Cell-Penetrating Peptides to Enhance Delivery of Oligonucleotide-Based Therapeutics

Graham McClorey, Subhashis Banerjee, Graham McClorey, Subhashis Banerjee

Abstract

The promise of nucleic acid based oligonucleotides as effective genetic therapies has been held back by their low bioavailability and poor cellular uptake to target tissues upon systemic administration. One such strategy to improve upon delivery is the use of short cell-penetrating peptides (CPPs) that can be either directly attached to their cargo through covalent linkages or through the formation of noncovalent nanoparticle complexes that can facilitate cellular uptake. In this review, we will highlight recent proof-of-principle studies that have utilized both of these strategies to improve nucleic acid delivery and discuss the prospects for translation of this approach for clinical application.

Keywords: antisense oligonucleotides; cell-penetrating peptides; delivery.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cell-penetrating peptides (CPPs) can be conjugated to their ASO cargo through direct covalent conjugation through a linker, most typically exemplified by cationic or amphipathic CPP conjugation to a neutral-charge oligonucleotide such as phosphorodiamidate morpholino (PMO). Noncovalent conjugation occurs through electrostatic and hydrophobic interactions between the CPP and ASO, exemplified by siRNA here, to form nanoparticle like complexes.
Figure 2
Figure 2
Cell-penetrating peptide internalization occurs through direct penetration (left) or endocytic pathways (right). Direct translocation of CPPs into the cellular space can occur through energy-independent mechanisms that cause membrane destabilization such as the “carpet-like” model or formation of inverted micelles, or through direct pore formation such as the “barrel-stave” model. The majority of CPPs are thought to be taken up through energy-dependent endocytic internalization either through clathrin-dependent, caveolin-mediated, and clathrin/caveolae independent endocytosis or micropinocytosis before escape from endosome compartments into the cellular environment.

References

    1. Nayerossadat N., Ali P., Maedeh T. Viral and nonviral delivery systems for gene delivery. Adv. Biomed. Res. 2012;1:27. doi: 10.4103/2277-9175.98152.
    1. Ramamoorth M., Narvekar A. Non viral vectors in gene therapy—An overview. J. Clin. Diagn. Res. 2015;9:GE01-6. doi: 10.7860/JCDR/2015/10443.5394.
    1. Lehto T., Ezzat K., Wood M.J.A., EL Andaloussi S. Peptides for nucleic acid delivery. Adv. Drug Deliv. Rev. 2016;106:172–182. doi: 10.1016/j.addr.2016.06.008.
    1. Kristensen M., Birch D., Nielsen H.M. Applications and challenges for use of cell-penetrating peptides as delivery vectors for peptide and protein cargos. Int. J. Mol. Sci. 2016;17:185. doi: 10.3390/ijms17020185.
    1. Frankel A.D., Pabo C.O. Cellular uptake of the tat protein from human immunodeficiency virus. Cell. 1988;55:1189–1193. doi: 10.1016/0092-8674(88)90263-2.
    1. Derossi D., Joliot A.H., Chassaing G., Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membranes. J. Biol. Chem. 1994;269:10444–10450.
    1. Pooga M., Hällbrink M., Zorko M., Langel Ü. Cell penetration by transportan. FASEB J. 1998;12:67–77. doi: 10.1096/fasebj.12.1.67.
    1. Futaki S., Suzuki T., Ohashi W., Yagami T., Tanaka S., Ueda K., Sugiura Y. Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J. Biol. Chem. 2001;276:5836–5840. doi: 10.1074/jbc.M007540200.
    1. Yin H., Moulton H.M., Seow Y., Boyd C., Boutilier J., Iverson P., Wood M.J. Cell-penetrating peptide-conjugated antisense oligonucleotides restore systemic muscle and cardiac dystrophin expression and function. Hum. Mol. Genet. 2008;17:3909–3918. doi: 10.1093/hmg/ddn293.
