Discovery of bioactive peptides targeting ion channels upregulated in cancer

发现针对癌症中上调离子通道的生物活性肽

• 批准号: 10702807
• 负责人: Ingrid Schroeder
• 金额: $ 39.98万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702807
• 关键词: Biological; Biological Assay; Cancer cell line; Cancerous; Cells; Chemicals; Development; Diagnostic; Disulfides; Electrophysiology (science); Evaluation; Event; Fluorescence; Goals; Ion Channel; Label; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of thyroid; Methodology; Molecular; Natural Products; Neoplasm Metastasis; Peptides; Plasma; Prognosis; Research; Structure; Up-Regulation; Venoms; anti-cancer therapeutic; base; covalent bond; diagnostic tool; disulfide bond; high throughput screening; interest; malignant breast neoplasm; novel; novel diagnostics; screening; tumor progression

The up-regulation of ion channels in cancerous cells typically lead to poor prognosis and increased metastasis. Identifying novel modulators for these ion channel would therefore be of great interest as it would allow us to delineate the ion channels function and molecular mechanism during these events. In addition, these novel ion channel modulators may lead to the development of novel diagnostic tools and potential anti-cancer therapeutics. To pursue this research we will be utilizing a high-throughput fluorescence-based screening platform in combination with detailed electrophysiological assays to identify and characterise novel peptidic ion-channel modulators from crude venom and natural products extracts. These novel modulators will be sequenced, chemically or recombinantely produced, their detailed activity assessed and their structures determined using NMR. These peptides are typically disulfide-rich and very stable in plasma. However, in order to avoid potential disulfide-bond scrambling, we will develop methodology to incorporate alternative covalent bonds instead of disulfide bonds. We will also develop disulfide-rich compatible conjugation strategies to be able to label these ion channel modulators for development of diagnostic probes.

癌细胞中离子通道的上调通常导致不良预后 和增加的转移。因此，识别这些离子通道的新型调节剂将 因为它将使我们能够描绘离子通道的功能和分子 在这些事件中的机制。此外，这些新的离子通道调节剂可能导致 开发新的诊断工具和潜在的抗癌疗法。追求这个 在研究中，我们将利用基于荧光的高通量筛选平台 结合详细的电生理测定来鉴定和鉴定新的 来自粗毒液和天然产物提取物的肽离子通道调节剂。这些新颖 调节剂将被测序，化学或重组产生，它们的详细活性 评估并使用NMR确定它们的结构。这些肽通常是 富含二硫化物并且在血浆中非常稳定。然而，为了避免潜在的二硫键， 混乱，我们将开发方法，以纳入替代共价键，而不是 二硫键我们还将开发富含二硫键的相容性缀合策略， 能够标记这些离子通道调节剂用于开发诊断探针。

项目成果

Multipurpose peptides: The venoms of Amazonian stinging ants contain anthelmintic ponericins with diverse predatory and defensive activities.

• DOI: 10.1016/j.bcp.2021.114693
• 发表时间: 2021-10
• 期刊: BIOCHEMICAL PHARMACOLOGY
• 影响因子: 5.8
• 作者: Nixon, Samantha A.;Robinson, Samuel D.;Agwa, Akello J.;Walker, Andrew A.;Choudhary, Shivani;Touchard, Axel;Undheim, Eivind A. B.;Robertson, Alan;Vetter, Irina;Schroeder, Christina I.;Kotze, Andrew C.;Herzig, Volker;King, Glenn F.
• 通讯作者: King, Glenn F.