conjugation of constrained peptides for cancer diagnostics

癌细胞中离子通道的上调通常导致预后不良和转移增加。因此，确定这些离子通道的新型调节剂将具有极大的意义，因为它将使我们能够描绘这些事件期间的离子通道功能和分子机制。此外，这些新的离子通道调节剂可能会导致新的诊断工具和潜在的抗癌治疗的发展。为了进行这项研究，我们将利用高通量的基于荧光的筛选平台，结合详细的电生理测定，从粗毒液和天然产物提取物中鉴定和鉴定新型肽离子通道调节剂。这些新的调节剂将被测序，化学或重组产生，其详细的活性评估和使用NMR确定其结构。这些肽通常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，我们将开发方法来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，以便能够标记这些离子通道调节剂用于开发诊断探针。

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.