Analyses and application of the recognition mechanism of carbohydrate structure by carbohydrate-binding antibiotics.

Pradimicin A及其衍生物BMY-28864具有抗hiv和抗真菌活性，是一类新的碳水化合物结合抗生素。本研究利用HIV糖蛋白gpl2O、各种天然糖蛋白和人工糖蛋白以及人工糖脂，研究了17种结构已明确但糖结合活性和抗HIV活性未知的Pradimicin A衍生物与油糖糖链结合的能力、特异性和亲和性，不仅以这些衍生物为先导化合物，开发出更有效的抗HIV糖结合剂；同时也可以获得针对其他细菌和病毒感染的新药设计信息。结果表明，17个Pradimicin A衍生物中有4个具有与Pradimicin A和BMY-28864相同的碳水化合物结合活性，其中3个具有比Pradimicin A和BMY-28864更强的结合亲和力。这些发现表明这些物质是碳水化合物结合的，也很有希望作为抗艾滋病毒的药物。有趣的是，四种具有碳水化合物结合性质的衍生物中有一种没有任何抗真菌作用。因此，通过详细研究这些物质的结构、碳水化合物结合活性和生理作用与低聚糖链识别位点之间的关系，可以获得更准确的药物设计所需的分子内位点信息。此外，还通过计算得到了普拉地米星a在真空条件下的稳定构象。因此，本研究的发现被认为是未来开发具有碳水化合物结合特性的更有效的抗hiv药物的重要药物设计信息。

Pradimicin A and its derivative BMY-28864 with anti-HIV and anti-fungal activities have been shown to be carbohydrate-binding antibiotics belonging to a novel category by our recent studies. In this study, for 17 Pradimicin A derivatives whose structures had been clarified but whose carbohydrate-binding activity and anti-HIV activity were unknown, the ability, specificity, and affinity of their binding to oil-gosaccharide chains were investigated using HIV glycoprotein gpl2O, various natural and artificial glycoproteins, and artificial glycohipids not only to develop a more effective anti-HIV carbohydrate-binding agent using the derivatives as lead compounds, but also to obtain drug design information for new agents against other bacterial and viral infections. The results showed that four of the 17 Pradimicin A derivatives examined exhibited a carbohydrate-binding activity as in the case of Pradimicin A and BMY-28864, and that three of them showed a stronger binding affinity than Pradimicin A and BMY-28864. These findings suggest that these substances are of carbohydrate-binding and very promising also as an anti-HIV agent. Interestingly, one of the four derivatives with carbohydrate-binding nature did not have any anti- fungal effect. Therefore, more accurate information about intramolecular sites required for the drug design could be obtained through detailed investigations on the relationship between the structure, carbohydrate-binding activity, and physiologicaleffects of these substances and on recognition sites in oligosaccharide chains. In addition, a stable conformation of Pradimicin A under vacuum condition could be figured by calculation. The findingss in this study are therefore considered to serve as an important drug design information for the development of more potent and effective anti-HIV agents with carbohydrate-binding property in the future.