Combinatorial Carbohydrate Libraries for Drug Discovery

描述（由申请人提供）：新抗菌化合物的开发 是迫切需要的，因为细菌对抗生素的耐药性已经进化到最后， 度假村.本提案的长期目标是确定新的 结合小核糖体亚基的碳水化合物， 特别是改变细菌翻译。500种新的氨基糖苷类药物将 可以使用溶液和固相方法制备。它们的结合亲和力， 特异性和在27个核苷酸的RNA模型上的位置， 电喷雾质谱法测定细菌A位点 光谱法以大于500 nM亲和力和更大亲和力结合的化合物 超过10倍的特异性将被转移到翻译测定中， 将确定致病菌株。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， 应用程序. 拟定商业应用： 需要新的抗菌化合物家族来抵消正在发展的耐药性。 一种新型抗菌化合物的鉴定和开发 保守的RNA靶点将产生巨大的市场机会。 治疗 目标可能包括肺炎球菌、肠球菌和结核病，特别是它们的 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.