Design, Synthesis and Activity Evaluation of Novel Bivalent HIV-1 Fusion Inhibitor

doi:10.7503/cjcu20130391

Abstract

Abstract:

Multivalent inhibitor is an efficient strategy for inhibitor design based on an additive effect of ΔG. In this work, we chose C34 and T20 as the template sequences to study bivalent inhibitors targeting HIV-1 gp41 NHR domain. We optimized the crosslink sites and linkers to improve anti-HIV activities of the bivalent fusion inhibitors. Compared to monovalent molecules, significant cooperative effects in the anti-cell-cell fusion activity were observed in the bivalent inhibitors, at either N- or C-terminal crosslink of both C34 and T20. β-Alanine may be the most suitable linker for N-terminal crosslink, while C34C is the best C-terminal crosslinked molecule. Specially, the anti-HIV IC₅₀ value of peptide BiCβAC34 was improved from 43.7 nmol/L to 6.4 nmol/L, indicating the two C-peptide chains had a cooperative effect. The results show that bivalent fusion inhibitor for gp41 design could appear a cooperative effect.

Key words: Transmembrane glycoprotein gp41, Human immunodeficiency virus(HIV), Bivalent molecule, Fusion inhibitor, Peptide

CLC Number:

O629.72

TrendMD:

LING Yan-Bo, WANG Kun, JIANG Xi-Feng, CAI Li-Feng, LIU Ke-Liang. Design, Synthesis and Activity Evaluation of Novel Bivalent HIV-1 Fusion Inhibitor[J]. Chem. J. Chinese Universities, 2013, 34(9): 2102.

References

[1] Shao B. S., Gong W. H., Gao J. L., Shen W. P., Grimm M. C., Deng X. Y., Murphy P. M., Oppenheim J. J., Wang J. M., Blood, 1999, 3(11), 3885—3892

[2] Blower S. M., Aschenbach A. N., Gershengorn H. B., Kahn J. O., Nat. Med., 2001, 7(9), 1016—1020

[3] Ketas T. J., Frank I., Klasse P. J., Sullivan B. M., Gardner J. P., Spenlehauer C., Nesin M., Olson W. C., Moore J. P., Pope M., J. Virol., 2003, 77 (4), 2762—2767

[4] Alam S. M., Paleos C. A., Liao H. X., Scearce R., Robinson J., Haynes B. F., AIDS Res. Hum. Retroviruses, 2004, 20(5), 836—845

[5] Cai L. F., Jiang S. B., Chem. Med. Chem., 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., Matthew T. J., AIDS Res. Hum. Retroviruses, 2000, 16(7), 2037—2041

[8] Cleveland S. M., McLain L., Cheung L., Jones T. D., Hollier M., Dimmock J., J. Gen. Virol., 2003, 84(13), 591—602

[9] Zhou J. M., Zhang Z. X., Mi Z. Y., Wang X., Zhang Q., Li Z. Y., Liang C., Cen S., Biochem., 2012, 51(6), 1288—1296

[10] Carmona R., Pérez-Alvarez L., Muñoz M., Casado G., Delgado E., Sierra M., J. Clin. Virol., 2005, 32(7), 248—253

[11] Simon V., Ho D. D., Karim Q. A., Lancet, 2006, 368(9534), 489—504

[12] Kawamura M., Naito T., Ueno M., Akagi T., Hiraishi K., Takai I., J. Med. Virol., 2002, 66(3), 291—298

[13] Cole J. L., Garsky V. M., Biochem., 2001, 40(19), 5633—5641

[14] Sia S. K., Carr P. A., Cochran A. G., Malashkevich V. N., Kim P. S., PNAS, 2002, 99(23), 14664—14669

[15] Lyon R. P., Hill J. J., Atkins W. M., Biochem., 2003, 42(19), 10418—10428

[16] Choi S. K., Synthetic Multivalent Molecules: Concepts and Biomedical Applications, John Wiley & Sons Press, Paris, 2004, 25—37

[17] Fan E., Zhang Z., Minke W. E., Hou Z., Verlinde C. L. M. J., Hol W. G. J., J. Am. Chem. Soc., 2000, 122(11), 2663—2664

[18] Tam J., Yu Q., Org. Lett., 2002, 4(23), 4167—4170

[19] Nomura W., Hashimoto C., Ohya A., Miyauchi K., Urano E., Tanaka T., Narumi T., Nakahara T., Komano J. A., Yamamoto N., Tamamura H., Chem. Med. Chem., 2012, 7(2), 205—208

[20] Xiao J., Hamilton B. S., Tolbert T. J., Bioconj. Chem., 2010, 21(11), 1943—1947