| 论文题目: | Enfuvirtide-PEG conjugate: A potent HIV fusion inhibitor with improved pharmacokinetic properties |
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| 作者: | Cheng Shuihong, Wang Yan, Zhang Zhenxing, Lv Xun, Gao George F, Shao Yiming, Ma Liying, and Li Xuebing* |
| 联系作者: | |
| 刊物名称: | Eur J Med Chem |
| 期: | |
| 卷: | 121 |
| 页: | 232-237 |
| 年份: | 2016 |
| 影响因子: | 3.946 |
| 论文下载: | 下载地址 |
| 摘要: | Enfuvirtide (ENF) is a clinically used peptide drug for the treatment of HIV infections, but its poor pharmacokinetic profile (T1/2 = 1.5 h in rats) and low aqueous solubility make the therapy expensive and inconvenience. In this study, we present a simple and practical strategy to address these problems by conjugating ENF with polyethylene glycol (PEG). Site-specific attachment of a 2 kDa PEG at the N-terminus of ENF resulted in an ENF-PEG (EP) conjugate with high solubility (>/=3 mg/mL) and long half-life in rats (T1/2 = 16.1 h). This conjugate showed similar antiviral activity to ENF against various primary HIV-1 isolates (EC50 = 6-91 nM). Mechanistic studies suggested the sources of the antiviral potency. The conjugate bound to a functional domain of the HIV gp41 protein in a helical conformation with high affinity (Kd = 307 nM), thereby inhibiting the gp41-mediated fusion of viral and host-cell membranes. As PEG conjugation has advanced many bioactive proteins and peptides into clinical applications, the EP conjugate described here represents a potential new treatment for HIV infections that may address the unmet medical needs associated with the current ENF therapy. |
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