中文
Earlier issues
Announcement
More
Progress in Chemistry 2014, Vol. 26 Issue (01): 100-109 DOI: 10.7536/PC130771 Previous Articles   Next Articles

• Review •

Chemical Synthesis and Applications of Stapled Peptides

Gao Shuai1,2, Guo Ye2, Li Haiyan2, Fang Gemin*1,2   

  1. 1. High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, China;
    2. Department of Chemistry, Tsinghua University, Beijing 100084, China
  • Received: Revised: Online: Published:
PDF ( 2133 ) Cited
Export

EndNote

Ris

BibTeX

Regulation of a variety of biological processes depends on the protein-protein interactions. Generally, the protein-protein interaction surface is too large to be selectively targeted by small molecule drugs. Besides, protein drug candidates cannot be used directly for this purpose because of their low cellular membrane permeability. Due to these problems, it is imperative to develop the next-generation therapeutic arsenals that combine the membrane permeability of small organic molecules with the broad targetability of protein-based drugs. To overcome this challenge, Verdine et al. designed a novel kind of peptides that were designated as hydrocarbon-stapled α -helical peptides. The synthetic mini-protein can strongly confine its conformation into α -helix by introducing an all-hydrocarbon chemical brace. The pharmacology of the stapled peptides, compared with their unstapled counterpart, is greatly improved, including enhancing proteolytic resistance and cellular permeability. In this paper, we will review the recent advances of the stapled peptides in respect of their chemical synthesis, biophysical properties and pharmaceutical applications of them in the cancer-, and HIV-associated treatment, the regulation of signal pathway and the repression of tumor-activated proteins.

Contents
1 Introduction
2 Synthesis and modification of stapled peptides
2.1 Selection of insertion sites of α-methyl, α-alkenylglycine
2.2 Chemical synthesis of stapled peptides
2.3 Modification on stapled peptides
2.4 Synthesis of long-chain stapled peptides
3 Biophysical properties of stapled peptides
3.1 Conformation of stapled peptides
3.2 High binding affinity to target proteins
3.3 Resistance to proteolytic enzymes
3.4 High cellular permeability
3.5 Characterization of its bioactivity
4 Function and application of stapled peptides
4.1 Application in cancer-associated treatment
4.2 Application in HIV-associated treatment
4.3 Application in regulation of signal pathway
4.4 Application in hepatitis-associated treatment
5 Conclusion and outlook

Key words: tapled peptides, protein-protein interactions, peptide drugs

CLC Number: 

