echemi logo
Product
  • Product
  • Supplier
  • Inquiry
    Home > Medical News > Medicines Company News > Cellular molecule through peptide design

    Cellular molecule through peptide design

    • Last Update: 2023-01-05
    • Source: Internet
    • Author: User
    Search more information of high quality chemicals, good prices and reliable suppliers, visit www.echemi.com

    Organisms fold and assemble proteins into higher spatial conformational tissues (secondary, tertiary, and quaternary structures)
    according to their primary structure, i.
    e.
    amino acid sequences.
    Based on the same principle, short peptides are also capable of taking on spatial secondary structures such as α helixes and β folds
    .

    These conformations are often driven by weak non-covalent interactions, such as electrostatic interactions, hydrogen bonding, hydrophobic interactions, or van der Waals forces
    .
    In addition, biparental short peptides are prone to self-assembly
    due to weak intermolecular interactions between peptide monomers.
    Advances in chemistry provide an environment for programming and control of molecular design: this article will focus on recent advances
    in the molecular design of Cell Penetrating Peptides (CPPs).

    Cell penetrating peptide is a class of short peptides about 5~30 amino acids long, which can carry peptides, nucleic acids, small molecule drugs and virus particles through the cell membrane into cells
    .
    It is used as a vehicle to transport carriers into cells
    .
    Past studies have demonstrated efficacy in treating cancer and inflammatory diseases with cell-penetrating peptides carrying proteins and peptides
    .
    Based on animal studies, it is thought that it will be possible
    for cells to penetrate peptides to carry DNA or SiRNA to treat diseases.

    Cell-penetrating peptides can also improve the efficiency of
    viral transfection.
    Therefore, for this double-edged sword, which can help treat diseases, but also help to cause abuse, and accelerate the spread of the virus, people need to increase research efforts to seek benefits and avoid harm
    .
    In addition, cell-penetrating peptides can carry fluorescent or radiometric reagents for imaging applications
    .
    In short, cell penetrating peptides carrying therapeutic genes or drug molecules into cells will have a very broad clinical application prospect.

    The Cell Penetrating Peptide Database was established in 2012 by Indraprastha Institue of Information Technology, India, and has been updated to version 2.
    0 and has a strong guiding effect
    on the molecular design of cell penetrating peptides.
    The Cell Penetrating Peptide Database shows 1699 unique cell penetrating peptide sequences, most of which are linear polypeptides (94.
    5%)
    .
    The carrying molecule aspect is mainly used for the transport of fluorophores (54%), and the main cargo molecule of biomedical relevance is nucleic acids (15%)
    .
    The remaining cargo molecules mainly include proteins (9%), biotin (8%), nanoparticles (7%), and peptide drugs (4%)
    .
    The main body of cell penetrating peptide research focuses on synthetic polypeptides composed of whole L-amino acids (84.
    3%) (54.
    8%)
    .
    In addition, the internalization efficiency and stability of cell-penetrating peptides composed of all D-amino acids, and cell-penetrating peptides composed of L- and D-amino acid mixtures, have also been reported
    in the literature.
    (Figure 1)

    Conventional molecular design of cell-penetrating peptides does not bypass the following three key parameters: guanidine content (or cationic amino acid content), hydrophobicity, and biphilia
    .
    Arginine-rich cell penetrating peptides (arginine side chains with guanidine groups with a pKa of about 12, and protonated guanidine cations at physiological pH) have undergone in-depth research
    in the field of primary structure-efficacy.

    Membrane models, membrane extracts, and in vivo studies play a key role in studying the amino acid sequence of cell-penetrating peptides and the contribution of individual amino acid residues (e.
    g.
    , positive charge), all of which guide the molecular design of cell-penetrating peptides
    .
    Despite these theoretical guidelines, it is still very difficult
    to predict membrane penetration from peptide sequences alone.

