Rusnati Marco, Vicenzi Elisa, Donalisio Manuela, Oreste Pasqua, Landolfo Santo, Lembo David
Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, 25123 Brescia, Italy.
Pharmacol Ther. 2009 Sep;123(3):310-22. doi: 10.1016/j.pharmthera.2009.05.001. Epub 2009 May 14.
Antiviral microbicides, topical agents that prevent sexually transmitted infections, mainly work by blocking the interaction between viral proteins and cell surface components. In many instances, virus-cell interaction is mediated by cell surface heparan sulfate proteoglycans (HSPGs). HSPGs are exploited as attachment receptors by three sexually transmitted viruses: Human Immunodeficiency Virus (HIV), Herpes Simplex Virus (HSV) and Human Papilloma Virus (HPV). Since these viruses can either infect or co-infect humans, virus/HSPGs interaction is a preferential target for the development of wide-spectrum antiviral microbicides. Several polyanionic compounds prevent HIV, HSV and HPV infections in cell culture models by acting as heparan sulfate (HS)-antagonists. However, three promising polyanionic compounds recently failed to pass phase III clinical trials designed to establish their efficacy in preventing HIV acquisition. In this scenario, new polyanionic compounds must be added to the pipeline of candidate microbicides and their development as effective drugs reconsidered. The capsular K5 polysaccharide from Escherichia coli has the same structure as the heparin/HS biosynthetic precursor. Chemical and enzymatic modifications have led to the synthesis of K5 derivatives with different degrees of sulfation and charge distribution and devoid of anticoagulant activity and cell toxicity. Recently attracting attention as candidate microbicides, they potently inhibit a broad spectrum of HIV-1 strains and genital types of HPV and HSV-1 and 2 in vitro. With a focus on the K5 derivatives, this article reviews the literature on polyanions as antiviral microbicides and discusses the possible therapeutic implications of this novel class of compounds.
抗病毒杀微生物剂是预防性传播感染的局部用药，主要通过阻断病毒蛋白与细胞表面成分之间的相互作用发挥作用。在许多情况下，病毒与细胞的相互作用是由细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）介导的。HSPG被三种性传播病毒用作附着受体，即人类免疫缺陷病毒（HIV）、单纯疱疹病毒（HSV）和人乳头瘤病毒（HPV）。由于这些病毒均可感染或共同感染人类，病毒与HSPG的相互作用是开发广谱抗病毒杀微生物剂的优先靶点。几种聚阴离子化合物通过作为硫酸乙酰肝素（HS）拮抗剂，在细胞培养模型中可预防HIV、HSV和HPV感染。然而，最近三种有前景的聚阴离子化合物未能通过旨在确定其预防HIV感染疗效的III期临床试验。在这种情况下，必须在候选杀微生物剂系列中添加新的聚阴离子化合物，并重新考虑将其开发为有效药物。来自大肠杆菌的荚膜K5多糖与肝素/HS生物合成前体具有相同结构。化学和酶促修饰已导致合成具有不同硫酸化程度和电荷分布且无抗凝活性和细胞毒性的K5衍生物。它们作为候选杀微生物剂最近受到关注，在体外能有效抑制多种HIV-1毒株以及HPV和HSV-1及2的生殖器类型。本文聚焦于K5衍生物，综述了关于聚阴离子作为抗病毒杀微生物剂的文献，并讨论了这类新型化合物可能的治疗意义。