    1. Wu B., Moulton H.M., Iversen P.L., Jiang J., Li J., Li J., Spurney C.F., Sali A., Guerron A.D., Nagaraju K., et al. Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer. Proc. Natl. Acad. Sci. USA. 2008;105:14814–14819. doi: 10.1073/pnas.0805676105.
    1. Leger A.J., Mosquea L.M., Clayton N.P., Wu I.-H., Weeden T., Nelson C.A., Phillips L., Roberts E., Piepenhagen P.A., Cheng S.H., et al. Systemic delivery of a Peptide-linked morpholino oligonucleotide neutralizes mutant RNA toxicity in a mouse model of myotonic dystrophy. Nucleic Acid Ther. 2013;23:109–117. doi: 10.1089/nat.2012.0404.
    1. Yin H., Moulton H.M., Betts C., Seow Y., Boutilier J., Iverson P.L., Wood M.J. A fusion peptide directs enhanced systemic dystrophin exon skipping and functional restoration in dystrophin-deficient mdx mice. Hum. Mol. Genet. 2009;18:4405–4414. doi: 10.1093/hmg/ddp395.
    1. Betts C.A., Saleh A.F., Carr C.A., Hammond S.M., Coenen-Stass A.M.L., Godfrey C., McClorey G., Varela M.A., Roberts T.C., Clarke K., et al. Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice. Sci. Rep. 2015;5 doi: 10.1038/srep08986.
    1. Godfrey C., Muses S., McClorey G., Wells K.E., Coursindel T., Terry R.L., Betts C., Hammond S., O’donovan L., Hildyard J., et al. How much dystrophin is enough: The physiological consequences of different levels of dystrophin in the mdx mouse. Hum. Mol. Genet. 2015;24 doi: 10.1093/hmg/ddv155.
    1. Betts C., Saleh A.F., Arzumanov A.A., Hammond S.M., Godfrey C., Coursindel T., Gait M.J., Wood M.J.A. Pip6-PMO, a new generation of peptide-oligonucleotide conjugates with improved cardiac exon skipping activity for DMD treatment. Mol. Ther. Nucleic Acids. 2012;1 doi: 10.1038/mtna.2012.30.
    1. Hammond S.M., Hazell G., Shabanpoor F., Saleh A.F., Bowerman M., Sleigh J.N., Meijboom K.E., Zhou H., Muntoni F., Talbot K., et al. Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy. Proc. Natl. Acad. Sci. USA. 2016;113:10962–10967. doi: 10.1073/pnas.1605731113.
    1. Gao X., Zhao J., Han G., Zhang Y., Dong X., Cao L., Wang Q., Moulton H.M., Yin H. Effective dystrophin restoration by a novel muscle-homing peptide-morpholino conjugate in dystrophin-deficient mdx mice. Mol. Ther. 2014;22:1333–1341. doi: 10.1038/mt.2014.63.
    1. Shabanpoor F., Hammond S.M., Abendroth F., Hazell G., Wood M.J.A., Gait M.J. Identification of a Peptide for Systemic Brain Delivery of a Morpholino Oligonucleotide in Mouse Models of Spinal Muscular Atrophy. Nucleic Acid Ther. 2017;27:130–143. doi: 10.1089/nat.2016.0652.
    1. Jirka S.M.G., Heemskerk H., Tanganyika-de Winter C.L., Muilwijk D., Pang K.H., de Visser P.C., Janson A., Karnaoukh T.G., Vermue R., ‘t Hoen P.A.C., et al. Peptide Conjugation of 2′-O-methyl Phosphorothioate Antisense Oligonucleotides Enhances Cardiac Uptake and Exon Skipping in mdx Mice. Nucleic Acid Ther. 2014;24:25–36. doi: 10.1089/nat.2013.0448.
    1. Burrer R., Neuman B.W., Ting J.P.C., Stein D.A., Moulton H.M., Iversen P.L., Kuhn P., Buchmeier M.J. Antiviral effects of antisense morpholino oligomers in murine coronavirus infection models. J. Virol. 2007;81:5637–5648. doi: 10.1128/JVI.02360-06.