    In addition to
    the sequence.
    Multiple chemical and physicochemical properties, such as charge, chirality, aromatics, and hydrophobicity, and their interactions are often important drivers of cell penetrating peptide internalization
    .
    It can be said that the peptide sequence is the foundation, and the interaction between molecules on this basis determines the efficacy
    of cells to penetrate peptides.
    To design efficient cell-penetrating peptides, numerous parameters including charge, guanidine group, chirality, hydrophobicity, and aromatics, and their interactions require further study
    .

    Based on the above considerations, the structure-activity relationship of cell-penetrating peptides and the spatial conformation of biparental polypeptides have been fully studied
    .
    Charge and biphilia are two major factors
    to consider when designing cell-penetrating peptide molecules.
    The internalization effect of cell-penetrating peptides varies depending on the overall properties of biphiles and polycations
    .
    In addition, peptide sequence length and spatial conformation are as important for peptide internalization as
    polycation.

    Peptide sequences rich in side-chain cationic amino acids are critical
    in the field of cell-penetrating peptides.
    The discovery of the Tat peptide (Figure 2) was a landmark event
    in the field of cell penetrating peptides.
    Tat (Transactivating transcriptional activator) peptides are peptide fragments
    of residues 48 to 60 in the original transcriptional activator of the human immunodeficiency virus (HIV-1).
    The gene delivery system modified by Tat shows enhanced transport function
    across multiple biomembranes, such as cell, endosomal and nuclear membranes.

    Tat peptide contains six arginine and two lysine residues, both of which are basic amino acids, and the side chains are guanidine and amino groups, all of which are positively charged
    due to protonation under physiological pH conditions.
    Given the significant guiding significance of Tat, it is not surprising that the simplest cell-penetrating peptide mimics are designed as oligoarginine
    .

    The correlation between the internalization effect of cell-penetrating peptides and cationic residues has been demonstrated
    .
    Inspired by Tat (GRKKRRQRRRPQ) and permosin (RQIKIWFQNRRMKWKK), the molecular design of cell-penetrating peptides mainly focuses on small cationic peptides (carrying 5 or so positive charges), such as polyarginine and polylysine peptides
    .
    The most in-depth cell penetrating peptide models are oligoarginine-based R8 and R9 (8 or 9 continuous arginine residue peptides, Figure 3).

    The absorption efficiency of polycationic cell penetrating peptides depends on the sequence length and the location
    of arginine residues in the peptide sequence.
    Cyclization has been reported to maximize the interaction between arginine and cell membranes, resulting in higher absorption efficiency
    .
    In addition to the guanidine group of the arginine side chain, the positive charge carried by the peptide can also be introduced through other amino acid side chains, such as lysine (side chain amino) and histidine (side chain imidazolyl).

    However, the internalization of polyarginine outperforms polylysine and polyhistidine
    .
    Therefore, polyarginine is also the most deeply studied cell-penetrating polypeptide
    in terms of internalization and introduction mechanisms.
    The internalization efficiency of linear polyarginine depends on the sequence length and the number and location
    of arginine residues.
    Guanidine groups have the ability to form double-tooth hydrogen bonds with membranes, so their peptide internalization should be associated with membrane translocation (Figure 4).

    In addition to the cationic moiety, the lipophilic moiety is also important
    for cellular uptake.
    In this regard, the researchers proposed a mechanism that believes that guanidine-rich cells penetrate peptides, and hydrophobic anti (anion) ions are formed near the main chain, which play a role
    in the internalization of cell penetrating peptides.
    The counterion effect is first manifested by the interaction of hydrogen bonds between arginine residues and membrane components to form complexes
    that can cross the membrane.
    In contrast, this strong antiion binding was not observed in lysine-rich polypeptides, a finding that reversely demonstrates the relevance
    of guanidine counterions to promote cell-penetrating peptide internalization.
    This ability of cell-penetrating peptides to bind to hydrophobic counterions is called the self-activating properties
    of these peptides.
    Therefore, while paying attention to the positive charge of peptides, the study of the hydrophobicity of cell-penetrating peptides and the contribution of
    single fat and aromatic functional groups cannot be ignored.

