细胞穿膜肽研究应用的新进展
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摘要
细胞穿膜肽(Cell-penetrating peptides,CPPs)是一类能够穿过细胞膜或组织屏障的短肽。CPPs可通过内吞和直接穿透等机制运载蛋白质、RNA、DNA等生物大分子进入细胞内发挥其效应功能。相比于其他非天然的化学分子,CPPs具有生物相容性佳、对细胞造成的毒性小、完成入胞转运后可降解、并能与生物活性蛋白直接融合重组表达等优点,因此成为以胞内分子为靶标的药物递送技术发展的重要工具,并在生物医学研究领域具有良好的应用前景。文中针对CPPs的分类特点、入胞转运机制及其治疗应用的新近研究进展进行综述和讨论。
Cell-penetrating peptides(CPPs)are short peptides that can penetrate the cell membrane or tissue barrier.CPPs can deliver a variety of biomacromolecules,such as proteins,RNA and DNA,into cells to produce intracellular functional effects.Endocytosis and direct penetration have been suggested as the two major uptake mechanisms for CPPs-mediated cargo delivery.Compared with other non-natural chemical molecules-based delivery reagents,the CPPs have better biocompatibility,lower cytotoxicity,are easily degraded after cargo delivery,and can be fused and recombined expressed with bioactive proteins.Because of these advantages,the CPPs have become an important potential tool for delivery of developing drugs which targets intracellular factors.As a novel delivery tool,the CPPs also show promising application prospects in biomedical researches.This review summarized recent advances regarding the classification characteristics,the cellular uptake mechanisms and therapeutic application potentials of CPPs.
Cell-penetrating peptides(CPPs)are short peptides that can penetrate the cell membrane or tissue barrier.CPPs can deliver a variety of biomacromolecules,such as proteins,RNA and DNA,into cells to produce intracellular functional effects.Endocytosis and direct penetration have been suggested as the two major uptake mechanisms for CPPs-mediated cargo delivery.Compared with other non-natural chemical molecules-based delivery reagents,the CPPs have better biocompatibility,lower cytotoxicity,are easily degraded after cargo delivery,and can be fused and recombined expressed with bioactive proteins.Because of these advantages,the CPPs have become an important potential tool for delivery of developing drugs which targets intracellular factors.As a novel delivery tool,the CPPs also show promising application prospects in biomedical researches.This review summarized recent advances regarding the classification characteristics,the cellular uptake mechanisms and therapeutic application potentials of CPPs.
引文
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[7]Zhang JF,Xiong HL,Cao JL,et al.A cell-penetrating whole molecule antibody targeting intracellular HBx suppresses hepatitis B virus via TRIM21-dependent pathway.Theranostics,2018,8(2):549-562.
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[9]Nakase I,Hirose H,Tanaka G,et al.Cell-surface accumulation of flock house virus-derived peptide leads to efficient internalization via macropinocytosis.Mol Ther,2009,17(11):1868-1876.
[10]Park J,Ryu J,Kim KA,et al.Mutational analysis of a human immunodeficiency virus type 1 Tat protein transduction domain which is required for delivery of an exogenous protein into mammalian cells.J Gen Virol,2002,83(Pt 5):1173-1181.
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[19]Lundberg P,Magzoub M,Lindberg M,et al.Cell membrane translocation of the N-terminal(1-28)part of the prion protein.Biochem Biophys Res Commun,2002,299(1):85-90.
[20]Magzoub M,Sandgren S,Lundberg P,et al.N-terminal peptides from unprocessed prion proteins enter cells by macropinocytosis.Biochem Biophys Res Commun,2006,348(2):379-385.
[21]Avci FG,Akbulut BS,Ozkirimli E.Membrane active peptides and their biophysical characterization.Biomolecules,2018,8(3):77.
[22]Oehlke J,Krause E,Wiesner B,et al.Extensive cellular-uptake into endothelial cells of an amphipathicβ-sheet forming peptide.FEBS Lett,1997,415(2):196-199.
[23]Martin I,Teixido M,Giralt E.Design,synthesis and characterization of a new anionic cell-penetrating peptide:SAP(E).Chembiochem,2011,12(6):896-903.
[24]Mardirossian M,Grzela R,Giglione C,et al.The host antimicrobial peptide Bac71-35 binds to bacterial ribosomal proteins and inhibits protein synthesis.Chem Biol,2014,21(12):1639-1647.