    1. Geller B.L., Marshall-Batty K., Schnell F.J., McKnight M.M., Iversen P.L., Greenberg D.E. Gene-silencing antisense oligomers inhibit acinetobacter growth in vitro and in vivo. J. Infect. Dis. 2013;208:1553–1560. doi: 10.1093/infdis/jit460.
    1. Crombez L., Morris M.C., Dufort S., Aldrian-Herrada G., Nguyen Q., Mc Master G., Coll J.-L., Heitz F., Divita G. Targeting cyclin B1 through peptide-based delivery of siRNA prevents tumour growth. Nucleic Acids Res. 2009;37:4559–4569. doi: 10.1093/nar/gkp451.
    1. Crombez L., Aldrian-Herrada G., Konate K., Nguyen Q.N., McMaster G.K., Brasseur R., Heitz F., Divita G. A new potent secondary amphipathic cell-penetrating peptide for siRNA delivery into mammalian cells. Mol. Ther. 2009;17:95–103. doi: 10.1038/mt.2008.215.
    1. Vaissière A., Aldrian G., Konate K., Lindberg M.F., Jourdan C., Telmar A., Seisel Q., Fernandez F., Viguier V., Genevois C., et al. A retro-inverso cell-penetrating peptide for siRNA delivery. J. Nanobiotechnol. 2017;15 doi: 10.1186/s12951-017-0269-2.
    1. Mäe M., EL Andaloussi S., Lundin P., Oskolkov N., Johansson H.J., Guterstam P., Langel Ü. A stearylated CPP for delivery of splice correcting oligonucleotides using a non-covalent co-incubation strategy. J. Control. Release. 2009;134:221–227. doi: 10.1016/j.jconrel.2008.11.025.
    1. El Andaloussi S., Lehto T., Mäger I., Rosenthal-Aizman K., Oprea I.I., Simonson O.E., Sork H., Ezzat K., Copolovici D.M., Kurrikoff K., et al. Design of a peptide-based vector, PepFect6, for efficient delivery of siRNA in cell culture and systemically in vivo. Nucleic Acids Res. 2011;39:3972–3987. doi: 10.1093/nar/gkq1299.
    1. Veiman K.L., Mäger I., Ezzat K., Margus H., Lehto T., Langel K., Kurrikoff K., Arukuusk P., Suhorutsenko J., Padari K., et al. PepFect14 peptide vector for efficient gene delivery in cell cultures. Mol. Pharm. 2013;10:199–210. doi: 10.1021/mp3003557.
    1. Ezzat K., El Andaloussi S., Zaghloul E.M., Lehto T., Lindberg S., Moreno P.M.D., Viola J.R., Magdy T., Abdo R., Guterstam P., et al. PepFect 14, a novel cell-penetrating peptide for oligonucleotide delivery in solution and as solid formulation. Nucleic Acids Res. 2011;39:5284–5298. doi: 10.1093/nar/gkr072.
    1. Kumar P., Wu H., McBride J.L., Jung K.-E., Hee Kim M., Davidson B.L., Lee S.K., Shankar P., Manjunath N. Transvascular delivery of small interfering RNA to the central nervous system. Nature. 2007;448:39–43. doi: 10.1038/nature05901.
    1. Cantini L., Attaway C.C., Butler B., Andino L.M., Sokolosky M.L., Jakymiw A. Fusogenic-Oligoarginine Peptide-Mediated Delivery of siRNAs Targeting the CIP2A Oncogene into Oral Cancer Cells. PLoS ONE. 2013;8 doi: 10.1371/journal.pone.0073348.
    1. Alexander-Bryant A.A., Zhang H., Attaway C.C., Pugh W., Eggart L., Sansevere R.M., Andino L.M., Dinh L., Cantini L.P., Jakymiw A. Dual peptide-mediated targeted delivery of bioactive siRNAs to oral cancer cells in vivo. Oral Oncol. 2017;72:123–131. doi: 10.1016/j.oraloncology.2017.07.004.