    Hydrophobicity can be achieved
    by adding aliphatic or aromatic structures.
    Some studies of cell-penetrating peptide mimics have confirmed that aromatic activation is superior to aliphatics
    .
    Lipidation is achieved by attaching hydrocarbon chains (alkyl groups) of different lengths to the N-terminus of known cell penetrating peptides or other suitable functional groups
    .
    This alkylation modification enhances the internalization of
    cell-penetrating peptides by enhancing hydrophobic interaction with membranes.
    In addition to integrating fat chains, the improvement of the hydrophobicity of peptide molecules can also be achieved
    by introducing hydrophobic amino acids (e.
    g.
    , leucine, isoleucine, alanine, valine, phenylalanine).
    It has been reported that after replacing methyl groups with more hydrophobic butyls, the activity of one cell-penetrating peptide increased threefold
    .
    8 Correspondingly, in the same study, when γ-dimethylsilaproline replaced Proline to construct a cell-penetrating peptide with a polyproline PPII helical structure (Figure 5), its internalization efficiency was improved
    .
    This result may be due to the increased
    overall hydrophobicity of the peptide.

    A hydrophobic viral peptide gH 625 with cell-penetrating properties (sequence: HGLASTLTRWAHYNALIRAF, Figure 6)
    was recently reported.
    This cell-penetrating peptide is derived from herpes simplex virus type I and is used to carry liposomes, quantum dots, dendritic macromolecules, disordered proteins, and SPIONS (superparamagnetic iron oxide nanoparticles).

    The biphility of its chemical structure is also evident
    .

    Peptide hydrophobicity can also be enhanced
    by the introduction of aromatic amino acid residues (tryptophan, phenylalanine and tyrosine).
    According to Wimley and White, aromatic residues have advantageous free energy
    during the insertion of peptides into the bilayer interface of cell membranes.
    Pyrene, halobenzene, and fullerenes have been shown to stimulate the activation of guanidine cations, allowing arginine-rich cells to penetrate peptides across cell membranes
    .

    Through a series of experiments, the researchers verified whether aromatic functional groups provide better internalization efficiency
    than aliphatic functional groups under the premise of maintaining the same hydrophobicity of polypeptides.
    These studies have found that aromatic functional groups are more conducive to the internalization
    of cell-penetrating peptides than to fat chains.
    Because aromatic polypeptides can interact with aromatic amino acids on membrane proteins π-π, they may help promote or stabilize peptide-membrane interactions and aid internalization
    .
    8 The concept is extended to include the effects
    of various π interactions (π-π, π-cation, π-anion, and π-dipole) on peptide molecule internalization.

    In the molecular design of cell-permeable peptides, cationic and hydrophobic characteristics need to be considered
    comprehensively.
    Penetratin peptides are such examples (Figure 7).

    Permothin is obtained from a Drosophila homologous protein
    .
    The non-electrostatic interaction of permothin with the non-polar portion of the plasma membrane is important for internalization (which also explains the basis of the biparental molecular design, which contains non-polar amino acid residues such as leucine, tryptophan, and phenylalanine).

    The number of cationic residues, their spacing on the primary structure, their relative position on the secondary structure, and the integration containing non-peptide elements such as hydrophobic lipid moieties are critical
    for the molecular design of cell penetrating peptides.

    Another example is PEP-1, which includes 5 tryptophan (hydrophobic amino acids to enhance the hydrophobic effect of the peptide with cell membranes) and a positively charged lysine-rich fragment (KKKRKV, nuclear localization sequence from the nuclear localization sequence on the viral SV-40 T-antigen), and a proline interval to increase the flexibility
    of the peptide.

