid composition containing either a high relative abundance of positively charged, cationic amino acids such as lysine or arginine, or have sequences that contain an alternating pattern of polar/charged amino acids and non-polar, hydrophobic amino acids3.  Some examples include: TAT peptide-YGRKKRRQRRR, lipid membrane translocating peptide-KKAAAVLLPVLLAAP and Antennapedia leader peptide-KKWKMRRNQFWVKVQRG.

    Classification

    Numerous CPPs have been identified to date and they belong to a wide variety of protein families. For example, some CPPs are amphipathic protein family members3.

    Mode of action

    CPPs enter the cell with their carrier by either of three mechanisms:  Direct delivery that involves energy independent entry of the CPPs in to the cell4, endocytosis where the cells take up the CPPs by imbibing them with their cell membranes5 and translocation through the formation of transient structures which is yet to be understood6. 

    Functions

    CPPs have found numerous applications in medicine as drug delivery agents in the treatment of different diseases including cancer, virus inhibitors, contrast agents for cell labeling a classical example is Green Fluorescent protein GFP, as MRI contrast agents, quantum dots7.  TAT is very effective in delivering drugs in vitro and in vivo and so far a peptide that matches its efficiency has not been found7.

    References

    1.     Wagstaff KM and David JA (2006). Protein Transduction: Cell Penetrating Peptides and Their Therapeutic Applications, Current Medicinal Chemistry, 13 (12), 1371-1387.

    2.     Feng S and Holland EC (1988). HIV-1 Tat trans-activation requires the loop sequence within Tar. Nature 334, 165–167.

    3.     Stewart KM, Horton KL, Kelley SO (2008). Cell-penetrating peptides as delivery vehicles for biology and medicine, Org Biomol Chem., 6(13), 2242-55.

    4.     Luo D, Saltzman WM (2000). Synthetic DNA delivery systems. Nat. Biotechnol, 18, 33-37.

    5.     Lundberg M., Wikstrom S and Johansson M (2003). Cell surface adherence and endocytosis of protein transduction domains, Mol. Ther., 8, 143–150.

    6.     Deshayes S, Gerbal-Chaloin S, Morris MC, Aldrian-Herrada G, Charnet P, Divita G (2004). On the mechanism of non-endosomial peptide-mediated cellular delivery of nucleic acids, Biochim. Biophys. Acta, 1667, 141–147.

    7.     Temsamani J and Vida P (2004). The use of cell-penetrating peptides for drug delivery, Drug Discovery Today, 9 (23), 1012-1019.

    Definition
    Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS), a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. Over 5000 HIV-related peptides have been synthesized, that inhibit different stages of viral life cycle.

    Discovery
    In 1983, two separate researchers Robert Gallo and Luc Montagnier independently declared that a novel retrovirus infecting AIDS patients. Several HIV related peptides including peptides (15-mers or 20-mers) of HIV glycoprotein 160 (gp160), gp120W16D, MN envelope (env) consensus B tat, consensus B VIF, HXB2 gag, SIVmac239, SIVmac239env, SIVmac239 gag have been used to study HIV life cycle. C34 peptide of Gp41 HIV Fragment is known as HR2, belongs to the helical region of gp41 of HIV, C-terminal heptad repeat 2 (HR2) defined as C helix or C peptide. It is known that HIV-1 enters cells by membrane fusion, C34 gp41 peptide is a potent inhibitors of HIV-1 fusion 1,2. The 86 amino acid trans-activator (Tat) protein of human immunodeficiency virus type 1 (HIV-1) is an RNA-binding transcriptional regulator. HIV-1 Tat proteins (wild type and Thr40Lys mutant) and the HIV-1 Tat peptide fragments Tat(32–48) and Tat(32–72) were chemically synthesized and used for HIV studies 3.

    HIV (gp120) fragment (254-274), this fragment with sequence homology to a domain of the external envelope glycoprotein (gp120) of the human immunodeficiency virus (HIV) is important for HIV infectivity and antibody neutralization 4. HIV (gp120) fragment (421-438), derived from the CD4 attachment region of HIV gp120, inhibited the syncytial formation in vitro 5. HIV-1 gag protein p17 (76-84), HLA-A*0201-restricted immunodominant CD8 epitope of the HIV gag protein used for the characterization of CD8+ -T cells of HIV-positiv patients 6. HIV-1 rev protein (34-50), this arginine-rich fragment interacts specifically with RNA. It has been shown that rev protein and rev protein (34-50) bind IIB RNA with a similar dissociation constant of approx. 10 nM 7.

    Structural Characteristics
    The HIV type-1 belongs to the family Retroviridae and consists of two basic components: a core of ribonucleic acid (RNA), called the genome, and a protein component that surrounds the genome, called a capsid. The single-stranded RNA is tightly bound to nucleocapsid proteins and enzymes needed for the morphogenesis of the virion such as reverse transcriptase, proteases, ribonuclease and integrase. A matrix composed of the viral protein that surrounds the capsid. Viral envelope is composed of two layers of fatty molecules taken from the membrane of a human cell during budding process. There are 70 copies of a complex HIV protein that protrudes through the surface of the virus particle, known as Env, consists of a cap, glycoprotein (gp) 120, and a stem, gp41 molecules. This glycoprotein complex is important for fusion of virus to host cell. Both these surface proteins are important targets for treatments or HIV vaccines 8.

