Pradimicin S, a Highly Soluble Nonpeptidic Small-Size Carbohydrate-Binding Antibiotic, Is an Anti-HIV Drug Lead for both Microbicidal and Systemic Use
Pradimicin S, a Highly Soluble Nonpeptidic Small-Size Carbohydrate-Binding Antibiotic, Is an Anti-HIV Drug Lead for both Microbicidal and Systemic Use
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DOI：
10.1128/aac.01347-09
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发表时间：
2010-04-01
影响因子：
4.9
通讯作者：
Schols, Dominique
中科院分区：
文献类型：
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作者：
Balzarini, Jan;Francois, Katrien O.;Schols, Dominique
Pradimicin S（PRM-S）是一种高度水溶性的，带负电荷的抗生素原始蛋白A（PRM-A）的衍生物，其中末端木糖部分已被3硫化的葡萄糖取代。 PRM-S不能预防人类免疫缺陷病毒（HIV）对CD4（+）T细胞的吸附，但它阻止了病毒进入其靶细胞。它抑制了各种细胞培养系统中的各种HIV-1实验室菌株和临床分离株，HIV-2和Simian免疫缺陷病毒（SIV）（50％和90％有效浓度[EC（50）S和EC（90） S]在较低的微摩尔范围内总是。 PRM-S抑制HIV-1和SIV感染的细胞与未感染的CD4（+）T淋巴细胞之间的合胞体形成，并防止树突状细胞特异性细胞特异性细胞间粘附分子-3-3-3-粘贴非整合蛋白（DC-SIGN）介导的HIV-1-Signed HIV-1介导的HIV-1-SIVENDIED HIV-SIDIADIDERMIDIDED HIV-SIDIEDS-MIDIDED MIDIDED MIDIDED MIDIVED MIDIDED MIDIDED MIDIDED MIDIVED MIDIDED MIDIDED HIV-1 SIV捕获并随后向CD4（+）T细胞传播病毒。表面等离子体共振（SPR）的研究表明，PRM-S在较高的纳摩尔范围内以亲和力常数（K-d）的方式以Ca2+依赖性方式与GP120结合。它的抗HIV活性和HIV-1 GP120结合特性可以依赖于（alpha-1,2）甘露糖三聚体的剂量逆转。 HIV-1感染细胞对PRM-S的剂量降低暴露最终导致了在包膜GP120中具有各种缺失的N-糖基化位点的突变病毒菌株的分离，并且强烈偏爱高曼诺糖型的缺失聚糖。基因型抗性发展发生缓慢，并且仅在GP120中多达六个突变的顺序出现之后才发生明显的表型抗性，这表明PRM-S的遗传障碍很高。抗生素针对多种细胞系无毒素，不是有丝分裂的，并且不会诱导外周血单单核细胞中的细胞因子和趋化因子，这是由生物质质子人类细胞因子27-plex测定法确定的。事实证明，它在高温和低pH值下稳定。因此，PRM-S可能有资格作为进一步（前）临床研究的潜在抗HIV药物候选者，包括其杀生型使用。
Pradimicin S (PRM-S) is a highly water-soluble, negatively charged derivative of the antibiotic pradimicin A (PRM-A) in which the terminal xylose moiety has been replaced by 3-sulfated glucose. PRM-S does not prevent human immunodeficiency virus (HIV) adsorption on CD4(+) T cells, but it blocks virus entry into its target cells. It inhibits a wide variety of HIV-1 laboratory strains and clinical isolates, HIV-2, and simian immunodeficiency virus (SIV) in various cell culture systems (50% and 90% effective concentrations [EC(50)s and EC(90)s] invariably in the lower micromolar range). PRM-S inhibits syncytium formation between persistently HIV-1- and SIV-infected cells and uninfected CD4(+) T lymphocytes, and prevents dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-mediated HIV-1 and SIV capture and subsequent virus transmission to CD4(+) T cells. Surface plasmon resonance (SPR) studies revealed that PRM-S strongly binds to gp120 in a Ca2+-dependent manner at an affinity constant (K-D) in the higher nanomolar range. Its anti-HIV activity and HIV-1 gp120-binding properties can be dose-dependently reversed in the presence of an (alpha-1,2) mannose trimer. Dose-escalating exposure of HIV-1- infected cells to PRM-S eventually led to the isolation of mutant virus strains that had various deleted N-glycosylation sites in the envelope gp120 with a strong preference for the deletion of the high-mannose-type glycans. Genotypic resistance development occurred slowly, and significant phenotypic resistance occurred only after the sequential appearance of up to six mutations in gp120, pointing to a high genetic barrier of PRM-S. The antibiotic is nontoxic against a variety of cell lines, is not mitogenic, and does not induce cytokines and chemokines in peripheral blood mononuclear cells as determined by the Bio-Plex human cytokine 27-plex assay. It proved stable at high temperature and low pH. Therefore, PRM-S may qualify as a potential anti-HIV drug candidate for further (pre) clinical studies, including its microbicidal use.