Polybiguanides, particularly polyethylene hexamethylene biguanide, have activity against human immunodeficiency virus type 1
Polybiguanides, particularly polyethylene hexamethylene biguanide, have activity against human immunodeficiency virus type 1
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DOI：
10.1016/j.biopha.2005.07.007
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发表时间：
2005-09-01
影响因子：
7.5
通讯作者：
Wigdahl, B
中科院分区：
文献类型：
--
作者：
Krebs, FC;Miller, SR;Wigdahl, B
聚六亚甲基双胍（PHMB）是一种具有抗菌活性的聚双胍（PBG）低聚物，作为消毒剂广泛而安全地使用。已报道的PHMB抗菌活性机制涉及与细胞膜组分的相互作用，这表明PHMB或其他基于pbg的化合物也可能对人类免疫缺陷病毒1型（HIV-1）具有抗病毒或杀病毒活性。PHMB在体外对无细胞HIV-1和细胞相关HIV-1都有适度的活性，以及干扰病毒结合和进入的能力。然而，PHMB在细胞毒性方面与杀精剂壬氧醇-9 （N-9）相当，后者在先前的研究中被认为具有细胞毒性，并对宫颈阴道上皮的完整性有害。为了鉴定具有更强抗HIV-1活性和/或更低细胞毒性的PHMB结构变体，合成了包含碳氢化合物连接单元长度变化的修饰版本的PHMB，并评估了体外细胞毒性和抑制HIV-1感染的能力。这些实验表明，PHMB变体聚乙烯六亚甲基双胍（PEHMB）对HIV-1的活性与PHMB一样，但比N-9或PHMB的细胞毒性小得多，导致体外治疗指数（TI）比N-9的TI高约114倍。在这些研究中，PEHMB已被确定为该化合物家族中有前途的杀微生物候选物，将成为进一步体外和体内抗hiv -1活性、毒性和作用机制评估的重点。(c) 2005 Elsevier SAS。版权所有。
Polyhexamethylene biguanide (PHMB) is a polybiguanide (PBG) oligomer with antimicrobial activity that is used extensively and safely as a disinfectant. The reported mechanism of PHMB antimicrobial activity, which involves interactions with cell membrane components, suggested that PHMB or other PBG-based compounds might also have antiviral or virucidal activity against the human immunodeficiency virus type 1 (HIV-1). PHMB had modest in vitro activity against both cell-free and cell-associated HIV-1, as well as the ability to interfere with viral binding and entry. However, PHMB was comparable in cytotoxicity to the spermicidal agent nonoxynol-9 (N-9), a compound that has been characterized in previous studies as generally cytotoxic and detrimental to cervicovaginal epithelial integrity. To identify structural variants of PHMB with greater anti-HIV-1 activity and/or less cytotoxicity, modified versions of PHMB incorporating length changes in the hydrocarbon linker units were synthesized and evaluated for in vitro cytotoxicity and inhibition of HIV-1 infectivity. These experiments demonstrated that the PHMB variant polyethylene hexamethylene biguanide (PEHMB) was just as active against HIV-1 as PHMB, yet was much less cytotoxic than either N-9 or PHMB, resulting in an in vitro therapeutic index (TI) approximately 114-fold greater than the TI of N-9. PEHMB, which has been identified in these studies as a promising microbicidal candidate in this family of compounds, will be the focus of further in vitro and in vivo evaluations of anti-HIV-1 activity, toxicity, and mechanisms of action. (c) 2005 Elsevier SAS. All rights reserved.