[1] Dawson P E, Muir T W, Lewis L C, Kent S B H. Science, 1994, 266: 776.
[2] Durek T, Torbeev V Y, Kent S B H. Proc. Natl. Acad. Sci. U. S. A., 2007, 104: 4846.
[3] Torbeev V Y, Kent S B H. Angew. Chem. Int. Ed., 2007, 46: 1667.
[4] McGinty R K, Kim J, Chatterjee C, Roeder R G, Muir T W. Nature, 2008, 453: 812.
[5] Fang G M, Wang J X, Liu L. Angew. Chem. Int. Ed., 2012, 51: 10347.
[6] Fang G M, Li Y M, Shen F, Huang Y C, Li J B, Lin Y, Cui H C, Liu L. Angew. Chem. Int. Ed., 2011, 50: 7645.
[7] Zheng J S, Chang H N, Wang F L, Liu L. J. Am. Chem. Soc., 2011, 133: 11080.
[8] Zheng J S, Huang Y C, Tang S, Liu L. Acc. Chem. Res., 2013, 46: 2475.
[9] Zheng J S, Tang S, Qi J Q, Wang Z P, Liu L. Nat. Protoc., 2013, 8: 2483.
[10] Chen Y X, Koch S, Uhlenbrock K, Weise K, Das D, Gremer L, Brunsveld L, Wittinghofer A, Winter R, Triola G, Waldmann H. Angew. Chem. Int. Ed., 2010, 49: 6090.
[11] Huang Y C, Li Y M, Chen Y, Pan M, Li Y T, Yu L, Guo Q X, Liu L. Angew. Chem. Int. Ed., 2013, 52: 4858.
[12] Dawson P E, Kent S B H. Biochem., 2000, 69: 923.
[13] Malins L R, Cergol K M, Payne R G. ChemBioChem, 2013, 14: 559.
[14] Dumas A, Spicer C D, Gao Z H, Takehana T, Lin Y A, Yasukohchi T, Davis B G. Angew. Chem. Int. Ed., 2013, 52: 3916.
[15] Binschik J, Mootz H D. Angew. Chem. Int. Ed., 2013, 52: 4260.
[16] Adams A L, Macmillan D. J. Pept. Sci., 2013, 19: 65.
[17] Fang G M, Cui H K, Zheng J S, Liu L. ChemBioChem, 2010, 11: 1061.
[18] Zheng J S, Cui H K, Fang G M, Xi W X, Liu L. ChemBioChem, 2010, 11: 511.
[19] Spokoyny A M, Zou Y K, Ling J J, Yu H T, Lin Y S, Pentelute B L. J. Am. Chem. Soc., 2013, 135: 5946.
[20] Gordon W R, Bang D, Hoff W D, Kent S B H. Bioorg. Med. Chem., 2013, 21: 3436.
[21] Li Y M, Yang M Y, Huang Y C, Li Y T, Chen P R, Liu L. ACS Chem. Biol., 2012, 7: 1015.
[22] Cronican J J, Thompson D B, Beier K T, McNaughton B R, Cepko C L, Liu D R. ACS Chem. Biol., 2010, 5: 747.
[23] Lawrence M S, Phillips K J, Liu D R. J. Am. Chem. Soc., 2007, 129: 10110.
[24] McNaughton B R, Cronican J J, Thompson D B, Liu D R. Proc. Natl. Acad. Sci. U. S. A., 2009, 106: 6111.
[25] Jenssen H, Aspmo S I. Methods Mol. Biol., 2008, 494: 177.
[26] Schafmeister C E, Po J, Verdine G L. J. Am. Chem. Soc., 2000, 122, 5891.
[27] Blackwell H E, Grubbs R H. Angew. Chem. Int. Ed., 1998, 37: 3281.
[28] Dastlik K A, Sundermerier U, Johns D M, Chen Y, Williams R M. Synlett, 2005, 4: 693.
[29] Williams R M, Im M N. J. Am. Chem. Soc., 1991, 113: 9276.
[30] Kim Y W, Grossmann T N, Verdine G L. Nat. Protoc., 2011, 6: 761.
[31] Muppidi A, Li X L, Chen J D, Lin Q. Bioorg. Med. Chem. Lett., 2011, 21: 7412.
[32] Greenfield N, Fasman G D. Biochem, 1969, 8: 4108.
[33] Baek S, Kutchukian P S, Verdine G L, Huber R, Holak T A, Lee K W, Popowicz G M. J. Am. Chem. Soc., 2012, 134: 103.
[34] Phillips C, Roberts L R, Schade M, Bazin R, Bent A, Davies N L, Moore R, Pannifer A D, Pickford A R, Prior S H, Read C M, Scott A, Brown D G, Xu B, Irving S L. J. Am. Chem. Soc., 2011, 133: 9696.
