Solid-Phase Synthesis of Orberryamides A–D and Their Derivatives Reveals PPARγ-Mediated Th17 Differentiation Inhibitors

Orberryamides A–D ( 1 – 4, respectively) make up a unique class of macrocyclic nonapeptides that exhibit significant inhibition of Th17 cell differentiation. Herein, we report a scalable total synthesis of these natural products and their derivatives using an integrated strategy that combines solid-phase peptide synthesis for macrocycle assembly with late-stage functionalization. Biological assays identified derivatives 27 and 29 as PPARγ agonists that inhibit Th17 cell differentiation, providing insights into the immunomodulatory mechanisms of this macrocyclic peptide family.