Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action
Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action
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长效HIV-1融合抑制肽及其作用机制
DOI：
10.3390/v11090811
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发表时间：
2019-09
期刊：
影响因子：
4.7
通讯作者：
Ma Liying
中科院分区：
文献类型：
--
作者：
Wang Chen;Cheng Shuihong;Zhang Yuanyuan;Ding Yibo;Chong Huihui;Xing Hui;Jiang Shibo;Li Xuebing;Ma Liying
HIV融合抑制剂恩夫韦肽（Enfuvirtide，T20）的半衰期短，限制了其临床应用。本文设计并合成了两个PEG化的C34肽PEG 2kC 34和PEG 5 kC 34，PEG链长分别为2和5 kDa，并评价了它们的抗HIV-1活性和作用机制。我们发现这两个聚乙二醇化的多肽可以与HIV-1多肽N36结合，形成高亲和力的复合物，具有高的α-螺旋度。肽PEG 2kC 34和PEG 5 kC 34有效地抑制HIV-1 Env介导的细胞-细胞融合，50%抑制的有效浓度（EC 50）为约36 nM。它们还抑制实验室适应的HIV-1毒株NL 4 -3的感染，EC 50约为4-5 nM，并抑制在中国流行的47种HIV-1临床分离株，PEG 2kC 34和PEG 5 kC 34的平均EC 50分别约为26 nM和32 nM。PEG 2kC 34和PEG 5 kC 34的血浆半衰期（t1/2）分别为2.6 h和5.1 h，PEG化C34的t1/2分别约为C34的2.4倍和4.6倍（约1.1 h）。这些发现表明，具有广谱抗HIV-1活性和延长半衰期的PEG化C34可以进一步开发为基于肽融合蛋白的长效抗HIV药物，用于临床治疗对当前抗逆转录病毒药物无效的HIV感染患者。
The clinical application of HIV fusion inhibitor, enfuvirtide (T20), was limited mainly because of its short half-life. Here we designed and synthesized two PEGylated C34 peptides, PEG2kC34 and PEG5kC34, with the PEG chain length of 2 and 5 kDa, respectively, and evaluated their anti-HIV-1 activity and mechanisms of action. We found that these two PEGylated peptides could bind to the HIV-1 peptide N36 to form high affinity complexes with high α-helicity. The peptides PEG2kC34 and PEG5kC34 effectively inhibited HIV-1 Env-mediated cell–cell fusion with an effective concentration for 50% inhibition (EC50) of about 36 nM. They also inhibited infection of the laboratory-adapted HIV-1 strain NL4-3 with EC50 of about 4–5 nM, and against 47 HIV-1 clinical isolates circulating in China with mean EC50 of PEG2kC34 and PEG5kC34 of about 26 nM and 32 nM, respectively. The plasma half-life (t1/2) of PEG2kC34 and PEG5kC34 was 2.6 h and 5.1 h, respectively, and the t1/2 of PEGylated C34 was about 2.4-fold and 4.6-fold longer than C34 (~1.1 h), respectively. These findings suggest that PEGylated C34 with broad-spectrum anti-HIV-1 activity and prolonged half-life can be further developed as a peptide fusion inhibitor-based long-acting anti-HIV drug for clinical use to treat HIV-infected patients who have failed to respond to current anti-retrovirus drugs.
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DOI：
10.3390/v11010056
发表时间：
2019-01
期刊：
Viruses
影响因子：
--
作者：
Shuai Xia;Qiaoshuai Lan;J. Pu;Cong Wang;Zezhong Liu;W. Xu;Qian Wang;Huan Liu;Shibo Jiang-
通讯作者：
Shuai Xia;Qiaoshuai Lan;J. Pu;Cong Wang;Zezhong Liu;W. Xu;Qian Wang;Huan Liu;Shibo Jiang-
影响因子：
2.2
作者：
A. Trotter;Steven Y Hong;P. Srikantiah;I. Abeyewickreme;S. Bertagnolio;M. Jordan
通讯作者：
A. Trotter;Steven Y Hong;P. Srikantiah;I. Abeyewickreme;S. Bertagnolio;M. Jordan
新型HIV融合抑制剂C34-PEG（4）-Chol的首次人类研究。
影响因子：
4.6
作者：
Quinn K;Traboni C;Penchala SD;Bouliotis G;Doyle N;Libri V;Khoo S;Ashby D;Weber J;Nicosia A;Cortese R;Pessi A;Winston A
通讯作者：
Winston A
HEPT 类似物 WPR-6 对不同血清型的多种非核苷逆转录酶耐药 HIV-1 菌株具有活性
影响因子：
4.9
作者：
Jiang S;Shao Y;Wang X;Ma L
通讯作者：
Ma L
影响因子：
5.2
作者：
Ngo-Giang-Huong, Nicole;Huynh, Thu H. K.;Ton Tran
通讯作者：
Ton Tran