Citation: Guo Ye, Fu Lili, Fan Xiaowen, Shi Xuanling. Stapled SC34EK fusion inhibitors with high potency against HIV-1 and improved protease resistance[J]. Chinese Chemical Letters, ;2018, 29(7): 1167-1170. doi: 10.1016/j.cclet.2018.03.024 shu

Stapled SC34EK fusion inhibitors with high potency against HIV-1 and improved protease resistance

Guo Ye ^a ,
Fu Lili ^b ,
Fan Xiaowen ^a ,
Shi Xuanling ^b,,

a.
School of Pharmacy, Baotou Medical College, Baotou 014060, China
b.
Comprehensive AIDS Research Center, School of Medicine, Tsinghua University, Beijing 100084, China

Corresponding author: Shi Xuanling, shixuanlingsk@mail.tsinghua.edu.cn
Received Date: 9 February 2018
Revised Date: 5 March 2018
Accepted Date: 19 March 2018
Available Online: 21 July 2018

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HIV fusion inhibitors are promising therapeutic agents for AIDS treatment. One fusion inhibitor has been approved as anti-HIV drug, while more of them are in preclinical studies or clinical trials. Highly active fusion inhibitors with excellent pharmacokinetic properties are still needed for development of anti-HIV drugs. We found that all-hydrocarbon staples inserted in SC34EK could not only enhance the inhibitory activity of inhibitors against HIV-1, but also improve protease resistance. Further study revealed that SC34EK-1 containing a staple was a potent fusion inhibitor with IC₅₀ value of 0.04-6.4 nmol/L towards diverse HIV-1 subtypes and half-life value of 112 min against protease hydrolysis. X-ray crystallography studies indicated that introduction of a hydrocarbon staple in SC34EK could make the amino acid at the interaction surface form perfect conformation to promote inhibitor peptide interacting with target.
- Fusion inhibitor,
- HIV-1,
- Stapled peptide,
- SC34EK
1. [1]
  R.J. Pomerantz, D.L. Horn, Nat. Med. 9(2003) 867-873. doi: 10.1038/nm0703-867
2. [2]
  S.G. Deeks, S.R. Lewin, D.V. Havlir, Lancet 382(2013) 1525-1533. doi: 10.1016/S0140-6736(13)61809-7
3. [3]
  G. Maartens, C. Celum, S.R. Lewin, Lancet 384(2014) 258-271. doi: 10.1016/S0140-6736(14)60164-1
4. [4]
  P.M. Sharp, B.H. Hahn, Cold Spring Harb. Perspect. Med. 1(2011) a006841.
5. [5]
  T. Bradley, J. Pollara, S. Santra, et al., Nat. Commun. (2017) 15711.
6. [6]
  L. Leal, C. Lucero, J.M. Gatell, et al., Expert. Rev. Vaccines. 16(2017) 587-600. doi: 10.1080/14760584.2017.1322513
7. [7]
  J.J. Tan, X.T. Ma, C. Liu, Curr. Pharm. Des. 19(2013) 1810-1817. doi: 10.2174/1381612811319100005
8. [8]
  M. Fumakia, S. Yang, J. Gu, et al., Rev. Med. Virol. 26(2016) 4-20. doi: 10.1002/rmv.1853
9. [9]
  D. Zhang, W. Li, S.B. Jiang, Expert. Opin. Ther. Pat. 25(2015) 159-173. doi: 10.1517/13543776.2014.987752
10. [10]
  C.G. Pan, S.W. Liu, S.B. Jiang, J. Formos. Med. Assoc. 109(2010) 94-105. doi: 10.1016/S0929-6646(10)60029-0
11. [11]
  M. Lu, S.C. Blacklow, P.S. Kim, Nat. Struct. Biol. 2(1995) 1075-1082. doi: 10.1038/nsb1295-1075
12. [12]
  Y.X. He, Curr. Pharm. Des. 19(2013) 1800-1809. doi: 10.2174/1381612811319100004
13. [13]
  F. Yu, L. Lu, L. Du, et al., Viruses 5(2013) 127-149. doi: 10.3390/v5010127
14. [14]
  J.P. Lalezari, K. Henry, M. O'Hearn, et al., N. Engl. J. Med. 348(2003) 2175-2185. doi: 10.1056/NEJMoa035026