    Similarly, the MPG peptide (GALFLGFLGAAGSTMGAWSQPKKKRKV) is designed to contain the same hydrophilic nuclear localization sequence and couple this sequence to a hydrophobic sequence of the HIV-gp-41 viral fragment
    .
    By integrating cationic amino acid residues, hydrophobic fragments, and biparental structures in the same peptide molecule in different ways, more efficient cell-penetrating peptides
    can be constructed and derived.

    Faced with various challenges in the realization of cell penetrating peptide function, such as internalization efficiency, endosomal escape efficiency, cycle time, and specificity and selectivity (for cells, tissues, diseases), cell penetrating peptide design has made corresponding progress
    .
    One example of this is cysteine-rich (CYS)-rich cell-penetrating peptides
    .

    The design of this molecule is inspired by Crotamine, a toxin found in snake venom, which contains two nuclear localization domains (CROT(2-18) and CROT(27-39)
    ).
    By examining Crot(27-39) (sequence: KMDCRWRWKCCKK), researchers designed a cysteine-rich decapeptide (CRWRWKCCKK) molecule using systematic substitution and/or omission of amino acid residues, as well as in-depth structure-activity studies (Figure 9).

    This potential cell-penetrating peptide has enhanced internalization efficiency
    .

    Cell-penetrating peptides have become a hot area of research
    for intracellular therapeutics.
    Because of the natural limitations of linear cell penetrating peptides, such as endosomal embedding, toxicity, poor cell specificity, poor stability and strong degradability, as well as imperfect cell penetration, modified cell penetrating cyclic peptides came into being
    .
    Compared to its straight-chain precursors, cell penetrating cyclic peptides have enhanced cell penetration and improved physicochemical properties, as well as stability
    against hydrolytic degradation.
    Some cell penetrating cyclic peptides can exhibit endosomal uptake-independent properties, and some cell penetrating cyclic peptides have been reported to have nuclear targeting properties
    .

    Figure 10 shows some cell penetrating cyclic peptides with monocyclic
    , bicyclic and tricyclic structures with arginine and other amino acid residues.

    [WR]4 and [WR]5, two cell penetrating cyclic peptide building blocks, are characterized by the presence
    of alternating positive charges (arginine) and hydrophobic amino acids (tryptophan) in the sequence.
    Monocyclic cell penetrating cyclic peptides containing tryptophan and arginine residues can also be conjugated
    to potential therapeutic agents.
    For example, monocyclic peptides are coupled with doxorubicin, paclitaxel, and camptothecin, wherein the adduct of doxorubicin-cyclic peptide demonstrates the effect
    of internalization.

    In addition, several monocyclic peptides containing cysteine and arginine residues also significantly enhance cellular uptake
    of impermeable phosphopeptide (F)-Gly-(pTyr)-Glu-Glu-Ile (F-GpYEEI).
    Cyclic decapeptides containing tryptophan and histidine effectively increase intracellular delivery
    of cell-impermeable phosphopeptides to the anti-HIV drug emtricitabine.
    [WR]4-[WR]4-[WR]4 tricyclic peptide contains alternating arginine and tryptophan residues, which improves cellular uptake
    of the breast cancer cell line MDA-MB-231 from F-GpYEEI and fluorescently labeled anti-HIV drugs (lamivudine (3TC), emtricitabine (FTC), and siRNA).

    In the above cell-penetrating cyclic peptide, the continuous arrangement and combination of tryptophan and arginine residues have derived different types of cell-penetrating cyclic peptides
    with different cell transport characteristics.
    These data reveal the molecular transport potential of monocyclic , bicyclic and tricyclic cell penetrating peptides and provide a good basis
    for designing the next generation of drug delivery peptides.

    It should be noted that when discussing the molecular design of cell-penetrating peptides, this article only introduces the effect
    of peptide primary structure, that is, amino acid sequence.
    Due to space reasons, the activity
    of secondary structures for cell-penetrating peptides has not been introduced for the time being.

