专肽生物_定制多肽合成服务_多肽合成定制服务_多肽合成厂家_多肽合成公司

P18IIIB, derived from the V3 loop of HIV-1 IIIB gp120 efficiently blocked HIV-1 IIIB infection of several T-cell lines and of normal human T cells. RIQRGPGRAFVTIGK also blocked syncytium formation in human cells. Moreover, P18IIIB was capable of inducing HIV-1 specific cytotoxic T lymphocyte responses that could effectively kill virus-infected cells and could thus find several therapeutic applications.

Peptide H-RIQRGPGRAFVTIGK-OH is a Research Peptide with significant interest within the field academic and medical research. Recent citations using H-RIQRGPGRAFVTIGK-OH include the following: An endogenous HIV envelope-derived peptide without the terminal NH3+ group anchor is physiologically presented by major histocompatibility complex class I Y Samino, D Lopez , S Guil, P de Leon - Journal of Biological , 2004 - ASBMBhttps://www.jbc.org/article/S0021-9258(18)52725-3/abstract Analysis of the mechanism for extracellular processing in the presentation of human immunodeficiency virus-1 envelope protein-derived peptide to epitope-specific Y Nakagawa, T Takeshita, JA Berzofsky - , 2000 - Wiley Online Libraryhttps://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2567.2000.00092.x Molecular analysis of TCR and peptide/MHC interaction using P18-I10-derived peptides with a single D-amino acid substitution Y Nakagawa, H Kikuchi, H Takahashi - Biophysical journal, 2007 - cell.comhttps://www.cell.com/biophysj/pdf/S0006-3495(07)71061-5.pdf Structural comparison of a 15 residue peptide from the V3 loop of HIV-1IIIb and an O-glycosylated analogue X Huang, M Charles Smith, JA Berzofsky - FEBS , 1996 - Wiley Online Libraryhttps://febs.onlinelibrary.wiley.com/doi/abs/10.1016/0014-5793(96)00912-X Role of conserved regions of class I MHC molecules in the activation of CD8+ cytotoxic T lymphocytes by peptide and purified cell-free class I molecules T Takeshita, S Kozlowski , RD England - International , 1993 - academic.oup.comhttps://academic.oup.com/intimm/article-abstract/5/9/1129/708906 Use of Helper T Cell-Inducing Peptides from Conserved Regions in HIV-1 env in a Noncovalent Mixture with a CTL-Inducing V3-Loop Peptide for in Vivo Induction of PN NEHETE, RB ARLINGHAUS, KJ SASTRY - Viral immunology, 1994 - liebertpub.comhttps://www.liebertpub.com/doi/abs/10.1089/vim.1994.7.189 Comparison and fine mapping of both high and low neutralizing monoclonal antibodies against the principal neutralization domain of HIV-1 JPM Langedijk , NKT Back, E Kinney-Thomas - Archives of , 1992 - Springerhttps://link.springer.com/article/10.1007/BF01309690 Enhanced immunogenicity of HIV-1 vaccine construct by modification of the native peptide sequence JD Ahlers, T Takeshita - Proceedings of the , 1997 - National Acad Scienceshttps://www.pnas.org/doi/abs/10.1073/pnas.94.20.10856 Induction of CD8+ cytotoxic T lymphocytes by immunization with syngeneic irradiated HIV-1 envelope derived peptide-pulsed dendritic cells H Takahashi, Y Nakagawa, K Yokomuro - International , 1993 - academic.oup.comhttps://academic.oup.com/intimm/article-abstract/5/8/849/653193 Structural requirements for class I MHC molecule-mediated antigen presentation and cytotoxic T cell recognition of an immunodominant determinant of the human H Takahashi, R Houghten, SD Putney - The Journal of , 1989 - rupress.orghttps://rupress.org/jem/article-abstract/170/6/2023/50194 NMR study of a peptide derived from the principal neutralization domain of HIV-1 and its conjugates with bovine pancreatic trypsin inhibitor G Wu - 1997 - search.proquest.comhttps://search.proquest.com/openview/1dbad4b41e1c9fef42522c8b6cb6bf5b/1?pq-origsite=gscholar&cbl=18750&diss=y Enhanced CD8+ T cell immune response against a V3 loop multi-epitope polypeptide (TAB13) of HIV-1 Env after priming with purified fusion protein and booster with CE Gomez , D RodrÃ\x84±Ã\x8cÂ\x81guez , JR RodrÃ\x84±Ã\x8cÂ\x81guez, F Abaitua - Vaccine, 2001 - Elsevierhttps://www.sciencedirect.com/science/article/pii/S0264410X01003899 Solid-phase peptide synthesis, lead generation, and optimization B Seligmann, M Lebl, KS Lam - Chemistry and Molecular Diversity in Drug , 1998 - 5z.comhttp://www.5z.com/mlebl/publications/1998CombChemMolDivDrugDisc.pdf

