共 36 条
Covalent stabilization of coiled coils of the HIV gp41 N region yields extremely potent and broad inhibitors of viral infection
被引:101
作者:
Bianchi, E
Finotto, M
Ingallinella, P
Hrin, R
Carella, AV
Hou, XS
Schleif, WA
Miller, MD
Geleziunas, R
Pessi, A
机构:
[1] Ist Ric Biol Mol P Angeletti, Dept Mol & Cell Biol, I-00040 Pomezia, Italy
[2] Merck Res Labs, West Point, PA 19486 USA
来源:
关键词:
fusion inhibitor;
D O I:
10.1073/pnas.0502449102
中图分类号:
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
Peptides from the N-heptad repeat region of the HIV gp41 protein can inhibit viral fusion, but their potency is limited by a low tendency to form a trimeric coiled-coil. Accordingly, stabilization of N peptides by fusion with the stable coiled-coil IZ yields nanomolar inhibitors [Eckert, D. M. & Kim, P. S. (2001) Proc. Natl. Acad. Sci. USA 98, 11187-11192]. Because the antiviral potency of IZN17 is limited by self-association equilibrium, we covalently stabilized the peptide by using interchain disulfide bonds. The resulting covalent trimer, (CCIZN17)(3), has an extraordinary thermodynamic stability that translates into unprecedented antiviral potency: (CCIZN17)3 (1) inhibits fusion in a cell-cell fusion assay (IC50 = 260 pM); (ii) is the most potent fusion inhibitor described to date (IC50 = 40-380 pM) in a single-cycle infectivity assay against HIVHXB2, HIVNL4-3, and HIVMN-1; (iii) efficiently neutralizes acute viral infection in peripheral blood mononuclear cells; and (iv) displays a broad antiviral profile, being able to neutralize 100 % of a large panel of HIV isolates, including R5, X4, and R5/X4 strains. In all of these assays, the potency of N-peptide inhibitor (CCIZN17)(3) was equal to or more than the C-peptide inhibitor in clinical use, DP178 (also known as Enfuvirtide and Fuzeon). More importantly, we show that the two inhibitors, which have different targets in gp41, synergize when used in combination. These features make (CCIZN17)(3) an attractive lead to develop as an antiviral drug, alone or in combination with DP178, as well as a promising immunogen to elicit a fusion-blocking neutralizing antibody response.
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页码:12903 / 12908
页数:6
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