Synthesis of Cholesterol Conjugated Non-native Derived Heptad Repeat Sequence Peptides as Potent HIV-1 Fusion Inhibitors†

doi:10.7503/cjcu20140572

Abstract

Abstract:

As addition of a cholesterol group to nature peptide fusion inhibitor can dramatically increase its antiviral potency, we designed and synthesized a series of cholesterol conjugated artificial peptide with low sequence homologous from HIV-1 gp41 as HIV-1 fusion inhibitors. The cholesterol moiety was introduced into C- or N-terminal of the peptide through a thioether in cysteine side chain and a β-alanine linker to study the effect of cholesterol modification to the activity of non-natural HR sequence and explore new method to overcome the problem of HIV drug resistance. Cell-cell fusion assays showed that the fusion inhibitory activity of the C-terminal cholesterol conjugated peptide was significantly increased, while the activity of N-terminal conjugated peptide was completely lost, consistent with the reported peptide conjugation using native peptide sequence, indicated that the designed non-natural sequences had a similar mechanism of action with natural sequences. This work provided a useful base for further drug optimization and discovery of highly active non-natural peptide sequences.

Key words: HIV fusion inhibitor, Peptide, Drug resistance, Non-natural sequence

CLC Number:

O629.72

TrendMD:

ZHANG Sha, SHI Weiguo, WANG Chao, CAI Lifeng, ZHENG Baohua, WANG Kun, FENG Siliang, JIA Qiyan, LIU Keliang. Synthesis of Cholesterol Conjugated Non-native Derived Heptad Repeat Sequence Peptides as Potent HIV-1 Fusion Inhibitors^†[J]. Chem. J. Chinese Universities, 2014, 35(12): 2542.

Figures/Tables 2

References 21

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Peptide	Sequence	M_w(calcd.)	MALDI-TOF-MS, m/z	Purity by HPLC(%)
4HR	(IEEYTKK)₄	3627	3626.8	>95
5HR	(IEEYTKK)₅	4519	4518.2	>95
4HR-βAla-C	(IEEYTKK)₄-βAla-C	3801	3801.5	>95
5HR-βAla-C	(IEEYTKK)₅-βAla-C	4693	4693.2	>95
C-βAla-4HR	C-βAla-(IEEYTKK)₄	3801	3800.9	>95
C-βAla-5HR	C-βAla-(IEEYTKK)₅	4693	4693.1	>95

Peptide	Sequence	M_w(calcd.)	MALDI-TOF-MS, m/z	Purity by HPLC(%)
4HR	(IEEYTKK)₄	3627	3626.8	>95
5HR	(IEEYTKK)₅	4519	4518.2	>95
4HR-βAla-C	(IEEYTKK)₄-βAla-C	3801	3801.5	>95
5HR-βAla-C	(IEEYTKK)₅-βAla-C	4693	4693.2	>95
C-βAla-4HR	C-βAla-(IEEYTKK)₄	3801	3800.9	>95
C-βAla-5HR	C-βAla-(IEEYTKK)₅	4693	4693.1	>95

Peptide	Sequence	M_w(calcd.)	MALDI-TOF-MS, m/z	Purity by HPLC^a(%)	Inhibiting cell fusion at 200 nmol/L(%)
4HR	(IEEYTKK)₄	3627	3626.8	96.1	ND^b
5HR	(IEEYTKK)₅	4519	4518.2	95.4	10
4HR-βAla-C-Chol	(IEEYTKK)₄-βAla-C-Chol	4228	4227.9	95.3	42
5HR-βAla-C-Chol	(IEEYTKK)₅-βAla-C-Chol	5119	5118.3	94.7	30
Chol-C-βAla-4HR	Chol-C-βAla-(IEEYTKK)₄	4185	4183.8	92.3	0
Chol-C-βAla-5HR	Chol-C-βAla-(IEEYTKK)₅	5077	5077.5	93.1	0
T-20	YTSLIHSLIEESQNQQEKNEQE	4492	4491.9	95.3	98
	LLELDKWASLWNWF

Peptide	Sequence	M_w(calcd.)	MALDI-TOF-MS, m/z	Purity by HPLC^a(%)	Inhibiting cell fusion at 200 nmol/L(%)
4HR	(IEEYTKK)₄	3627	3626.8	96.1	ND^b
5HR	(IEEYTKK)₅	4519	4518.2	95.4	10
4HR-βAla-C-Chol	(IEEYTKK)₄-βAla-C-Chol	4228	4227.9	95.3	42
5HR-βAla-C-Chol	(IEEYTKK)₅-βAla-C-Chol	5119	5118.3	94.7	30
Chol-C-βAla-4HR	Chol-C-βAla-(IEEYTKK)₄	4185	4183.8	92.3	0
Chol-C-βAla-5HR	Chol-C-βAla-(IEEYTKK)₅	5077	5077.5	93.1	0
T-20	YTSLIHSLIEESQNQQEKNEQE	4492	4491.9	95.3	98
	LLELDKWASLWNWF