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核苷逆转录酶抑制剂的聚-L-精氨酸-脂肪酰基衍生物的设计、合成、抗病毒活性及制剂前研究

Design, synthesis, antiviral activity, and pre-formulation development of poly-L-arginine-fatty acyl derivatives of nucleoside reverse transcriptase inhibitors.

作者信息

Pemmaraju Bhanu P, Malekar Swapnil, Agarwal Hitesh K, Tiwari Rakesh K, Oh Donghoon, Doncel Gustavo F, Worthen David R, Parang Keykavous

机构信息

a Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy , University of Rhode Island , Kingston , RI , United States.

出版信息

Nucleosides Nucleotides Nucleic Acids. 2015;34(1):1-15. doi: 10.1080/15257770.2014.945649.

DOI:10.1080/15257770.2014.945649
PMID:25513860
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4269296/
Abstract

The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell-penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC) were synthesized. In general, the compounds exhibited anti-HIV activity against X4 and R5 cell-free virus with EC50 values of 1.5-16.6 μM. FLT-CO-(CH2)12-CO-(Arg)7 exhibited EC50 values of 2.9 μM and 3.1 μM against X4 and R5 cell-free virus, respectively. The FLT conjugate was selected for further preformulation studies by determination of solution state degradation and lipid solubility. The compound was found to be stable in neutral and oxidative conditions and moderately stable in heated conditions.

摘要

这项工作的目的是设计抗HIV核苷与脂肪酸及细胞穿透性聚-L-精氨酸（聚精氨酸）肽缀合而成的缀合物。合成了聚精氨酸细胞穿透肽与阿洛苷（FLT）、拉米夫定（3TC）和恩曲他滨（FTC）的脂肪酰衍生物的三种缀合物。总体而言，这些化合物对X4和R5无细胞病毒表现出抗HIV活性，EC50值为1.5 - 16.6μM。FLT-CO-(CH2)12-CO-(Arg)7对X4和R5无细胞病毒的EC50值分别为2.9μM和3.1μM。通过测定溶液状态降解和脂溶性，选择FLT缀合物进行进一步的制剂前研究。发现该化合物在中性和氧化条件下稳定，在加热条件下中度稳定。

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