Synthesis of disulfide fragments for use in high throughput disulfide-exchange screening

Historically, therapeutic compounds were discovered by chance, often through medicinal plants. Today, drug discovery relies on screening large libraries of single compounds against disease-associated pathways to identify promising candidates. Disulfide fragments selectively bind cysteine residues within protein binding grooves, forming covalent bonds detectable via mass spectrometry. Their synthesis involves two simple steps: amide coupling and disulfide exchange, followed by purification. Binding affinity and selectivity are assessed through biochemical assays and dose-response experiments. This poster explores the application of disulfides in scaffolding protein 14-3-3 and its disease-associated client, estrogen receptor alpha (ERα), highlighting their potential role in targeted drug discovery.