Design, Synthesis and Activity Prescreening of Small Molecule-Peptide Conjugates as HIV-1 Fusion Inhibitors Targeting gp41†

doi:10.7503/cjcu20140495

Abstract

Abstract:

HIV-1 fusion inhibitors target the transmembrane subunit(gp41) of HIV-1 envelopeglycoproteins. Previous studies had shown that the small molecule pyrrole derivatives, Noc or Npc, can act as a substitute for the pocket binding domain of the C34 peptide, and the small molecule-peptide conjugates exhibit low nanomolar IC₅₀ value in the cell-cell fusion assay. In this paper, pocket-specific small molecule and P27 peptide were covalently linked together through specified linkers with different lengths and flexibilities. Small molecule-peptide conjugates exhibited significant inhibitory activity on HIV-1 Env-mediated cell-cell fusion assay.

Key words: HIV-1, Fusion inhibitor, Conjugate

CLC Number:

O629.72

TrendMD:

LIANG Guodong, WANG Chao, SHI Weiguo, WANG Kun, JIANG Xifeng, XU Xiaoyu, LIU Keliang. Design, Synthesis and Activity Prescreening of Small Molecule-Peptide Conjugates as HIV-1 Fusion Inhibitors Targeting gp41^†[J]. Chem. J. Chinese Universities, 2014, 35(10): 2100.

Figures/Tables 2

References 20

[1]	Simon V., Ho D. D., Karim Q. A., Lancet,2006, 368(9534), 489—504
[2]	Kawamura M., Naito T., Ueno M., Akagi T., Hiraishi K., Takai I., Makino M., Serizawa T., Sugimura K., Akashi M., Baba M., J. Med. Virol., 2002, 66(3), 291—298
[3]	Cole J. L., Garsky V. M., Biochem., 2001, 40(19), 5633—5641
[4]	Sia S. K., Carr P. A., Cochran A. G., Malashkevich V. N., Kim P. S., Proc. Natl. Acad. Sci. USA,2002, 99(23), 14664—14669
[5]	Cai L. F., Jiang S. B., ChemMedChem,2010, 5(11), 1813—1824
[6]	Otaka A., Nakamura M., Nameki D., Kodama E., Uchiyama S., Nakamura S., Nakano H., Tamamura H., Kobayashi Y., Matsuoka M., Fujii N., Angew. Chem. Int. Ed., 2002, 41(16), 2937—2940
[7]	Chen C. H., Greenberg M. L., Bolognesi D. P., Matthews T. J., AIDS Res. Hum. Retroviruses,2000, 16(8), 2037—2041
[8]	Cleveland S. M., McLain L., Cheung L., Jones T. D., Hollier M., Dimmock N. J., J. Gen. Virol., 2003, 84(3), 591—602
[9]	Shi W. G., Jia Q. Y., Liu K. L., Acta Pharmaceutica Sinica,2010, 45(2), 184—193
	(史卫国, 贾启燕, 刘克良. 药学学报, 2010, 45(2), 184—193)
[10]	Zhou J., Zhang Z., Mi Z., Wang X., Zhang Q., Li X., Liang C., Cen S., Biochemi., 2012, 51(6), 1288—1296
[11]	Carmona R., Pérez-Alvarez L., Muñoz M., Casado G., Delgado E., Sierra M., Thomson M., Vega Y., Vázquez de Parga E., Contreras G., Medrano L., Nájera R., J. Clin. Virol., 2005, 32(7), 248—253
[12]	Chan D. C., Fass D., Berger J. M., Kim P. S., Cell,1997, 89(2), 263—273
[13]	Jia Q. Y., Cai L. F., Liu K. L., Science China: Chemistry,2013, 43(8), 984—994
	(贾启燕, 蔡利峰, 刘克良. 中国科学: 化学, 2013, 43(8), 984—994)
[14]	Chan D. C., Chutkowski C. T., Kim P. S., Proc. Natl. Acad. Sci. USA,1998, 95(26), 15613—15617
[15]	Jiang S. B., Lu H., Liu S., Zhao Q., He Y., Debnath A. K., Antimicrob. Agents Chemother., 2004, 48(11), 4349—4359
[16]	Qi Z., Shi W. G., Xue N., Pan C. G., Jing W. G., Liu K. L., Jiang S. B., J. Biol. Chem., 2008, 283(44), 30376—30384
[17]	Shi W. G., Cai L. F., Lu L., Wang C., Wang K., Xu L., Zhang S., Han H., Jiang X. F., Zheng B. H., Jiang S. B., Liu K. L., Chem. Commun., 2012, 48(94), 11579—11581
[18]	Liu S. W., Jing W. G., Cheung B., Lu H., Sun J., Yan X. X., Niu J. K., Farmar J., Wu S. G., Jiang S. B., J. Biol. Chem., 2007, 282(13), 9612—9620
[19]	Wang C., Shi W. G., Cai L. F., Lu L., Wang Q., Zhang T. H., Li J. L., Zhang Z. Q., Wang K., Xu L., Jiang X. F., Jiang S. B., Liu K. L., J. Med. Chem., 2013, 56(6), 2527—2539
[20]	Ling Y. B., Wang K., Jiang X. F., Cai L. F., Liu K. L., Chem. J. Chinese Universities,2013, 34(4), 2102—2107
	(凌彦博, 王昆, 姜喜凤, 蔡利峰, 刘克良. 高等学校化学学报, 2013, 34(4), 2102—2107)

Name^b	Structure	IC₅₀/(nmol·L^-1)
C34	Ac-WMEWDREINNYTSLIHSLIEESQNQQEKNEQELL-NH₂	1.91±0.12
P27	Ac-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	1341±126
Noc-βAla-P27	Noc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	10.38±1.25
Noc-Aca-P27	Noc-Aca-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	15.31±1.41
Noc-PEG₃-P27	Noc-PEG₃-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	17.09±2.33
Npc-βAla-P27	Npc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	314.5±23.5
Npc-Aca-P27	Npc-Aca-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	649.8±32.1
Npc-PEG₃-P27	Npc-PEG₃-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	345.7±15.3
T20	Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH₂	2.27±0.41

Name^b	Structure	IC₅₀/(nmol·L^-1)
C34	Ac-WMEWDREINNYTSLIHSLIEESQNQQEKNEQELL-NH₂	1.91±0.12
P27	Ac-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	1341±126
Noc-βAla-P27	Noc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	10.38±1.25
Noc-Aca-P27	Noc-Aca-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	15.31±1.41
Noc-PEG₃-P27	Noc-PEG₃-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	17.09±2.33
Npc-βAla-P27	Npc-βAla-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	314.5±23.5
Npc-Aca-P27	Npc-Aca-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	649.8±32.1
Npc-PEG₃-P27	Npc-PEG₃-INNYTSLIHSLIEESQNQQEKNEQELL-NH₂	345.7±15.3
T20	Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH₂	2.27±0.41