    1. Leng Q., Scaria P., Lu P., Woodle M.C., Mixson A.J. Systemic delivery of HK Raf-1 siRNA polyplexes inhibits MDA-MB-435 xenografts. Cancer Gene Ther. 2008;15:485–495. doi: 10.1038/cgt.2008.29.
    1. Sazani P., Gemignani F., Kang S.H., Maier M.A., Manoharan M., Persmark M., Bortner D., Kole R. Systemically delivered antisense oligomers upregulate gene expression in mouse tissues. Nat. Biotechnol. 2002;20:1228–1233. doi: 10.1038/nbt759.
    1. Bendifallah N., Rasmussen F.W., Zachar V., Ebbesen P., Nielsen P.E., Koppelhus U. Evaluation of cell-penetrating peptides (CPPs) as vehicles for intracellular delivery of antisense peptide nucleic acid (PNA) Bioconjug. Chem. 2006;17:750–758. doi: 10.1021/bc050283q.
    1. Boffa L.C., Cutrona G., Cilli M., Matis S., Damonte G., Mariani M.R., Millo E., Moroni M., Roncella S., Fedeli F., et al. Inhibition of Burkitt’s lymphoma cells growth in SCID mice by a PNA specific for a regulatory sequence of the translocated c-myc. Cancer Gene Ther. 2007;14:220–226. doi: 10.1038/sj.cgt.7701002.
    1. Fabani M.M., Abreu-Goodger C., Williams D., Lyons P.A., Torres A.G., Smith K.G.C., Enright A.J., Gait M.J., Vigorito E. Efficient inhibition of miR-155 function in vivo by peptide nucleic acids. Nucleic Acids Res. 2010;38:4466–4475. doi: 10.1093/nar/gkq160.
    1. Stirchak E.P., Summerton J.E., Weller D.D. Uncharged Stereoregular Nucleic Acid Analogues. 1. Synthesis of a Cytosine-Containing Oligomer with Carbamate Internucleoside Linkages. J. Org. Chem. 1987;52:4202–4206. doi: 10.1021/jo00228a010.
    1. Moulton H.M., Nelson M.H., Hatlevig S.A., Reddy M.T., Iversen P.L. Cellular Uptake of Antisense Morpholino Oligomers Conjugated to Arginine-Rich Peptides. Bioconjug. Chem. 2004;15:290–299. doi: 10.1021/bc034221g.
    1. Boisguérin P., Deshayes S., Gait M.J., O’Donovan L., Godfrey C., Betts C.A., Wood M.J.A., Lebleu B. Delivery of therapeutic oligonucleotides with cell penetrating peptides. Adv. Drug Deliv. Rev. 2015;87:52–67. doi: 10.1016/j.addr.2015.02.008.
    1. Amantana A., Moulton H.M., Cate M.L., Reddy M.T., Whitehead T., Hassinger J.N., Youngblood D.S., Iversen P.L. Pharmacokinetics, biodistribution, stability and toxicity of a cell-penetrating peptide—Morpholino oligomer conjugate. Bioconjug. Chem. 2007;18:1325–1331. doi: 10.1021/bc070060v.
    1. Abes S., Moulton H.M., Clair P., Prevot P., Youngblood D.S., Wu R.P., Iversen P.L., Lebleu B. Vectorization of morpholino oligomers by the (R-Ahx-R)4peptide allows efficient splicing correction in the absence of endosomolytic agents. J. Control. Release. 2006;116:304–313. doi: 10.1016/j.jconrel.2006.09.011.
    1. Lim K.R.Q., Maruyama R., Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des. Dev. Ther. 2017;11:533–545. doi: 10.2147/DDDT.S97635.
    1. Goyenvalle A., Griffith G., Babbs A., El Andaloussi S., Ezzat K., Avril A., Dugovic B., Chaussenot R., Ferry A., Voit T., et al. Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat. Med. 2015;21:270–275. doi: 10.1038/nm.3765.
