硼化浓缩 DNA 作为异染色质辐射靶模型。

Boronated Condensed DNA as a Heterochromatic Radiation Target Model.

机构信息

Department of Basic Sciences, School of Medicine, Loma Linda University, 11085 Campus Street, Loma Linda, California 92350, United States.

Department of Radiation Oncology, University of California San Francisco, 1600 Divisadero Street, San Francisco, California 94115, United States.

出版信息

Biomacromolecules. 2021 Apr 12;22(4):1675-1684. doi: 10.1021/acs.biomac.1c00106. Epub 2021 Mar 22.

DOI:10.1021/acs.biomac.1c00106

PMID:33750108

Abstract

The compound 4-dihydroxyboryl-l-phenylalanine (BPA) has found use in clinical trials of boron neutron capture therapy (BNCT). Here, we have examined the interaction with DNA of an amide-blocked BPA derivative of hexa-l-arginine (Ac-BPA-Arg-NH). Physical and spectroscopic assays show that this peptide binds to and condenses DNA. The resulting condensates are highly resistant to the effects of nuclease incubation (68-fold) and gamma (38-fold) irradiation. Radioprotection was modeled by Monte Carlo track structure simulations of DNA single strand breaks (SSBs) with TOPAS-nBio. The differences between experimental and simulated SSB yields for uncondensed and condensed DNAs were . 2 and 18%, respectively. These observations indicate that the combination of a plasmid DNA target, the BPA-containing peptide, and track structure simulation provides a powerful approach to characterize DNA damage by the high-LET radiation associated with neutron capture on boron.

摘要

4-二羟基硼基-l-苯丙氨酸（BPA）已在硼中子俘获治疗（BNCT）的临床试验中得到应用。在这里，我们研究了六聚-l-精氨酸（Ac-BPA-Arg-NH）酰胺封端的 BPA 衍生物与 DNA 的相互作用。物理和光谱分析表明，这种肽与 DNA 结合并使其浓缩。所得的凝聚物对核酸酶孵育（68 倍）和γ（38 倍）辐射的影响具有高度抗性。通过 TOPAS-nBio 对 DNA 单链断裂（SSB）进行蒙特卡罗轨迹结构模拟来模拟放射防护。未浓缩和浓缩 DNA 的实验和模拟 SSB 产率之间的差异分别为.2 和 18%。这些观察结果表明，质粒 DNA 靶标、含 BPA 的肽和轨迹结构模拟的组合提供了一种强大的方法来表征与硼捕获中子相关的高传能线密度辐射引起的 DNA 损伤。