Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, United States.
The Nebraska Center for Integrated Biomolecular Communication (NCIBC), University of Nebraska-Lincoln, Lincoln, Nebraska 68588, United States.
ACS Chem Biol. 2021 Feb 19;16(2):251-263. doi: 10.1021/acschembio.0c00950. Epub 2021 Feb 4.
Intercellular signaling events mediated by neuropeptides and peptide hormones represent important targets for both basic science and drug discovery. For many bioactive peptides, the protein receptors that transmit information across the receiving cell membrane are not known, severely limiting these signaling pathways as potential therapeutic targets. Identifying the receptor(s) for a given peptide of interest is complicated by several factors. Most notably, cell-cell signaling peptides are generated through dynamic biosynthetic pathways, can act on many different families of receptor proteins, and can participate in complex ligand-receptor interactions that extend beyond a simple one-to-one archetype. Here, we discuss recent methodological advances to identify signaling partners for bioactive peptides. Recent efforts have centered on methods to identify candidate receptors via transcript expression, methods to match peptide-receptor pairs through high throughput screening, and methods to capture direct ligand-receptor interactions using chemical probes. Future applications of the receptor identification approaches discussed here, as well as technical advancements to address their limitations, promise to lead to a greater understanding of how cells communicate to deliver complex physiologies. Importantly, such advancements will likely provide novel targets for the treatment of human diseases within the central nervous and endocrine systems.
细胞间信号事件由神经肽和肽类激素介导，是基础科学和药物发现的重要靶点。对于许多生物活性肽，将信息传递到受体细胞膜的蛋白质受体尚不清楚，这严重限制了这些信号通路作为潜在治疗靶点的可能性。确定特定感兴趣肽的受体（多个）受到几个因素的影响。最值得注意的是，细胞间信号肽是通过动态生物合成途径产生的，可作用于许多不同的受体蛋白家族，并且可以参与超出简单一对一原型的复杂配体-受体相互作用。在这里，我们讨论了鉴定生物活性肽信号伙伴的最新方法学进展。最近的努力集中在通过转录表达鉴定候选受体的方法、通过高通量筛选匹配肽-受体对的方法，以及使用化学探针捕获直接配体-受体相互作用的方法。这里讨论的受体鉴定方法的未来应用，以及解决其局限性的技术进步，有望增进对细胞如何传递复杂生理机能进行通讯的理解。重要的是，此类进展可能会为中枢神经系统和内分泌系统中人类疾病的治疗提供新的靶点。
