Poster Presentation The 16th Australian Peptide Conference 2025

Macrocyclic Sulfopeptide-Based LYTACs for Targeted Degradation of Chemokines (#100)

Bernardo Cavallazzi Sebold 1 2 , Joshua J Dilly 1 2 , Jessica Zhong 1 2 , Sarah L Bouchaava 1 2 , Leo Corcillius 1 2 , Sameer S Kulkarnia 1 2 , David McDonald 2 3 , Richard J Payne 1 2
  1. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW
  2. School of Chemistry, University of Sydney, Camperdown, NSW
  3. Department of Chemistry, Yale University, New Haven, Connecticut, United States

Sulfation of tyrosine, a common post-translational modification in chemokine receptors, has been shown to enhance binding affinity to multiple chemokine ligands (CCLs). Leveraging this property to address chemokine redundancy, we employed Random Nonstandard Peptides Integrated Discovery mRNA display with genetic code reprogramming⁴ to generate a library of macrocyclic sulfopeptides incorporating sulfotyrosine. The resulting peptides exhibited broad-spectrum binding to key eosinophil-attracting chemokines: CCL2, CCL7, CCL11, and CCL24.The lead candidate, SP11, demonstrated high affinity for all four ligands and tolerated C-terminal modification for the addition of targeting ligands for therapeutic applications.