Nature Communications: CycloSEL — Massive Barcode-Free Macrocyclic Library Screening Identifies 16M Drug-Like Bioactive Hits
A Nature Communications paper introduced CycloSEL (Cyclic Self-Encoded Libraries), an end-to-end workflow that screens synthetic macrocycle libraries enriched in drug-like 'beyond rule of five' features using affinity selections and tandem mass spectrometry — eliminating the genetic-barcode requirement of traditional macrocyclic peptide discovery. The team validated the approach against the oncology target carbonic anhydrase IX with a 16-million-member library, achieving robust enrichment and accurate identification of true binders. The platform shifts peptide drug discovery toward small molecule-like drug-likeness optimization from day one.