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.

定义
酶是用于生化反应的非常有效的催化剂。它们通过提供较低活化能的替代反应途径来加快反应速度。酶作用于底物并产生产物。一些物质降低或什至停止酶的催化活性被称为抑制剂。
发现
1965年，Umezawa H分析了微生物产生的酶抑制剂，并分离出了抑制亮肽素和抗痛药的胰蛋白酶和木瓜蛋白酶，乳糜蛋白酶抑制的胰凝乳蛋白酶，胃蛋白酶抑制素抑制胃蛋白酶，泛磷酰胺抑制唾液酸酶，乌藤酮抑制酪氨酸羟化酶，多巴汀抑制多巴胺3-羟硫基嘧啶和多巴胺3-羟色胺酶酪氨酸羟化酶和多巴胺J3-羟化酶。最近，一种替代方法已应用于预测新的抑制剂：合理的药物设计使用酶活性位点的三维结构来预测哪些分子可能是抑制剂1。已经开发了用于识别酶抑制剂的基于计算机的方法，例如分子力学和分子对接。
结构特征
已经确定了许多抑制剂的晶体结构。已经确定了三种与凝血酶复合的高效且选择性的低分子量刚性肽醛醛抑制剂的晶体结构。这三种抑制剂全部在P3位置具有一个新的内酰胺部分，而对胰蛋白酶选择性最高的两种抑制剂在P1位置具有一个与S1特异性位点结合的胍基哌啶基。凝血酶的抑制动力学从慢到快变化，而对于胰蛋白酶，抑制的动力学在所有情况下都快。根据两步机理2中稳定过渡态络合物的缓慢形成来检验动力学。
埃米尔•菲舍尔（Emil Fischer）在1894年提出，酶和底物都具有特定的互补几何形状，彼此恰好契合。这称为“锁和钥匙”模型3。丹尼尔·科什兰（Daniel Koshland）提出了诱导拟合模型，其中底物和酶是相当灵活的结构，当底物与酶4相互作用时，活性位点通过与底物的相互作用不断重塑。
在众多生物活性肽的成熟过程中，需要由其谷氨酰胺（或谷氨酰胺）前体形成N末端焦谷氨酸（pGlu）。游离形式并与底物和三种咪唑衍生抑制剂结合的人QC的结构揭示了类似于两个锌外肽酶的α/β支架，但有多个插入和缺失，特别是在活性位点区域。几种活性位点突变酶的结构分析为针对QC相关疾病5的抑制剂的合理设计提供了结构基础。
作用方式
酶是催化化学反应的蛋白质。酶与底物相互作用并将其转化为产物。抑制剂的结合可以阻止底物进入酶的活性位点和/或阻止酶催化其反应。抑制剂的种类繁多，包括：非特异性，不可逆，可逆-竞争性和非竞争性。可逆抑制剂 以非共价相互作用（例如疏水相互作用，氢键和离子键）与酶结合。非特异性抑制方法包括最终使酶的蛋白质部分变性并因此不可逆的任何物理或化学变化。特定抑制剂 对单一酶发挥作用。大多数毒药通过特异性抑制酶发挥作用。竞争性抑制剂是任何与底物的化学结构和分子几何结构非常相似的化合物。抑制剂可以在活性位点与酶相互作用，但是没有反应发生。非竞争性抑制剂是与酶相互作用但通常不在活性位点相互作用的物质。非竞争性抑制剂的净作用是改变酶的形状，从而改变活性位点，从而使底物不再能与酶相互作用而产生反应。非竞争性抑制剂通常是可逆的。不可逆抑制剂与酶形成牢固的共价键。这些抑制剂可以在活性位点附近或附近起作用。
功能
工业应用中， 酶在商业上被广泛使用，例如在洗涤剂，食品和酿造工业中。蛋白酶用于“生物”洗衣粉中，以加速蛋白质在诸如血液和鸡蛋等污渍中的分解。商业上使用酶的问题包括：它们是水溶性的，这使得它们难以回收，并且一些产物可以抑制酶的活性（反馈抑制）。
药物分子，许多药物分子都是酶抑制剂，药用酶抑制剂通常以其特异性和效力为特征。高度的特异性和效力表明该药物具有较少的副作用和较低的毒性。酶抑制剂在自然界中发现，并且也作为药理学和生物化学的一部分进行设计和生产6。
天然毒物 通常是酶抑制剂，已进化为保护植物或动物免受天敌的侵害。这些天然毒素包括一些已知最剧毒的化合物。
神经气体（ 例如二异丙基氟磷酸酯（DFP））通过与丝氨酸的羟基反应生成酯，从而抑制了乙酰胆碱酯酶的活性位点。
参考
1、Scapin G (2006). Structural biology and drug discovery. Curr. Pharm. Des.,      12(17):2087–2097.
2、Krishnan R, Zhang E, Hakansson K, Arni RK, Tulinsky A, Lim-Wilby MS, Levy OE, Semple JE, Brunck TK (1998). Highly selective mechanism-based thrombin inhibitors:  structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes. Biochemistry, 37 (35):12094-12103.
3、Fischer E (1894). Einfluss der configuration auf die wirkung der enzyme. Ber. Dt. Chem. Ges., 27:2985–2993.
4、Koshland DE (1958). Application of a theory of enzyme specificity to protein synthesis. PNAS., 44 (2):98–104.
5、Huang KF, Liu YL, Cheng WJ, Ko TP, Wang AH (2005). Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation. PNAS., 102(37):13117-13122.
6、Holmes CF, Maynes JT, Perreault KR, Dawson JF, James MN (2002). Molecular enzymology underlying regulation of protein phosphatase-1 by natural toxins. Curr Med Chem., 9(22):1981-1989.

