Design, Sythesis and Biological Evaluation of Polyphenol-α-helical Peptide Conjugates as Potent HIV-1 Fusion Inhibitors†

doi:10.7503/cjcu20160295

Abstract

Abstract:

De novo-designed peptide sequences with an α-helical conformation can prevent fusogenic gp41 six-helical bundle(6HB) formation by specifically interacting with the Human Immunodificiency virus type 1(HIV-1) gp41 N-terminal heptad repeat(NHR) region, thus inhibiting HIV-1-cell membrane fusion. Meanwhile, polyphenols, such as hydroxytyrosol(HT) and (-)-epigallocatechin gallate(EGCG), are a major group of natural compounds with a broad spectrum of antiviral activity. In this paper, mHT were designed and obtained based on 3,4-dihydroxymethylacetic acid. Then, mHT and other bioactive polyphenols, were covalently conjugated to a certain α-helical peptide through specific linkers with different lengths and flexibilities. These conjugates interacted with the gp41 NHR region and exhibited promising fusion inhibitory activity, with IC₅₀ values in the low micromolar range. This study provides a promising strategy for the development of fusion inhibitors against viruses with class I fusion proteins.

Key words: Human immunodificiency virus type 1(HIV-1), Fusion inhibitor, α-Helical peptide, Polyphenol

CLC Number:

O629.72

TrendMD:

CHENG Siqi, LIANG Guodong, JIANG Xifeng, WANG Chao, LIU Keliang. Design, Sythesis and Biological Evaluation of Polyphenol-α-helical Peptide Conjugates as Potent HIV-1 Fusion Inhibitors^†[J]. Chem. J. Chinese Universities, 2016, 37(7): 1287.

Figures/Tables 5

Fig.1 Ineraction between NHR and CHR of HIV gp41(A) Association of the CHR to NHR to form 6-HB; (B) CHR and NHR interact in antiparallel orientation to form 6HB.

Scheme 1 Synthesis routes of compound 5

Fig.2 Structures of polyphenols and designed conjugates(A) Chemical formula of mHT, PA and GA; (B) sequence of designed conjugates.

Fig.3 CD spectra of mHT-βAla-m4HR and its complex with gp41 NHR peptidesa. mHT-βAla-m4HR; b. N36; c. mHT-βAla-m4HR+N36; d. mHT-βAla-m4HR/N36.

Table 1 Inhibitory activities of conjugates on HIV-1 Env-mediated cell-cell fusiona

Compd.	Structure	I $C 50 b$ /(μmol·L^-1)
m4HR	Ac-IEELIKK SEELIKK IEEQIKK QEESIKK	36.910±2.047
mHT-βAla-m4HR	mHT-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK	11.247±1.490
mHT-Aca-m4HR	mHT-Aca-IEELIKK SEELIKK IEEQIKK QEESIKK	5.346±0.8233
mHT-PEG₃-m4HR	mHT-PEG₃-IEELIKK SEELIKK IEEQIKK QEESIKK	7.036±1.0327
PA-βAla-m4HR	PA-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK	11.538±1.568
GA-βAla-m4HR	GA-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK	23.373±2.495

Table 1 Inhibitory activities of conjugates on HIV-1 Env-mediated cell-cell fusiona

Compd.	Structure	I $C 50 b$ /(μmol·L^-1)
m4HR	Ac-IEELIKK SEELIKK IEEQIKK QEESIKK	36.910±2.047
mHT-βAla-m4HR	mHT-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK	11.247±1.490
mHT-Aca-m4HR	mHT-Aca-IEELIKK SEELIKK IEEQIKK QEESIKK	5.346±0.8233
mHT-PEG₃-m4HR	mHT-PEG₃-IEELIKK SEELIKK IEEQIKK QEESIKK	7.036±1.0327
PA-βAla-m4HR	PA-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK	11.538±1.568
GA-βAla-m4HR	GA-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK	23.373±2.495

