Combinatorial Carbohydrate Libraries for Drug Discovery

说明书(申请人提供)：新抗菌化合物的开发 随着细菌对LAST的抗生素产生抗药性，迫切需要 度假村。这项提议的长期目标是确定新的 与小核糖体亚基结合的碳水化合物 特别是改变细菌的翻译。500个新的氨基糖苷类药物将 使用溶液法和固相法制备。它们的结合亲和力， 特异性和定位在27个核苷酸的RNA模型上的共识 电喷雾电离质量法测定细菌A位 光谱分析。具有大于500 nM亲和力和更高亲和力的化合物 超过10倍的特异性将被转移到翻译分析及其MIC值 将病原菌确定为致病菌。药代动力学和毒理学 最好的化合物的性能将在第二阶段进行测量和改进 申请。 建议的商业应用： 需要新的抗微生物化合物家族来抵消不断发展的耐药性。 一种新型抗菌化合物的鉴定与开发 保守的RNA靶标将产生巨大的市场机会。治疗性的 目标可能包括肺炎球菌、肠球菌和结核病--特别是他们的 耐药菌株。

DESCRIPTION (provided by applicant): Development of new antimicrobial compounds is urgently needed as bacteria evolve resistance to the antibiotics of last resort. The long-term objective of this proposal is to identify new carbohydrate-based compounds that bind to the small ribosomal subunit and specifically alter bacterial translation. Five hundred new aminoglycosides will be prepared using solution and solid-phase methods. Their binding affinity, specificity, and location on a 27 nucleotide RNA model of the consensus bacterial A site about determined using electrospray ionization mass spectrometry. Compounds that bind with greater than 500 nM affinity and greater than 10x specificity will be moved into translation assays and their MIC values will be determined pathogenic strains. The pharmacokinetic and toxicological properties of the best compounds will be measured and improved in a Phase II application. PROPOSED COMMERCIAL APPLICATION: New families of antimicrobial compounds are needed to offset developing drug resistance. Identification and development of a new class of antimicrobial compounds based on a conserved RNA target would generate a significant market opportunity. Therapeutic targets could include pneumococci, enterococci, and tuberculosis - especially their drug-resistant strains.