Definition
Enzymes are very efficient catalysts for biochemical reactions. They speed up reactions by providing an alternative reaction pathway of lower activation energy. Enzyme acts on substrate and gives rise to a product. Some substances reduce or even stop the catalytic activities of enzymes are called inhibitors.

Discovery
In 1965, Umezawa H analysed enzyme inhibitors produced by microorganisms and isolated leupeptin and antipain inhibiting trypsin and papain, chymostatin inhibiting chymotrypsin, pepstatin inhibiting pepsin, panosialin inhibiting sialidases, oudenone inhibiting tyrosine hydroxylase, dopastin inhibiting dopamine 3-hydroxylase, aquayamycin and chrothiomycin inhibiting tyrosine hydroxylase and dopamine J3-hydroxylase . Recently, an alternative approach has been applied to predict new inhibitors: rational drug design uses the three-dimensional structure of an enzyme's active site to predict which molecules might be inhibitors 1. Computer-based methods for identifying inhibitor for an enzyme have been developed, such as molecular mechanics and molecular docking.

Structural Characteristics
The crystal structures of many inhibitors have been determined. The crystal structures of three highly potent and selective low-molecular weight rigid peptidyl aldehyde inhibitors complexed with thrombin have been determined. All the three inhibitors have a novel lactam moiety at the P3 position, while the two with greatest trypsin selectivity have a guanidinopiperidyl group at the P1 position that binds in the S1 specificity site. The kinetics of inhibition vary from slow to fast with thrombin and are fast in all cases with trypsin. The kinetics are examined in terms of the slow formation of a stable transition-state complex in a two-step mechanism 2.