    1. Samoylova T.I., Smith B.F. Elucidation of muscle-binding peptides by phage display screening. Muscle Nerve. 1999;22:460–466. doi: 10.1002/(SICI)1097-4598(199904)22:4<460::AID-MUS6>;2-L.
    1. Echigoya Y., Nakamura A., Nagata T., Urasawa N., Lim K.R.Q., Trieu N., Panesar D., Kuraoka M., Moulton H.M., Saito T., et al. Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy. Proc. Natl. Acad. Sci. USA. 2017;114:4213–4218. doi: 10.1073/pnas.1613203114.
    1. Ivanova G.D., Arzumanov A., Abes R., Yin H., Wood M.J.A., Lebleu B., Gait M.J. Improved cell-penetrating peptide-PNA conjugates for splicing redirection in HeLa cells and exon skipping in mdx mouse muscle. Nucleic Acids Res. 2008;36:6418–6428. doi: 10.1093/nar/gkn671.
    1. Yin H., Saleh A.F., Betts C., Camelliti P., Seow Y., Ashraf S., Arzumanov A., Hammond S., Merritt T., Gait M.J., et al. Pip5 transduction peptides direct high efficiency oligonucleotide-mediated dystrophin exon skipping in heart and phenotypic correction in mdx mice. Mol. Ther. 2011;19:1295–1303. doi: 10.1038/mt.2011.79.
    1. Du L., Kayali R., Bertoni C., Fike F., Hu H., Iversen P.L., Gatti R.A. Arginine-rich cell-penetrating peptide dramatically enhances AMO-mediated ATM aberrant splicing correction and enables delivery to brain and cerebellum. Hum. Mol. Genet. 2011;20:3151–3160. doi: 10.1093/hmg/ddr217.
    1. Mercuri E., Darras B.T., Chiriboga C.A., Day J.W., Campbell C., Connolly A.M., Iannaccone S.T., Kirschner J., Kuntz N.L., Saito K., et al. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N. Engl. J. Med. 2018;378:625–635. doi: 10.1056/NEJMoa1710504.
    1. Finkel R.S., Mercuri E., Darras B.T., Connolly A.M., Kuntz N.L., Kirschner J., Chiriboga C.A., Saito K., Servais L., Tizzano E., et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N. Engl. J. Med. 2017;377:1723–1732. doi: 10.1056/NEJMoa1702752.
    1. Fletcher S., Adams A.M., Johnsen R.D., Greer K., Moulton H.M., Wilton S.D. Dystrophin isoform induction in vivo by antisense-mediated alternative splicing. Mol. Ther. 2010;18:1218–1223. doi: 10.1038/mt.2010.45.
    1. Kang J.K., Malerba A., Popplewell L., Foster K., Dickson G. Antisense-induced myostatin exon skipping leads to muscle hypertrophy in mice following octa guanidine morpholino oligomer treatment. Mol. Ther. 2011;19:159–164. doi: 10.1038/mt.2010.212.
    1. Malerba A., Kang J.K., McClorey G., Saleh A.F., Popplewell L., Gait M.J., Wood M.J.A., Dickson G. Dual myostatin and dystrophin exon skipping by morpholino nucleic acid oligomers conjugated to a cell-penetrating peptide is a promising therapeutic strategy for the treatment of duchenne muscular dystrophy. Mol. Ther. Nucleic Acids. 2012;1 doi: 10.1038/mtna.2012.54.
    1. Lu-Nguyen N., Malerba A., Popplewell L., Schnell F., Hanson G., Dickson G. Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice. Mol. Ther. Nucleic Acids. 2017;6:15–28. doi: 10.1016/j.omtn.2016.11.009.
    1. Shabanpoor F., McClorey G., Saleh A.F., Jarver P., Wood M.J.A., Gait M.J. Bi-specific splice-switching PMO oligonucleotides conjugated via a single peptide active in a mouse model of Duchenne muscular dystrophy. Nucleic Acids Res. 2015;43:29–39. doi: 10.1093/nar/gku1256.
