|
|
|
| Stapled SC34EK fusion inhibitors with high potency against HIV-1 and improved protease resistance |
| Ye Guoa, Lili Fub, Xiaowen Fana, Xuanling Shib |
a School of Pharmacy, Baotou Medical College, Baotou 014060, China;
b Comprehensive AIDS Research Center, School of Medicine, Tsinghua University, Beijing 100084, China |
|
|
|
| Guide A single all-hydrocarbon staple introduction in SC34EK can afford a potent HIV inhibitor with high protease resistance for ADIS treatment. |
|
|
Abstract 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.
|
|
Received: 09 February 2018
|
| Fund:We thank Professor Yuxian He for the help on T20-resistance test and Professor Xinquan Wang for SC34EK-1/T21 complex structure determination. We thank Dr. Linqi Zhang for his kind support and helpful suggestion. This work was supported by the National Natural Science Foundation of China (No. 21602121), the Natural Science Foundation of Inner Mongolia (No. 2016BS0201), the Inner Mongolia Autonomous Region Higher School Youth scientific Talents Support Project(No. NJYT-17-B22), the Research Funds of Baotou Medical College (Nos. BSJJ201620, BYJJ-YF 201707) and Beijing Tongzhou District Science and Technology Project (No. KJ2017CX039-14). |
|
Corresponding Authors:
Xuanling Shi, shixuanlingsk@mail.tsinghua.edu.cn
E-mail: shixuanlingsk@mail.tsinghua.edu.cn
|
|
|
|
| [1] |
R.J. Pomerantz, D.L. Horn, Nat. Med. 9(2003) 867-873.
|
| [2] |
S.G. Deeks, S.R. Lewin, D.V. Havlir, Lancet 382(2013) 1525-1533.
|
| [3] |
G. Maartens, C. Celum, S.R. Lewin, Lancet 384(2014) 258-271.
|
| [4] |
P.M. Sharp, B.H. Hahn, Cold Spring Harb. Perspect. Med. 1(2011) a006841.
|
| [5] |
T. Bradley, J. Pollara, S. Santra, et al., Nat. Commun. (2017) 15711.
|
| [6] |
L. Leal, C. Lucero, J.M. Gatell, et al., Expert. Rev. Vaccines. 16(2017) 587-600.
|
| [7] |
J.J. Tan, X.T. Ma, C. Liu, Curr. Pharm. Des. 19(2013) 1810-1817.
|
| [8] |
M. Fumakia, S. Yang, J. Gu, et al., Rev. Med. Virol. 26(2016) 4-20.
|
| [9] |
D. Zhang, W. Li, S.B. Jiang, Expert. Opin. Ther. Pat. 25(2015) 159-173.
|
| [10] |
C.G. Pan, S.W. Liu, S.B. Jiang, J. Formos. Med. Assoc. 109(2010) 94-105.
|
| [11] |
M. Lu, S.C. Blacklow, P.S. Kim, Nat. Struct. Biol. 2(1995) 1075-1082.
|
| [12] |
Y.X. He, Curr. Pharm. Des. 19(2013) 1800-1809.
|
| [13] |
F. Yu, L. Lu, L. Du, et al., Viruses 5(2013) 127-149.
|
| [14] |
J.P. Lalezari, K. Henry, M. O'Hearn, et al., N. Engl. J. Med. 348(2003) 2175-2185.
|
| [15] |
J.M. Kilby, S. Hopkins, T.M. Venetta, Nat. Med. 4(1998) 1302-1307.
|
| [16] |
M.D. Miller, D.J. Hazuda, Drug Resist. Updat. 7(2004) 89-95.
|
| [17] |
M.L. Greenberg, N. Cammack, J. Antimicrob. Chemother. 54(2004) 333-340.
|
| [18] |
L. Cai, C. Pan, L. Xu, et al., FASEB J. 26(2012) 1018-1026.
|
| [19] |
Y.X. He, Y.H. Xiao, H.F. Song, et al., J. Biol. Chem. 283(2008) 11126-11134.
|
| [20] |
D.C. Chan, C.T. Chutkowski, P.S. Kim, Proc. Natl. Acad. Sci. U. S. A. 95(1998) 15613-15617.
|
| [21] |
L.T. Rimsky, D.C. Shugars, T.J. Matthews, J. Virol. 72(1998) 986-993.
|
| [22] |
F. Miyamoto, E.N. Kodama, Antivir. Chem. Chemother. 22(2012) 151-158.
|
| [23] |
A. Otaka, M. Nakamura, D. Nameki, et al., Angew. Chem. Int. Ed. 41(2002) 2937-2940.
|
| [24] |
K. Shimura, D. Nameki, K. Kajiwara, J. Biol. Chem. 285(2010) 39471-39480.
|
| [25] |
G.H. Bird, N. Madani, A.F. Perry, et al., Proc. Natl. Acad. Sci. U. S. A. 107(2010) 14093-14098.
|
| [26] |
C.E. Schafmeister, J. Po, G.L. Verdine, J. Am. Chem. Soc. 122(2000) 5891-5892.
|
| [27] |
F. Bernal, A.F. Tyler, S.J. Korsmeyer, et al., J. Am. Chem. Soc. 129(2007) 2456-2457.
|
| [28] |
R.E. Moellering, M. Cornejo, T.N. Davis, et al., Nature 462(2009) 182-188.
|
| [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] |
H.K. Cui, J. Qing, Y. Guo, et al., Bioorg. Med. Chem. 21(2013) 3547-3554.
|
| [31] |
H. Nishikawa, S. Nakamura, E. Kodama, et al., Int. J. Biochem. Cell Biol. 41(2009) 891-899.
|
| [32] |
Y.W. Kim, T.N. Grossmann, G.L. Verdine, Nat. Protoc. 6(2011) 761-771.
|
| [33] |
G.M. Fang, Y.M. Li, F. Shen, et al., Angew. Chem. Int. Ed. 50(2011) 7645-7649.
|
| [34] |
G.M. Fang, J.X. Wang, L. Liu, Angew. Chem. Int. Ed. 51(2012) 10347-10350.
|
| [35] |
J.S. Zheng, S. Tang, Y.K. Qi, et al., Nat. Protoc. 8(2013) 2483-2495.
|
| [36] |
D. Wang, K. Chen, J.L. Kulp Ⅲ, P.S. Arora, J. Am. Chem. Soc. 128(2006) 9248-9256.
|
| [37] |
G.L. Verdine, G.J. Hilinski, Drug Discov. Today Technol. 9(2012) e1-e70.
|
| [38] |
W. Weissenhorn, A. Dessen, S.C. Harrison, et al., Nature 387(1997) 426-430.
|
|
|
|
