Design, Synthesis and Activity Screening of Isopeptide Bond-tethered N Peptides as HIV-1 Fusion Inhibitors†

doi:10.7503/cjcu20160125

Abstract

Abstract:

Peptides derived from the N-terminal heptad repeat(N-peptides) of HIV-1 gp41 can exhibit highly potent anti-HIV-1 activity when presented in a trimeric coiled-coil conformation. In this paper, the NHR trimeric coiled coils were designed based on a naturally occurring N-peptide, e.g. N38, on which engineered acyl transfer active sites were incorporated at the e/g-positions of heptad repeats to generate isopeptide bond cross-links. These isopeptide bond-tethered N-peptides exhibited exceptional thermal stability and possessed promising inhibitory activity on HIV-1 env-mediated cell-cell fusion.

Key words: HIV-1, Fusion inhibitor, N-terminal heptad repeat, Coiled coil

CLC Number:

O629.72

TrendMD:

LI Xue, LAI Wenqing, JIANG Xifeng, WANG Chao, LIU Keliang. Design, Synthesis and Activity Screening of Isopeptide Bond-tethered N Peptides as HIV-1 Fusion Inhibitors^†[J]. Chem. J. Chinese Universities, 2016, 37(5): 881.

Figures/Tables 4

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Peptide	Sequence
	g	abcdefg	abcdefg	abcdefg	abcdefg	abcdefg	ab
N38	L	LSGIVQQ	QNNLLRA	IEAQQHL	LQLTVWG	IKQLQAR	IL
(N38M)₃	(L	ISGIVQK	IHHIERA	IEAIQHL	LQLTVWG	IKQLQAR	IL)₃
(N38MEK)₃	(L	IEEIVKK	IHHIERA	IEAIQKL	LQLTVWG	IKQLQAR	IL)₃
(N38MEKK)₃	(K	IEEIVKK	IHHIERA	IEAQQKL	LQLTVWG	IKQLQAR	IL)₃

Peptide	Sequence
	g	abcdefg	abcdefg	abcdefg	abcdefg	abcdefg	ab
N38	L	LSGIVQQ	QNNLLRA	IEAQQHL	LQLTVWG	IKQLQAR	IL
(N38M)₃	(L	ISGIVQK	IHHIERA	IEAIQHL	LQLTVWG	IKQLQAR	IL)₃
(N38MEK)₃	(L	IEEIVKK	IHHIERA	IEAIQKL	LQLTVWG	IKQLQAR	IL)₃
(N38MEKK)₃	(K	IEEIVKK	IHHIERA	IEAQQKL	LQLTVWG	IKQLQAR	IL)₃

Peptide	Helicity(%)	T_m/℃	IC₅₀/(μmol·L^-1)(n=3)
N38	60	Aggregated	3.267±0.336
(N38M)₃	43	>90	0.379±0.097
(N38MEK)₃	99	>90	0.104±0.123
(N38MEKK)₃	100	>90	0.026±0.003
T20			0.005±0.001

Peptide	Helicity(%)	T_m/℃	IC₅₀/(μmol·L^-1)(n=3)
N38	60	Aggregated	3.267±0.336
(N38M)₃	43	>90	0.379±0.097
(N38MEK)₃	99	>90	0.104±0.123
(N38MEKK)₃	100	>90	0.026±0.003
T20			0.005±0.001