    1. Xue X.Y., Mao X.G., Zhou Y., Chen Z., Hu Y., Hou Z., Li M.-K., Meng J.-R., Luo X.-X. Advances in the delivery of antisense oligonucleotides for combating bacterial infectious diseases. Nanomed. Nanotechnol. Biol. Med. 2018;14:745–758. doi: 10.1016/j.nano.2017.12.026.
    1. Morris M.C., Vidal P., Chaloin L., Heitz F., Divita G. A new peptide vector for efficient delivery of oligonucleotides into mammalian cells. Nucleic Acids Res. 1997;25:2730–2736. doi: 10.1093/nar/25.14.2730.
    1. Wolfrum C., Shi S., Jayaprakash K.N., Jayaraman M., Wang G., Pandey R.K., Rajeev K.G., Nakayama T., Charrise K., Ndungo E.M., et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat. Biotechnol. 2007;25:1149–1157. doi: 10.1038/nbt1339.
    1. Chorev M., Goodman M. Recent developments in retro peptides and proteins—An ongoing topochemical exploration. Trends Biotechnol. 1995;13:438–445. doi: 10.1016/S0167-7799(00)88999-4.
    1. Leng Q., Scaria P., Zhu J., Ambulos N., Campbell P., Mixson A.J. Highly branched HK peptides are effective carriers of siRNA. J. Gene Med. 2005;7:977–986. doi: 10.1002/jgm.748.
    1. Järver P., Zaghloul E.M., Arzumanov A.A., Saleh A.F., McClorey G., Hammond S.M., Hällbrink M., Langel Ü., Smith C.I., Wood M.J., et al. Peptide Nanoparticle Delivery of Charge-Neutral Splice-Switching Morpholino Oligonucleotides. Nucleic Acid Ther. 2015;25:65–77. doi: 10.1089/nat.2014.0511.
    1. Kumar P., Ban H.S., Kim S.S., Wu H., Pearson T., Greiner D.L., Laouar A., Yao J., Haridas V., Habiro K., et al. T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice. Cell. 2008;134:577–586. doi: 10.1016/j.cell.2008.06.034.
    1. Martín I., Teixidó M., Giralt E. Building cell selectivity into CPP-mediated strategies. Pharmaceuticals. 2010;3:1456–1490. doi: 10.3390/ph3051456.
    1. Olson E.S., Aguilera T.A., Jiang T., Ellies L.G., Nguyen Q.T., Wong E.H., Gross L.A., Tsien R.Y. In vivo characterization of activatable cell penetrating peptides for targeting protease activity in cancer. Integr. Biol. (Camb.) 2009;1:382–393. doi: 10.1039/b904890a.
    1. Xiang B., Jia X.L., Qi J.L., Yang L.P., Sun W.H., Yan X., Yang S.-K., Cao D.-Y., Du Q., Qi X.-R. Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system. Int. J. Nanomed. 2017;12:2385–2405. doi: 10.2147/IJN.S129574.
    1. Luneberg J., Martin I., Nussler F., Ruysschaert J.M., Herrmann A. Structure and topology of the influenza virus fusion peptide in lipid bilayers. J. Biol. Chem. 1995;270:27606–27614. doi: 10.1074/jbc.270.46.27606.
    1. Vivès E., Brodin P., Lebleu B. A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J. Biol. Chem. 1997;272:16010–16017. doi: 10.1074/jbc.272.25.16010.
    1. Pouny Y., Rapaport D., Mor A., Nicolas P., Shai Y. Interaction of antimicrobial dermaseptin and its fluorescently labeled analogues with phospholipid membranes. Biochemistry. 1992;31:12416–12423. doi: 10.1021/bi00164a017.
    1. Shai Y. Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by α-helical antimicrobial and cell non-selective membrane-lytic peptides. Biochim. Biophys. Acta Biomembr. 1999;1462:55–70. doi: 10.1016/S0005-2736(99)00200-X.
