Molecular Recognition by Bleomycin

说明(申请人提供)：博莱菌素是一类糖肽类抗肿瘤抗生素，最初从轮纹链霉菌中分离出来。一些博莱霉素被用于临床治疗鳞状细胞癌和恶性淋巴瘤。尽管在过去的几十年里，人们对博莱霉素进行了大量的研究，但很少有研究涉及博莱霉素的两个显著特性，即它的肿瘤寻找特性和它在生理条件下靶向DNA底物的方式。本项目基于新的策略，这些策略提供了(I)监测博莱霉素的找瘤特性的简便方法和(Ii)识别博莱霉素的高亲和力核酸靶标的方法。该项目的目标包括鉴定肿瘤靶向所需的博莱霉素中的结构成分，以及被识别的细胞成分。还提出了用博莱霉素非常高效地结合和切割DNA基序的鉴定方法。 公共卫生相关性：博莱霉素用于临床治疗软组织中发生的某些肿瘤。这里提出的研究将有助于了解该药物针对肿瘤的方式，以及结合和降解肿瘤组织中的核酸的方式。因此，这些研究将使博莱霉素的制备具有更好的性能。

DESCRIPTION (provided by applicant): The bleomycins are a family of glycopeptides derived antitumor antibiotics originally isolated from Streptomyces verticillus. Some of the bleomycins are used clinically for the treatment of squamous cell carcinomas and malignant lymphomas. While numerous studies of bleomycin have been carried out in the past few decades, few of these have addressed two remarkable properties of bleomycin, namely its tumor seeking properties and the way in which it targets its DNA substrates under physiological conditions. The present project is based on new strategies which provide (i) a facile method for monitoring the tumor seeking properties of bleomycin and (ii) an approach for identifying high affinity nucleic acid targets for bleomycin. Goals of the project include identification of the structural elements in bleomycin that are required for tumor targeting, as well as the cellular constituents that are recognized. Also proposed is the identification of DNA motifs that are bound and cleaved with exceptionally high efficiency by bleomycin. PUBLIC HEALTH RELEVANCE: The bleomycins are used clinically for the treatment of certain tumors that occur in soft tissues. The studies proposed here will facilitate an understanding of the way that this drug targets tumors, and binds to and degrades the nucleic acids in tumor tissue. As such, these studies will enable the preparation of bleomycins with improved properties.