15. [15]
  J.M. Kilby, S. Hopkins, T.M. Venetta, Nat. Med. 4(1998) 1302-1307. doi: 10.1038/3293
16. [16]
  M.D. Miller, D.J. Hazuda, Drug Resist. Updat. 7(2004) 89-95. doi: 10.1016/j.drup.2004.03.003
17. [17]
  M.L. Greenberg, N. Cammack, J. Antimicrob. Chemother. 54(2004) 333-340. doi: 10.1093/jac/dkh330
18. [18]
  L. Cai, C. Pan, L. Xu, et al., FASEB J. 26(2012) 1018-1026. doi: 10.1096/fj.11-195289
19. [19]
  Y.X. He, Y.H. Xiao, H.F. Song, et al., J. Biol. Chem. 283(2008) 11126-11134. doi: 10.1074/jbc.M800200200
20. [20]
  D.C. Chan, C.T. Chutkowski, P.S. Kim, Proc. Natl. Acad. Sci. U. S. A. 95(1998) 15613-15617. doi: 10.1073/pnas.95.26.15613
21. [21]
  L.T. Rimsky, D.C. Shugars, T.J. Matthews, J. Virol. 72(1998) 986-993.
22. [22]
  F. Miyamoto, E.N. Kodama, Antivir. Chem. Chemother. 22(2012) 151-158. doi: 10.3851/IMP1930
23. [23]
  A. Otaka, M. Nakamura, D. Nameki, et al., Angew. Chem. Int. Ed. 41(2002) 2937-2940. doi: 10.1002/1521-3773(20020816)41:16<2937::AID-ANIE2937>3.0.CO;2-J
24. [24]
  K. Shimura, D. Nameki, K. Kajiwara, J. Biol. Chem. 285(2010) 39471-39480. doi: 10.1074/jbc.M110.145789
25. [25]
  G.H. Bird, N. Madani, A.F. Perry, et al., Proc. Natl. Acad. Sci. U. S. A. 107(2010) 14093-14098. doi: 10.1073/pnas.1002713107
26. [26]
  C.E. Schafmeister, J. Po, G.L. Verdine, J. Am. Chem. Soc. 122(2000) 5891-5892. doi: 10.1021/ja000563a
27. [27]
  F. Bernal, A.F. Tyler, S.J. Korsmeyer, et al., J. Am. Chem. Soc. 129(2007) 2456-2457. doi: 10.1021/ja0693587
28. [28]
  R.E. Moellering, M. Cornejo, T.N. Davis, et al., Nature 462(2009) 182-188. doi: 10.1038/nature08543
29. [29]
  (a) T. N. Grossmanna, J. T. H. Yeha, B. R. Bowman, et al., Proc. Natl. Acad. Sci. U. S. A. 109(2012) 17942-17947;
  (b) H. K. Cui, B. Zhao, Y. H. Li, et al., Cell Res. 23(2013) 581-584.
30. [30]
  H.K. Cui, J. Qing, Y. Guo, et al., Bioorg. Med. Chem. 21(2013) 3547-3554. doi: 10.1016/j.bmc.2013.02.011
31. [31]
  H. Nishikawa, S. Nakamura, E. Kodama, et al., Int. J. Biochem. Cell Biol. 41(2009) 891-899. doi: 10.1016/j.biocel.2008.08.039
32. [32]
  Y.W. Kim, T.N. Grossmann, G.L. Verdine, Nat. Protoc. 6(2011) 761-771. doi: 10.1038/nprot.2011.324
33. [33]
  G.M. Fang, Y.M. Li, F. Shen, et al., Angew. Chem. Int. Ed. 50(2011) 7645-7649. doi: 10.1002/anie.201100996
34. [34]
  G.M. Fang, J.X. Wang, L. Liu, Angew. Chem. Int. Ed. 51(2012) 10347-10350. doi: 10.1002/anie.201203843
35. [35]
  J.S. Zheng, S. Tang, Y.K. Qi, et al., Nat. Protoc. 8(2013) 2483-2495. doi: 10.1038/nprot.2013.152
36. [36]
  D. Wang, K. Chen, J.L. Kulp Ⅲ, P.S. Arora, J. Am. Chem. Soc. 128(2006) 9248-9256. doi: 10.1021/ja062710w
37. [37]
  G.L. Verdine, G.J. Hilinski, Drug Discov. Today Technol. 9(2012) e1-e70.
38. [38]
  W. Weissenhorn, A. Dessen, S.C. Harrison, et al., Nature 387(1997) 426-430. doi: 10.1038/387426a0
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  Linhui Liu , Wuwan Xiong , Mingli Fu , Junliang Wu , Zhenguo Li , Daiqi Ye , Peirong Chen . Efficient NO_x abatement by passive adsorption over a Pd-SAPO-34 catalyst prepared by solid-state ion exchange. Chinese Chemical Letters, 2024, 35(4): 108870-. doi: 10.1016/j.cclet.2023.108870
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