STRUCTURE BASED DESIGN OF ANTI-INFECTIVE DRUGS

基于结构的抗感染药物设计

• 批准号: 7955117
• 负责人: Charles Richard Kissinger
• 金额: $ 0.22万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955117
• 关键词: Aminoglycoside Antibiotics; Anti-Infective Agents; Antibiotics; Bacterial Infections; Base Pairing; Binding; Cells; Cessation of life; Complex; Computer Retrieval of Information on Scientific Projects Database; Crystal Formation; Development; Drug resistance; Elements; Funding; Genomics; Grant; Hepatitis C; Hepatitis C virus; Institution; Internal Ribosome Entry Site; Ions; Ligands; Metals; Molecular Conformation; Paromomycin; Play; Positioning Attribute; Protein Biosynthesis; Publishing; RNA; RNA Conformation; Research; Research Personnel; Resolution; Resources; Ribosomes; Role; Shapes; Site; Source; Strontium; Structure; Tobramycin; Translations; United States National Institutes of Health; Viral; Virus Diseases; Water; Work; World Health; antibiotic design; base; combat; design; divalent metal; improved; inhibitor/antagonist; magnesium ion; small molecule; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The discovery and development of new anti-infective drugs is urgently needed, as drug-resistant bacterial and viral diseases become an increasingly serious world health problem. The bacterial ribosome is a primary target of aminoglycoside antibiotics designed to combat bacterial infection. For instance, antibiotics such as paromomycin and tobramycin bind to the RNA aminoacyl decoding site (A-site) within the 16S ribosomal subunit and interfere with translation by inducing miscoding during the protein synthesis, which in turn leads to the death of the bacterial cell. The hepatitis C (HCV) internal ribosome entry site (IRES) element plays a central role in cap-independent translation of the viral genomic RNA. The unique conformation of IRES domain II is critical for 80S ribosomal assembly and initiation of viral translation. Here, the crystal structure of subdomain IIa of the HCV IRES has been determined at 2.3 A resolution, revealing the positions of divalent metal ions and complex inter-strand interactions that stabilize the L-shaped conformation of the RNA. The presence of divalent metal ions was necessary for crystal formation. Magnesium ions occupy specific sites that appear to be critical for the formation of the folded conformation. Subdomain IIa also was crystallized in the presence of strontium, which improved the diffraction quality of the crystals and the ability to identify interactions of the RNA with metal ions and tightly bound water molecules. The hinge region and noncanonical G-U base-pair motifs are stabilized by divalent metal ions and provide unique structural features that are potential interaction sites for small-molecule ligands. The information obtained from the crystal structure provides a basis for structure-guided design of HCV translation inhibitors targeting disruption of ribosomal assembly. This work was published in Acta Cryst. D.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 随着抗药性细菌和病毒疾病成为日益严重的世界卫生问题，迫切需要发现和开发新的抗感染药物。细菌核糖体是氨基糖苷类抗生素的主要靶点，旨在对抗细菌感染。例如，巴洛霉素和妥布霉素等抗生素与16S核糖体亚基内的RNA氨酰解码位点(A位点)结合，通过在蛋白质合成过程中诱导错误编码来干扰翻译，进而导致细菌细胞死亡。 丙型肝炎病毒内部核糖体进入位点(IRES)元件在病毒基因组RNA的帽非依赖性翻译中起着核心作用。IRES结构域II的独特构象对80s核糖体组装和病毒翻译的启动至关重要。在这里，丙型肝炎病毒IRES的IIa亚域的晶体结构已经在2.3A的分辨率下被确定，揭示了二价金属离子的位置和复杂的链间相互作用，稳定了L形状的核糖核酸构象。二价金属离子的存在是晶体形成所必需的。镁离子占据特定的位置，似乎对折叠构象的形成至关重要。在锶的存在下，亚区IIa也被结晶，这提高了晶体的衍射质量，并提高了识别RNA与金属离子和紧密结合水分子相互作用的能力。铰链区和非正则G-U碱基对基序由二价金属离子稳定，提供了独特的结构特征，是小分子配体潜在的相互作用部位。从晶体结构中获得的信息为以破坏核糖体组装为靶点的丙型肝炎病毒翻译抑制剂的结构指导设计提供了基础。这项研究发表在《晶体学报》上。D.