[25]Daniels DS,Schepartz A.Intrinsically cell-permeable miniature proteins based on a minimal cationic PPII motif.J Am Chem Soc,2007,129(47):14578-14579.
[26]Gomez JA,Chen J,Ngo J,et al.Cell-penetrating penta-peptides(CPP5s):measurement of cell entry and protein-transduction activity.Pharmaceuticals,2010,3(12):3594-3613.
[27]Jones S,Lukanowska M,Suhorutsenko J,et al.Intracellular translocation and differential accumulation of cell-penetrating peptides in bovine spermatozoa:evaluation of efficient delivery vectors that do not compromise human sperm motility.Hum Reprod,2013,28(7):1874-1889.
[28]Gao S,Simon MJ,Hue CD,et al.An unusual cell penetrating peptide identified using a plasmid display-based functional selection platform.ACS Chem Biol,2011,6(5):484-491.
[29]Brock R.The uptake of arginine-rich cell-penetrating peptides:putting the puzzle together.Bioconjugate Chem,2014,25(5):863-868.
[30]Kosuge M,Takeuchi T,Nakase I,et al.Cellular internalization and distribution of arginine-rich peptides as a function of extracellular peptide concentration,serum,and plasma membrane associated proteoglycans.Bioconjugate Chem,2008,19(3):656-664.
[31]Duchardt F,Fotin-Mleczek M,Schwarz H,et al.Acomprehensive model for the cellular uptake of cationic cell-penetrating peptides.Traffic,2007,8(7):848-866.
[32]Fretz MM,Penning NA,Al-Taei S,et al.Temperature-,concentration-and cholesterol-dependent translocation of L-and D-octa-arginine across the plasma and nuclear membrane of CD34+leukaemia cells.Biochem J,2007,403(2):335-342.
[33]Palm-Apergi C,L?nn P,Dowdy SF.Do cell-penetrating peptides actually“penetrate”cellular membranes?Mol Ther,2012,20(4):695-697.
[34]LeCher JC,Nowak SJ,McMurry JL.Breaking in and busting out:cell-penetrating peptides and the endosomal escape problem.Biomol Concepts,2017,8(3/4):131-141.
[35]Al Soraj M,He L,Peynshaert K,et al.siRNA and pharmacological inhibition of endocytic pathways to characterize the differential role of macropinocytosis and the actin cytoskeleton on cellular uptake of dextran and cationic cell penetrating peptides octaarginine(R8)and HIV-Tat.J Control Release,2012,161(1):132-141.
[36]Conner SD,Schmid SL.Regulated portals of entry into the cell.Nature,2003,422(6927):37-44.
[37]Nakase I,Tadokoro A,Kawabata N,et al.Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis.Biochemistry,2007,46(2):492-501.
[38]Bloomfield G,Kay RR.Uses and abuses of macropinocytosis.J Cell Sci,2016,129(14):2697-2705.
[39]Tanaka G,Nakase I,Fukuda Y,et al.CXCR4 stimulates macropinocytosis:implications for cellular uptake of arginine-rich cell-penetrating peptides and HIV.Chem Biol,2012,19(11):1437-1446.
[40]Watkins CL,Schmaljohann D,Futaki S,et al.Low concentration thresholds of plasma membranes for rapid energy-independent translocation of a cell-penetrating peptide.Biochem J,2009,420(2):179-189.
[41]Pae J,S??lik P,Liivam?gi L,et al.Translocation of cell-penetrating peptides across the plasma membrane is controlled by cholesterol and microenvironment created by membranous proteins.J Control Release,2014,192:103-113.
[42]Islam MZ,Sharmin S,Moniruzzaman M,et al.Elementary processes for the entry of cell-penetrating peptides into lipid bilayer vesicles and bacterial cells.Appl Microbiol Biotechnol,2018,102(9):3879-3892.
[43]Mishra A,Lai GH,Schmidt NW,et al.Translocation of HIV TAT peptide and analogues induced by multiplexed membrane and cytoskeletal interactions.Proc Natl Acad Sci USA,2011,108(41):16883-16888.
[44]Ciobanasu C,Siebrasse JP,Kubitscheck U.Cell-penetrating HIV1 TAT peptides can generate pores in model membranes.Biophys J,2010,99(1):153-162.
[45]Swiecicki JM,Bartsch A,Tailhades J,et al.The efficacies of cell-penetrating peptides in accumulating in large unilamellar vesicles depend on their ability to form inverted micelles.Chembiochem,2014,15(6):884-891.
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