    1. Derossi D., Calvet S., Trembleau A., Brunissen A., Chassaing G., Prochiantz A. Cell internalization of the third helix of the antennapedia homeodomain is receptor-independent. J. Biol. Chem. 1996;271:18188–18193. doi: 10.1074/jbc.271.30.18188.
    1. Richard J.P., Melikov K., Vives E., Ramos C., Verbeure B., Gait M.J., Chernomordik L.V., Lebleu B. Cell-penetrating peptides: A reevaluation of the mechanism of cellular uptake. J. Biol. Chem. 2003;278:585–590. doi: 10.1074/jbc.M209548200.
    1. Rydström A., Deshayes S., Konate K., Crombez L., Padari K., Boukhaddaoui H., Aldrian G., Pooga M., Divita G. Direct translocation as major cellular uptake for CADY self-assembling peptide-based nanoparticles. PLoS ONE. 2011;6 doi: 10.1371/journal.pone.0025924.
    1. Nakase I., Tadokoro A., Kawabata N., Takeuchi T., Katoh H., Hiramoto K., Negishi M., Nomizu M., Sugiura Y., Futaki S. Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis. Biochemistry. 2007;46:492–501. doi: 10.1021/bi0612824.
    1. Säälik P., Elmquist A., Hansen M., Padari K., Saar K., Viht K., Langel U., Pooga M. Protein cargo delivery properties of cell-penetrating peptides. A comparative study. Bioconjug. Chem. 2004;15:1246–1253. doi: 10.1021/bc049938y.
    1. Fittipaldi A., Ferrari A., Zoppé M., Arcangeli C., Pellegrini V., Beltram F., Giacca M. Cell Membrane Lipid Rafts Mediate Caveolar Endocytosis of HIV-1 Tat Fusion Proteins. J. Biol. Chem. 2003;278:34141–34149. doi: 10.1074/jbc.M303045200.
    1. Gestin M., Dowaidar M., Langel Ü. Uptake mechanism of cell-penetrating peptides. Adv. Exp. Med. Biol. 2017;1030:255–264. doi: 10.1007/978-3-319-66095-0_11.
    1. Soomets U., Lindgren M., Gallet X., Hällbrink M., Elmquist A., Balaspiri L., Zorko M., Pooga M., Brasseur R., Langel U. Deletion analogues of transportan. Biochim. Biophys. Acta Biomembr. 2000;1467:165–176. doi: 10.1016/S0005-2736(00)00216-9.
    1. Lehto T., Alvarez A.C., Gauck S., Gait M.J., Coursindel T., Wood M.J.A., Lebleu B., Boisguerin P. Cellular trafficking determines the exon skipping activity of Pip6a-PMO in mdx skeletal and cardiac muscle cells. Nucleic Acids Res. 2014;42:3207–3217. doi: 10.1093/nar/gkt1220.
    1. Pang H.-B., Braun G.B., Ruoslahti E. Neuropilin-1 and heparan sulfate proteoglycans cooperate in cellular uptake of nanoparticles functionalized by cationic cell-penetrating peptides. Sci. Adv. 2015;1:e1500821. doi: 10.1126/sciadv.1500821.
    1. Helmfors H., Lindberg S., Langel Ü. SCARA involvement in the uptake of nanoparticles formed by cell-penetrating peptides. Methods Mol. Biol. 2015;1324:163–174. doi: 10.1007/978-1-4939-2806-4_11.
    1. Canton J., Neculai D., Grinstein S. Scavenger receptors in homeostasis and immunity. Nat. Rev. Immunol. 2013;13:621–634. doi: 10.1038/nri3515.
    1. Ezzat K., Helmfors H., Tudoran O., Juks C., Lindberg S., Padari K., El-Andaloussi S., Pooga M., Langel U. Scavenger receptor-mediated uptake of cell-penetrating peptide nanocomplexes with oligonucleotides. FASEB J. 2012;26:1172–1180. doi: 10.1096/fj.11-191536.