    Although the molecular design of cell-penetrating peptides currently reported in the literature is very detailed, translating them into a clinical setting remains a formidable challenge
    .
    The application field of cell-penetrating peptides is broad and evolving, and deeper mechanistic exploration has led to increased
    molecular design complexity.
    This includes the development of stable and multi-domain circular or self-assembling nanostructures
    .
    In addition, selectivity, targeting, high efficiency and other aspects need to be further developed
    .
    Many researchers have proposed to improve the stability and activity of cell penetrating peptides by controlled spatial folding, cyclization, dimerization, staple, self-assembly, and even peptide mimetics with different backbones
    .

    However, due to the development of various complex internalization mechanisms, the heterogeneity of diseases, and the wide variety of cell lines available for in vitro studies, there is still no uniform standard to evaluate internalization efficiency improvements
    in one molecular design relative to another.
    In addition, the large heterogeneity of cargo molecules means that more parameters
    need to be considered in assessing the efficiency and activity of cells in penetrating peptides.
    In this regard, standardized harmonization and more in-depth comparative studies are needed to measure the performance
    of different types of cell-penetrating peptides.
    Although great progress has been made in the design of cell-penetrating peptides, there is undoubtedly still a lot of room
    for development in this field.

    References:

           [1] Pujals, S.
    ; Fernández-Carneado, J.
    ; Kogan, M.
    J.
    ; Martinez, J.
    ; Cavelier, F.
    ; Giralt, E.
    Replacement of a proline with silaproline causes a 20-fold increase in the cellular uptake of a pro-rich peptide.
    J.
    Am.
    Chem.
    Soc.
    2006, 128, 8479–8483.

           [2] Eiríksdóttir, E.
    ; Konate, K.
    ; Langel, ü.
    ; Divita, G.
    ; Deshayes, S.
    Secondary structure of cell-penetrating peptides controls membrane interaction and insertion.
    Biochim.
    Biophys.
    Acta, 2010, 1798, 1119–1128.

           [3] Tang, H.
    ; Yin, L.
    ; Kim, K.
    H.
    ; Cheng, J.
    Helical poly(arginine) mimics with superior cell-penetrating and molecular transporting properties.
    Chem.
    Sci.
    2013, 4, 3839.

           [4] Jones, A.
    T.
    ; Sayers, E.
    J.
    Cell entry of cell penetrating peptides: Tales of tails wagging dogs.
    J.
    Control.
    Release.
    2012, 161, 582–591.

           [5] L?ttig-tünnemann, G.
    ; Prinz, M.
    ; Hoffmann, D.
    ; Behlke, J.
    ; Palm-apergi, C.
    ; Morano, I.
    ; Herce, H.
    D.
    ; Cardoso, M.
    C.
    Backbone rigidity and static presentation of guanidinium groups increases cellular uptake of arginine-rich cell-penetrating peptides.
    Nat.
    Commun.
    2011, 2, 453.

           [6] Som, A.
    ; Tezgel, A.
    O.
    ; Gabriel, G.
    J.
    ; Tew, G.
    N.
    Self-activation in de novo designed mimics of cell-penetrating peptides.
    Angew.
    Chem.
    Int.
    Ed.
    2011, 50, 6147–6150.

           [7] Sakai, N.
    ; Matile, S.
    Anion-Mediated Transfer of Polyarginine across Liquid and Bilayer Membranes.
    J.
    Am.
    Chem.
    Soc.
    2003, 125, 14348–14356.

           [8] Som, A.
    ; Tezgel, A.
    O.
    ; Gabriel, G.
    J.
    ; Tew, G.
    N.
    Self-activation in de novo designed mimics of cell-penetrating peptides.
    Angew.
    Chem.
    Int.
    Ed.
    2011, 50, 6147–6150.