References 28

[1]	Lu M., Blacklow S. C., Kim P. S., Nat. Struct. Biol., 1995, 2, 1075—1082
[2]	Moore J. P., Doms R. W., Proc. Natl. Acad. Sci. USA,2003, 100, 10598—10602
[3]	Liu S., Zhao Q., Jiang S., Peptides,2003, 24(9), 1303—1313
[4]	Donegan E., Stuart M., Niland J. C., Ann. Intern. Med., 1990, 113(10), 733—739
[5]	Cai L. F., Jiang S. B., Chem. Med. Chem., 2010, 5(11), 1813—1824
[6]	Jiang S., Lin K., Strick N., Neurath A. R., Nature,1993, 365, 113—114
[7]	Wild C. T., Shugars D. C., Greenwell T. K., McDanal C. B., Matthews T. J., Proc. Natl. Acad. Sci. USA ,1994, 91, 9770—9774
[8]	Chen C. H., Greenberg M. L., Bolognesi D. P., Matthews T. J., AIDS Res. Hum. Retroviruses,2000, 16(8), 2037—2041
[9]	Zhang S., Shi W. G., Wang C., Cai L. F., Zheng B. H., Wang K., Feng S. L., Jia Q.Y., Liu K. L., Chem. J. Chinese Universities ,2014, 35(12), 2542—2546(张沙, 史卫国, 王潮, 蔡利峰, 郑保华, 王昆, 冯思良, 贾启燕, 刘克良. 高等学校化学学报, 2014, 35(12), 2542—2546)
[10]	Joly V., Jidar K., Tatay M., Yeni P., Expert Opin. Pharmacother., 2010, 11, 2701—2713
[11]	Chan D. C., Fass D., Berger J. M., Kim P. S., Cell,1997, 89(2), 263—273
[12]	Judice J. K., Tom J. Y., Huang W., Wrin T., Vennari J., Petropoulos C. J., McDowell R. S., Proc. Natl. Acad. Sci. USA,1997, 94, 13426—13430
[13]	Yu Y. G., Kim K. S., Jin B. S., Peptides for Inhibition of HIV Infection, US 6489449 B2,2002-12-03
[14]	Shi W., Qi Z., Pan C., Xue N., Asim K. D., Qie J. K., Jiang S. B., Liu K. L., Biochem. Biophys. Res. Commun., 2008, 374(4), 767—772
[15]	Shi W., Cai L., Lu L., Wang C., Wang K., Xu L., Zhang S., Han H., Jiang X., Zheng B., Jiang S., Liu K., Chem. Commun., 2012, 48, 11579—11581
[16]	Huang S., Li Z., Huang P., Chang Y., Huang P., Biochem. Biophys. Res. Commun., 2003, 307, 1029—1037
[17]	Helieh S., Jeffrey O., Ebersole L., J. Cancer Ther., 2010, 1(3), 105—113
[18]	Di P. R., Mazzon E., Muià C.,Genovese T., Menegazzi M., Zaffini R., Suzuski H., Cuzzocrea S., Respir Res., 2005, 6, 66—78
[19]	Massimo D., Carmela F., Roberta D., Raffaella G., Claudio G., Roberta M., Ann Ist Super Sanità,2007, 43(4), 348—361
[20]	Liu S., Lu H., Zhao Q., He Y., Niu J., Debnath A. K., Wu S., Jiang S., Biochim. Biophys. Acta,2005, 1723, 270—281
[21]	Fassina G., Buffa A., Benelli R., Varnier O. E., Noonan D. M., Albini A., AIDS,2002, 16, 939—941
[22]	Lee H. S., Huang P. L., Zhang D., Lee J. W., Bao J., Sun Y., Chang Y. T., Zhang J. Z., Huang P. L., Biochem. Biophys. Res. Commun., 2007, 354, 872—878
[23]	Bao J., Zhang D. W., Zhang J. Z. H., Huang P. L., Huang P. L., Huang S. L., FEBS Letters,2007, 581, 2737—2742
[24]	Wang C., Shi W., Cai L., Lu L., Yu F., Wang Q., Jiang X., Xu X., Wang K., Xu L., Jiang S., Liu K., J. Antimicrob. Chemo-ther., 2014, 69, 1537—1545
[25]	Jayan N., Yoshio H., Junfa F., Kenneth L. K., Bioorg. Chem., 2003, 31, 191—197
[26]	Gambacorta A., Tofani D., Bernini R., Migliorini A., J. Agric. Food Chem., 2007, 55, 3386—3391
[27]	Mary K. L., Shawn B., Kelly I. G., Teresa B. B., Stephen R. P. Jr., Gene M., Biochemistry,1996, 35, 13697—13708
[28]	Liang G. D., Wang C., Shi W. G., Wang K., Jiang X. F., Xu X. Y., Liu K. L., Chem. J. Chinese Universities,2014, 35(10), 2100—2103(梁国栋, 王潮, 史卫国, 王昆, 姜喜凤, 许笑宇, 刘克良. 高等学校化学学报, 2014, 35(10), 2100—2103)