Emil Fischer in 1894 suggested that both the enzyme and the substrate possess specific complementary geometric shapes that fit exactly into one another.This is known as "the lock and key" model 3. Daniel Koshland suggested induced fit model where substrate and enzymes are rather flexible structures, the active site is continually reshaped by interactions with the substrate as the substrate interacts with the enzyme 4.

N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or glutamyl) precursor is required in the maturation of numerous bioactive peptides. The structure of human QC in free form and bound to a substrate and three imidazole-derived inhibitors reveals an alpha/beta scaffold akin to that of two-zinc exopeptidases but with several insertions and deletions, particularly in the active-site region. The structural analyses of several active-site-mutant enzymes provide a structural basis for the rational design of inhibitors against QC-associated disorders 5.

Mode of Action
Enzymes are proteins that catalyze chemical reactions. Enzymes interact with substrate and convert them into products. Inhibitor binding can stop a substrate from entering the enzyme's active site and/or hinder the enzyme from catalyzing its reaction. There are a variety of types of inhibitors including: nonspecific, irreversible, reversible - competitive and noncompetitive. Reversible inhibitors bind to enzymes with non-covalent interactions like hydrophobic interactions, hydrogen bonds, and ionic bonds. Non-specific methods of inhibition include any physical or chemical changes which ultimately denature the protein portion of the enzyme and are therefore irreversible. Specific Inhibitors exert their effects upon a single enzyme. Most poisons work by specific inhibition of enzymes. A competitive inhibitor is any compound which closely resembles the chemical structure and molecular geometry of the substrate. The inhibitor may interact with the enzyme at the active site, but no reaction takes place. A noncompetitive inhibitor is a substance that interacts with the enzyme, but usually not at the active site.  The net effect of a non competitive inhibitor is to change the shape of the enzyme and thus the active site, so that the substrate can no longer interact with the enzyme to give a reaction. Non competitive inhibitors are usually reversible. Irreversible Inhibitors form strong covalent bonds with an enzyme.  These inhibitors may act at, near, or remote from the active site .

Functions
Industrial application, enzymes are widely used commercially, for example in the detergent, food and brewing industries. Protease enzymes are used in 'biological' washing powders to speed up the breakdown of proteins in stains like blood and egg. Problems using enzymes commercially include: they are water soluble which makes them hard to recover and some products can inhibit the enzyme activity (feedback inhibition) .

Drug molecules, many drug molecules are enzyme inhibitors and a medicinal enzyme inhibitor is usually characterized by its specificity and its potency. A high specificity and potency suggests that a drug will have fewer side effects and less toxic. Enzyme inhibitors are found in nature and are also designed and produced as part of pharmacology and biochemistry 6.

Natural poisons are often enzyme inhibitors that have evolved to defend a plant or animal against predators. These natural toxins include some of the most poisonous compounds known.

Nerve gases such as diisopropylfluorophosphate (DFP) inhibit the active site of acetylcholine esterase by reacting with the hydroxyl group of serine to make an ester.

References

Scapin G (2006). Structural biology and drug discovery. Curr. Pharm. Des.,      12(17):2087–2097.

Krishnan R, Zhang E, Hakansson K, Arni RK, Tulinsky A, Lim-Wilby MS, Levy OE, Semple JE, Brunck TK (1998). Highly selective mechanism-based thrombin inhibitors:  structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes. Biochemistry, 37 (35):12094-12103.

Fischer E (1894). Einfluss der configuration auf die wirkung der enzyme. Ber. Dt. Chem. Ges., 27:2985–2993.

Koshland DE (1958). Application of a theory of enzyme specificity to protein synthesis. PNAS., 44 (2):98–104.

Huang KF, Liu YL, Cheng WJ, Ko TP, Wang AH (2005). Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation. PNAS., 102(37):13117-13122.

Holmes CF, Maynes JT, Perreault KR, Dawson JF, James MN (2002). Molecular enzymology underlying regulation of protein phosphatase-1 by natural toxins. Curr Med Chem., 9(22):1981-1989.