Candidate topical microbicides bind herpes simplex virus glycoprotein B and prevent viral entry and cell-to-cell spread
Candidate topical microbicides bind herpes simplex virus glycoprotein B and prevent viral entry and cell-to-cell spread
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DOI：
10.1128/aac.48.6.2025-2036.2004
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发表时间：
2004-06-01
影响因子：
4.9
通讯作者：
Herold, BC
中科院分区：
文献类型：
--
作者：
Cheshenko, N;Keller, MJ;Herold, BC
迫切需要旨在预防性传播感染的局部杀微生物剂。壬苯醇醚-9是唯一市售的杀精剂，它会损害上皮细胞，并可能增强人类免疫缺陷病毒的传播。单纯疱疹病毒（HSV）和人类免疫缺陷病毒结合硫酸乙酰肝素的观察结果为开发硫酸化或磺化聚合物作为局部药物提供了理论基础。虽然几种聚合物已进入临床试验，但抗HSV活性的谱和机制以及对可溶性炎症介质的影响尚未进行评估。目前的研究解决这些差距。结果表明，PRO 2000、聚苯乙烯磺酸盐、纤维素硫酸盐和聚亚甲基氢醌磺酸盐抑制HSV感染10，000倍，并对临床分离株（包括阿昔洛韦耐药变体）具有活性。该化合物与糖蛋白B形成稳定的复合物，并抑制病毒结合、进入和细胞间扩散。由于硫酸化化合物-病毒复合物的高亲和力和稳定性，该作用可能是持久的，如表面等离子体共振研究所证明的。候选杀微生物剂在宫颈分泌物存在的情况下和在较宽的pH范围内保留其抗病毒活性。人宫颈内膜细胞反复暴露于这些化合物后，细胞活力几乎没有降低，尽管观察到分泌性白细胞蛋白酶抑制剂水平降低。这些研究支持这些候选杀微生物剂的进一步开发和严格评价。
Topical microbicides designed to prevent acquisition of sexually transmitted infections are urgently needed. Nonoxynol-9, the only commercially available spermicide, damages epithelium and may enhance human immunodeficiency virus transmission. The observation that herpes simplex virus (HSV) and human immunodeficiency virus bind heparan sulfate provided the rationale for the development of sulfated or sulfonated polymers as topical agents. Although several of the polymers have advanced to clinical trials, the spectrum and mechanism of anti-HSV activity and the effects on soluble mediators of inflammation have not been evaluated. The present studies address these gaps. The results indicate that PRO 2000, polystyrene sulfonate, cellulose sulfate, and polymethylenehydroquinone sulfonate inhibit HSV infection 10,000-fold and are active against clinical isolates, including an acyclovir-resistant variant. The compounds formed stable complexes with glycoprotein B and inhibit viral binding, entry, and cell-to-cell spread. The effects may be long lasting due to the high affinity and stability of the sulfated compound-virus complex, as evidenced by surface plasmon resonance studies. The candidate microbicides retained their antiviral activities in the presence of cervical secretions and over a broad pH range. There was little reduction in cell viability following repeated exposure of human endocervical cells to these compounds, although a reduction in secretory leukocyte protease inhibitor levels was observed. These studies support further development and rigorous evaluation of these candidate microbicides.