           [9] Perret, F.
    ; Nishihara, M.
    ; Takeuchi, T.
    ; Futaki, S.
    ; Lazar, A.
    N.
    ; Coleman, A.
    W.
    ; Sakai, N.
    ; Matile, S.
    Anionic fullerenes, calixarenes, coronenes, and pyrenes as activators of oligo/polyarginines in model membranes and live cells.
    J.
    Am.
    Chem.
    Soc.
    2005, 127, 1114–1115.

           [10] Galdiero, S.
    ; Falanga, A.
    ; Vitiello, M.
    ; Browne, H.
    ; Pedone, C.
    ; Galdiero, M.
    Fusogenic domains in herpes simplex virus type 1 glycoprotein H.
    J.
    Biol.
    Chem.
    2005, 280, 28632–28643.

           [11] Wimley, W.
    C.
    ; White, S.
    H.
    Experimentally determined hydrophobicity scale for proteins at membrane interfaces.
    Nature, 1996, 3, 842–848.

           [12] Perret, F.
    ; Nishihara, M.
    ; Takeuchi, T.
    ; Futaki, S.
    ; Lazar, A.
    N.
    ; Coleman, A.
    W.
    ; Sakai, N.
    ; Matile, S.
    Anionic fullerenes, calixarenes, coronenes, and pyrenes as activators of oligo/polyarginines in model membranes and live cells.
    J.
    Am.
    Chem.
    Soc.
    2005, 127, 1114–1115.

    [13] (a) Canine, B.
    F.
    ; Wang, Y.
    ; Hatefi, A.
    evaluation of the effect of vector architecture on DNA condensation and gene transfer efficiency.
    J.
    Control.
    Release, 2008, 129, 117–123; (b) Marshall, N.
    B.
    ; Oda, S.
    K.
    ; London, C.
    A.
    ; Moulton, H.
    M.
    ; Iversen, P.
    L.
    ; Kerkvliet, N.
    I.
    and Mourich, D.
    V.
    Arginine-rich cellpenetrating peptides facilitate delivery of antisense oligomers into murine leukocytes and alter pre-mRNA splicing.
    J.
    Immunol.
    Methods, 2007, 325, 114–126; (c) Rothbard, J.
    B.
    ; Kreider, E.
    ; VanDeusen, C.
    L.
    ; Wright, L.
    ; Wylie, B.
    ; Wender, P.
    A.
    Arginine-rich molecular transporters for drug delivery: Role of backbone spacing in cellular uptake.
    J.
    Med.
    Chem.
    2002, 45, 3612–3618; (d) Siprashvili, Z.
    ; Scholl, F.
    A.
    ; Oliver, S.
    F.
    ; Adams, A.
    ; Contag, C.
    H.
    ; Wender, P.
    A.
    ; Khavari, P.
    A.
    Gene transfer via reversible plasmid condensation with cysteine-flanked, internally spaced arginine-rich peptides.
    Hum.
    Gene Ther.
    2004, 14, 1225–1233; (e) Futaki, S.
    ; Ohashi,W.
    ; Suzuki, T.
    ; Niwa, M.
    ; Tanaka, S.
    ; Ueda, K.
    ; Harashima, H.
    ; Sugiura, Y.
    Stearylated arginine-rich peptides: A new class of transfection systems.
    Bioconjug.
    Chem.
    2001, 12, 1005–1011.

           [14] Jha, D.
    ; Mishra, R.
    ; Gottschalk, S.
    ; Wiesm, K.
    ; Ugurbil, K.
    ; Maier, M.
    E.
    CyLoP-1: A Novel Cysteine-Rich Cell-Penetrating Peptide for Cytosolic Delivery of Cargoes.
    Bioconj.
    Chem.
    2011, 22, 319–328.

           [15] Mandal, D.
    ; Nasrolahi Shirazi, A.
    ; Parang, K.
    Cell-penetrating homochiral cyclic peptides as nuclear-targeting molecular transporters.
    Angew.
    Chem.
    Int.
    Ed.
    2011, 50, 9633–9637.

