A SuFEx Click Reaction Streamlines DNA-Encoded Macrocyclic Peptide Libraries
- DNA-encoded libraries (DELs) let researchers screen ultralarge collections of macrocyclic peptides to find hit compounds for drug discovery, but efficient on-DNA cyclization chemistry has remained a bottleneck.
- A new on-DNA macrocyclization method uses sulfur(VI) fluoride exchange (SuFEx), a fast, click-type reaction, to close peptide rings directly on DNA tags.
- The design embeds a phenol and an aryl sulfonyl fluoride within a single DNA-tagged peptide, positioning the two groups to react with each other intramolecularly.
- Simply dissolving the construct in basic aqueous buffer triggers rapid, high-conversion cyclization without added catalysts or harsh conditions.
- The method enables efficient, high-yielding synthesis of ultralarge DNA-encoded macrocyclic peptide libraries, expanding the chemical space available for DEL-based hit discovery.
On-DNA chemistry is where good click reactions go to die — CuAAC needs copper that chews up your barcode, most coupling chemistry leaves truncation side-products you chase off HPLC for weeks. SuFEx actually respects the constraints: no metal, no coupling reagent, just a phenol and an ArSO2F sitting in basic water reacting with each other. That's "click" chemistry finally earning its name in DEL work instead of just borrowing the marketing. High conversion with zero catalyst also means boring QC, in the best sense — fewer truncated/uncyclized side-populations polluting the pool means the hits you pull downstream are more likely real signal, not artifacts of your worst-yielding step. For macrocycles — the space between small molecules and biologics everyone wants but few can screen efficiently — a clean cyclization step is what lets you scale diversity without sacrificing quality. This is the unglamorous methods advance that keeps unlocking new DEL generations.
SuFEx Cyclization Enables DNA-Encoded Macrocyclic Peptide Libraries for Drug Discovery ↗