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

普拉米星A及其衍生物BMY-28864具有抗HIV和抗真菌活性，是一类新型的碳水化合物结合抗生素。在本研究中，对于17种结构已明确但其碳水化合物结合活性和抗HIV活性未知的普拉米星A衍生物，使用HIV糖蛋白gp 120、各种天然和人工糖蛋白，和人工糖脂，不仅可以开发出更有效的抗HIV碳水化合物结合剂，而且还获得用于对抗其它细菌和病毒感染的新药剂的药物设计信息。结果表明，所检测的17种普拉米星A衍生物中有4种表现出与普拉米星A和BMY-28864相同的碳水化合物结合活性，其中3种表现出比普拉米星A和BMY-28864更强的结合亲和力。这些结果表明，这些物质是碳水化合物结合的，也是非常有希望的抗HIV剂。有趣的是，具有碳水化合物结合性质的四种衍生物之一没有任何抗真菌作用。因此，通过对这些物质的结构、碳水化合物结合活性和生理效应之间的关系以及对寡糖链中识别位点的详细研究，可以获得药物设计所需的分子内位点的更准确信息。此外，通过计算还可以得出普拉米星A在真空条件下的稳定构象。本研究的结果为今后开发具有糖结合特性的抗HIV药物提供了重要的药物设计信息。

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.