[35] Bernal F, Tyler A F, Korsmeyer S J, Walensky L D, Verdine G L. J. Am. Chem. Soc., 2007, 129: 2456.
[36] Moellering R E, Cornejo M, Davis T N, Bianco C D, Aster J C, Blacklow S C, Kung A L, Gilliland D G, Verdine G L, Bradner J E. Nature, 2009, 462: 182.
[37] Walensky L D, Kung A L, Escher I, Malia T J, Barbuto S, Wright R D, Wagner G, Verdine G L, Korsmeyer S J. Science, 2004, 305: 1466.
[38] Zhang H, Zhao Q, Bhattacharya S, Waheed A A, Tong X, Hong A, Heck S, Curreli F, Goger M, Cowburn D, Freed E O, Debnath A K. J. Mol. Biol., 2008, 378: 565.
[39] Bautista A D, Appelbaum J S, Craig C J, Michel J, Schepartz A. J. Am. Chem. Soc., 2010, 132: 2904.
[40] Bird G H, Bernal F, Pitter K, Walensky L D. Methods Enzymol., 2008, 446: 369.
[41] Verdine G L, Hilinski G J. Methods in Enzymology, 2012, 503: 3.
[42] Gavathiotis E, Suzuki M, Davis M L, Pitter K, Bird G H, Katz S G, Tu H C, Kim H, Cheng E H, Tjandra N T, Walens L D. Nature, 2008, 455: 1076.
[43] Pitter K, Bernal F, Labelle J, Walensky L D. Methods Enzymol., 2008, 446: 387.
[44] Stewart M L, Fire E, Keating A E, Walensky L D. Nat. Chem. Biol., 2010, 6: 595.
[45] Walensky L D, Pitter K, Morash J, Oh K J, Barbuto S, Fisher J, Smith E, Verdine G L, Korsmeyer S J. Mol. Cell, 2006, 24: 199.
[46] Bernal F, Wade M, Godes M, Davis T N, Whitehead D G, Kung A L, Wahl G M, Walensky L D. Cancer Cell, 2010, 18: 411.
[47] Danial N N, Gramm C F, Scorrano L, Zhang C-Y, Krauss S, Ranger A M, Datta S R, Greenberg M E, Licklider L J, Lowell B B, Gygi S P, Korsmeyer S J. Nature, 2003, 424: 952.
[48] Plas D R, Thompson C B. Trends Endocrin. Met., 2002, 13: 74.
[49] Pinton P, Rizzuto R. Cell Death Differ., 2006, 13: 1409.
[50] Karbowski M, Norris K L, Cleland M M, Jeong S Y, Youle R J. Nature, 2006, 443: 658.
[51] Sticht J, Humbert M, Findlow S, Bodem J, Muller B, Dietrich U, Werner J, Krausslich H G. Nat. Struct. Mol. Biol., 2005, 12: 671.
[52] Sakalian M, McMurtrey C P, Deeg F J, Maloy C W, Li F, Wild C T, Salzwedel K. J. Virol., 2006, 80: 5715.
[53] Bird G H, Madani N, Perry A F, Princiotto A M, Supko J G, He X Y, Gavathiotis E, Sodroski J G, Walensky L D. Proc. Natl. Acad. Sci. U. S. A., 2010, 107: 14093.
[54] Cui H K, Zhao B, Li Y H, Guo Y, Hu H, Liu L, Chen Y G. Cell Res., 2013, 23: 581.
[55] Cui H K, Qing J, Guo Y, Wang Y J, Cui L J, He T H, Zhang L Q, Liu L. Bioorg. Med. Chem., 2013, 21: 3547.
[56] Cascales L, Craik D J. Org. Biomol. Chem., 2010, 8: 5035.
[57] Göransson U, Burman R, Gunasekera S, Strömstedt A A, Rosengren K J. J. Biol. Chem., 2012, 287: 27001.
[58] Zheng J S, Tang S, Guo Y, Chang H N, Liu L. ChemBioChem, 2012, 13: 542.
[59] Cowper B, Craik D J, Macmillan D. ChemBioChem 2013, 14: 809.
[60] Zheng J S, Chang H N, Shi J, Liu L. Sci. China Chem., 2012, 55: 64.
[61] Thorstholm L, Craik D J. Drug Discov. Today Tech. 2012, 9: e13.