           [16] (a) Darwish, S.
    ; Sadeghiani, N.
    ; Fong, S.
    ; Mozaffari, S.
    ; Hamidi, P.
    ; Withana, T.
    ; Yang, S.
    ; Tiwari, R.
    K.
    ; Parang, K.
    Synthesis and antiproliferative activities of doxorubicin thiol conjugates and doxorubicin-SS-cyclic peptide.
    Eur.
    J.
    Med.
    Chem.
    2019, 161, 594–606; (b) El-Sayed, N.
    S.
    ; Shirazi, A.
    N.
    ; Sajid, M.
    I.
    ; Park, S.
    E.
    ; Parang, K.
    ; Tiwari, R.
    K.
    Synthesis and antiproliferative activities of conjugates of paclitaxel and camptothecin with a cyclic cell-penetrating peptide.
    Molecules, 2019, 24, 1427.

           [17] Shirazi, A.
    N.
    ; El-Sayed, N.
    S.
    ; Mandal, D.
    ; Tiwari, R.
    K.
    ; Tavakoli, K.
    ; Etesham, M.
    ; Parang, K.
    Cysteine and arginine-rich peptides as molecular carriers.
    Bioorg.
    Med.
    Chem.
    Lett.
    2016, 26, 656–661.

           [18] Shirazi, A.
    ; Mozaffari, S.
    ; Sherpa, R.
    ; Tiwari, R.
    ; Parang, K.
    Efficient intracellular delivery of cell-impermeable cargo molecules by peptides containing tryptophan and histidine.
    Molecules, 2018, 23, 1536–1548.

           [19] Kumar, S.
    ; Mandal, D.
    ; El-Mowafi, S.
    A.
    ; Mozaffari, S.
    ; Tiwari, R.
    K.
    ; Parang, K.
    Click-free synthesis of a multivalent tricyclic peptide as a molecular transporter.
    Pharmaceutics, 2020, 12, 842–859.

           [20] Daniela Kalafatovic, Ernest Giralt.
    Cell-Penetrating Peptides: Design Strategies beyond

           Primary Structure and Amphipathicity.
    Molecules.
    2017, 22, 1929.

    ={"common":{"bdSnsKey":{},"bdText":"","bdMini":"1","bdMiniList":false,"bdPic":"","bdStyle":"0","bdSize":"32"},"share":{},"image":{"viewList":[" weixin","sqq","qzone","tsina","tqq","tsohu","tieba","renren","youdao","fx","ty","fbook","twi","copy","print"],"viewText":"share:","viewSize":"24"},"selectShare":{" bdContainerClass":null,"bdSelectMiniList":["weixin","sqq","qzone","tsina","tqq","tsohu","tieba","renren","youdao","fx","ty","fbook","twi","copy","print"]}}; with(document)0[(getElementsByTagName('head')[0]|| body).
    appendChild(createElement('script')).
    src='http://bdimg.
    share.
    baidu.
    com/static/api/js/share.
    js?v=89860593.
    js?cdnversion='+~(-new Date()/36e5)];
    This article is an English version of an article which is originally in the Chinese language on echemi.com and is provided for information purposes only. This website makes no representation or warranty of any kind, either expressed or implied, as to the accuracy, completeness ownership or reliability of the article or any translations thereof. If you have any concerns or complaints relating to the article, please send an email, providing a detailed description of the concern or complaint, to service@echemi.com. A staff member will contact you within 5 working days. Once verified, infringing content will be removed immediately.

    Contact Us

    The source of this page with content of products and services is from Internet, which doesn't represent ECHEMI's opinion. If you have any queries, please write to service@echemi.com. It will be replied within 5 days.

    Moreover, if you find any instances of plagiarism from the page, please send email to service@echemi.com with relevant evidence.