    1. Juks C., Lorents A., Arukuusk P., Langel Ü., Pooga M. Cell-penetrating peptides recruit type A scavenger receptors to the plasma membrane for cellular delivery of nucleic acids. FASEB J. 2017;31:975–988. doi: 10.1096/fj.201600811R.
    1. Ezzat K., Aoki Y., Koo T., McClorey G., Benner L., Coenen-Stass A., O’Donovan L., Lehto T., Garcia-Guerra A., Nordin J., et al. Self-Assembly into Nanoparticles Is Essential for Receptor Mediated Uptake of Therapeutic Antisense Oligonucleotides. Nano Lett. 2015;15:4364–4373. doi: 10.1021/acs.nanolett.5b00490.
    1. Dowaidar M., Gestin M., Cerrato C.P., Jafferali M.H., Margus H., Kivistik P.A., Ezzat K., Hallberg E., Pooga M., Hällbrink M., et al. Role of autophagy in cell-penetrating peptide transfection model. Sci. Rep. 2017;7:12635. doi: 10.1038/s41598-017-12747-z.
    1. Pryor P.R., Luzio J.P. Delivery of endocytosed membrane proteins to the lysosome. Biochim. Biophys. Acta Mol. Cell Res. 2009;1793:615–624. doi: 10.1016/j.bbamcr.2008.12.022.
    1. El-Sayed A., Futaki S., Harashima H. Delivery of Macromolecules Using Arginine-Rich Cell-Penetrating Peptides: Ways to Overcome Endosomal Entrapment. AAPS J. 2009;11:13–22. doi: 10.1208/s12248-008-9071-2.
    1. Erazo-Oliveras A., Muthukrishnan N., Baker R., Wang T.Y., Pellois J.P. Improving the endosomal escape of cell-penetrating peptides and their cargos: Strategies and challenges. Pharmaceuticals. 2012;5:1177–1209. doi: 10.3390/ph5111177.
    1. Wadia J.S., Stan R.V., Dowdy S.F. Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis. Nat. Med. 2004;10:310–315. doi: 10.1038/nm996.
    1. Lo S.L., Wang S. An endosomolytic Tat peptide produced by incorporation of histidine and cysteine residues as a nonviral vector for DNA transfection. Biomaterials. 2008;29:2408–2414. doi: 10.1016/j.biomaterials.2008.01.031.
    1. Agrawal P., Bhalla S., Usmani S.S., Singh S., Chaudhary K., Raghava G.P.S., Gautam A. CPPsite 2.0: A repository of experimentally validated cell-penetrating peptides. Nucleic Acids Res. 2016;44:D1098–D1103. doi: 10.1093/nar/gkv1266.
    1. Wei L., Xing P., Su R., Shi G., Ma Z.S., Zou Q. CPPred-RF: A Sequence-based Predictor for Identifying Cell-Penetrating Peptides and Their Uptake Efficiency. J. Proteome Res. 2017;16:2044–2053. doi: 10.1021/acs.jproteome.7b00019.
    1. Margus H., Arukuusk P., Langel U., Pooga M. Characteristics of Cell-Penetrating Peptide/Nucleic Acid Nanoparticles. Mol. Pharm. 2016;13:172–179. doi: 10.1021/acs.molpharmaceut.5b00598.
    1. Carter E., Lau C.Y., Tosh D., Ward S.G., Mrsny R.J. Cell penetrating peptides fail to induce an innate immune response in epithelial cells in vitro: Implications for continued therapeutic use. Eur. J. Pharm. Biopharm. 2013;85:12–19. doi: 10.1016/j.ejpb.2013.03.024.
    1. Moulton H.M., Moulton J.D. Morpholinos and their peptide conjugates: Therapeutic promise and challenge for Duchenne muscular dystrophy. Biochim. Biophys. Acta Biomembr. 2010;1798:2296–2303. doi: 10.1016/j.bbamem.2010.02.012.

Source: PubMed

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