    Mode of Action
    HIV binds to a CD4 receptor and one of two co-receptors on the surface of a CD4+ T- lymphocyte. After fusion, the virus releases RNA, its genetic material, into the host cell. An HIV enzyme called reverse transcriptase converts the single- stranded HIV RNA to double-stranded HIV DNA. The newly formed HIV DNA enters the host cell's nucleus. The integrated HIV DNA is called provirus. The provirus may remain inactive for several years, producing few or no new copies of HIV. When the host cell receives a signal to become active, the provirus uses a host enzyme called RNA polymerase to create copies of the HIV genomic material, as well as shorter strands of RNA called messenger RNA (mRNA). The mRNA is used as a blueprint to make long chains of HIV proteins. An HIV enzyme called protease cuts the long chains of HIV proteins into smaller individual proteins. As the smaller HIV proteins come together with copies of HIV's RNA genetic material, a new virus particle is assembled. The newly assembled virus buds out from the host cell. During budding, the new virus acquires part of the cell's outer envelope. This envelope is embedded with viral glycoproteins which are necessary for host cell recognition.

    Functions

    CD8 cytotoxic, HIV-1 specific CD8 cytotoxic T lymphocyte (CTL) responses play a critical role in controlling HIV-1 replication. TCR avidity correlates with CTL function, and CTLs expressing TCRs with high avidity for their cognate MHC-viral peptide complex play an important in vivo role in neutralizing virus infections, terminating virus infection and delaying systemic AIDS virus dissemination from the mucosal inoculation site.

    HIV-1 envelope transmembrane protein that contain highly positively charged amphipathic helices (designated LLP) in have both cytolytic and calmodulin (CaM) binding/inhibitory properties that contribute to cytopathogenesis during a viral infection.

    HIV-1 vif, The human immunodeficiency virus type 1 (HIV-1) auxiliary gene vif is essential for virus propagation in peripheral blood lymphocytes, macrophages, and in some T-cell lines. (i) Vif protein binds HIV-1 PR (protease), but not covalently linked tethered PR-PR; (ii) the four amino acids residing at the N terminus of HIV-1 PR are essential for Vif/PR interaction; (iii) synthetic peptide derived from the N terminus of HIV-1 PR inhibits Vif/PR binding; and (iv) this peptide inhibits the propagation of HIV-1 in restrictive cells 9.

    References

    1.     Bianchi E, Finotto M, Ingallinella P, Hrin R, Carella AV, Hou XS, Schleif WA, Miller MD, Geleziunas R, Pessi A (2005). Covalent stabilization of coiled coils of the HIV gp41 N region yields extremely potent and broad inhibitors of viral infection. PNAS., 102(36):12903-12908

    2.     de Rosny E, Vassell R, Jiang S, Kunert R, Weiss CD (2004). Binding of the 2F5 monoclonal antibody to native and fusion-intermediate forms of human immunodeficiency virus type 1 gp41: implications for fusion-inducing conformational changes. J. Virol., 78(5):2627-2631.
    3.     Klostermeier D, Bayer P, Kraft M, Frank RW, Rösch P (1997). Spectroscopic investigations of HIV-1 trans-activator and related peptides in aqueous solutions. Biophysical Chemistry, 63(2):87-96.

    4.     Ho DD, Kaplan JC, Rackauskas IE, Gurney ME (1988). Second conserved domain of gp120 is important for HIV infectivity and antibody neutralization. Science, 239(4843):1021-1023.

    5.     Morrow WJ, Williams WM, Whalley AS, Ryskamp T, Newman R, Kang CY, Chamat S, Köhler H, Kieber-Emmons T (1992). Synthetic peptides from a conserved region of gp120 induce broadly reactive anti-HIV responses. Immunology, 75(4):557-564.

    6.     Wilkinson J, Cope A, Gill J, Bourboulia D, Hayes P, Imami N, Kubo T, Marcelin A, Calvez V, Weiss R, Gazzard B, Boshoff C, Gotch F (2002). Identification of Kaposi's sarcoma-associated herpesvirus (KSHV)-specific cytotoxic T-lymphocyte epitopes and evaluation of reconstitution of KSHV-specific responses in human immunodeficiency virus type 1-Infected patients receiving highly active antiretroviral therapy. J. Virol., 76(6):2634-2640.

    7.     Kjems J, Calnan BJ, Frankel AD, Sharp PA (1992). Specific binding of a basic peptide from HIV-1 Rev. EMBO J., 11(3):1119-29.
    8.     Chan DC, Fass D, Berger JM, Kim PS (1997). Core structure of gp41 from the HIV   envlope glycoprotein . Cell, 89:263–73.

    9.     Hutoran M, Britan E, Baraz L, Blumenzweig I, Steinitz M, Kotler M (2004). Abrogation of Vif function by peptide derived from the N-terminal region of the human immunodeficiency virus type 1 (HIV-1) protease. Virology, 330(1):261-270.

  • DOI名称
    10.1016/s0006-291x(03)01135-5Uptake of analogs of penetratin, Tat(48-60) and oligoarginine in live cells下载
    10.1002/cphc.200600306The cell-penetrating peptide TAT(48-60) induces a non-lamellar phase in DMPC membranes下载
    10.1074/jbc.272.25.16010A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus下载
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