[62] Daly N L, Rosengren K J, Craik D J. Curr. Protein Pept. Sci., 2004, 5: 297.
[63] Göransson U, Svangård E, Claeson P, Bohlin L. Curr. Protein Pept. Sci., 2004, 5: 317.
[64] Tang Y Q, Yuan J, Osapay G, Osapay K, Tran D, Miller C J, Ouellette A J, Selsted M E. Science, 1999, 286: 498.
[65] Cui H K, Guo Y, He Y, Wang F L, Chang H N, Wang Y J, Wu F M, Tian C L, Liu L. Angew. Chem. Int. Ed., 2013, 52: 9558.
[1] Juan Ren, Shen Bian, Yiyun Wang, Xianglei Kong. Magic-Number Cluster of Serine Octamer: Structure and Chiral Characteristics [J]. Progress in Chemistry, 2018, 30(4): 383-397.
[2] Xiao Xiao, Changsheng Chen, Weiqiang Liu, Yeshun Zhang. Structure, Features and Biomedical Applications of Silk Sericin [J]. Progress in Chemistry, 2017, 29(5): 513-523.
[3] Zhao Yanan, Wang Mengfan, Qi Wei, Su Rongxin, He Zhimin. Supramolecular Artificial Enzyme Based on Assembling Peptide Gel [J]. Progress in Chemistry, 2016, 28(11): 1664-1671.
[4] Jiang Ge, Luo Feng, Xu Yaozhong, Zhang Xiaohui. UVA Assisted 4-Thiothymidine for Cancer Treatment [J]. Progress in Chemistry, 2016, 28(8): 1224-1237.
[5] Yuan Shuo, Sun Dequn. The Conformational Restriction of β-Peptidomimetics in Drug Design [J]. Progress in Chemistry, 2016, 28(7): 1084-1098.
[6] Song Ping, Ye Dekai, Song Shiping, Wang Lihua, Zuo Xiaolei. Preparation and Biological Applications of DNA Hydrogel [J]. Progress in Chemistry, 2016, 28(5): 628-636.
[7] Ma Xiaochuan, Fei Hao. The Use of Metal Coordination in Peptide and Protein Research [J]. Progress in Chemistry, 2016, 28(2/3): 184-192.
[8] Jiang Yu, Tan Lianjiang, Yin Yan, Shen Yu-Mei, Gong Bing, Shao Zhifeng. Cleavable Linkers in DNA Sequencing by Synthesis [J]. Progress in Chemistry, 2016, 28(1): 58-66.
[9] Ding Peng, Chen Xian, Li Xiuling, Qing Guangyan, Sun Taolei, Liang Xinmiao. The Separation and Enrichment of Glycoproteins or Glycopeptides Based on Nanoparticles [J]. Progress in Chemistry, 2015, 27(11): 1628-1639.
[10] Wang Jun, Zhang Afang. Peptide-Mediated Supramolecular Helical Polymers [J]. Progress in Chemistry, 2015, 27(10): 1413-1424.
[11] Hou hui, Sun Dequn. Conformational Restriction of Peptidomimetics in Drug Design [J]. Progress in Chemistry, 2015, 27(9): 1260-1274.
[12] Dong Shibiao, Jiao Xiong, Zhao Rongtao, Xu Jinkun, Song Hongbin, Hao Rongzhang. The DNA Tetrahedron Nanostructure Materials and Their Applications [J]. Progress in Chemistry, 2015, 27(9): 1191-1197.
[13] Zhao Yuan, Zeng Jin, Lin Yingwu. Rational Design of Artificial Hydrolases in Protein Scaffolds [J]. Progress in Chemistry, 2015, 27(8): 1102-1109.
[14] Wang Jianwei, Song Lifeng, Zhao Jin, Yuan Xubo. Polymer Hydrogels Based on Peptide Structure [J]. Progress in Chemistry, 2015, 27(4): 373-384.
[15] Tian Danbi, Zhang Wei, Tang Yan, Jiang Ling, Liu Jia, Hu Yi. Bioconjugate Probe for Enzyme Activity Based on the Gold Nanoparticles [J]. Progress in Chemistry, 2015, 27(2/3): 267-274.