Targeting Melanocortin Receptors Using SNAr-Type Macrocyclization: A Doubly Orthogonal Route to Cyclic Peptide Conjugates

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Abstract

While a range of strategies exist to accomplish peptide macrocyclization, they are frequently limited by the need for orthogonal protection or provide little opportunity for structural diversification. We have evaluated an efficient macrocyclization method that employs nucleophilic aromatic substitution (SNAr) to create thioether macrocycles. This versatile macrocyclization, orthogonal to conventional peptide synthesis, can be performed in solution on unprotected peptidomimetics or on resin-bound peptides with side-chain protection in place. We show that the electron-withdrawing groups present in the products can be further utilized in subsequent orthogonal reactions to alter the peptide properties or to add prosthetic groups. The macrocyclization strategy was applied to the design of melanocortin ligands, generating a library of potent melanocortin agonists that exhibit distinct subtype selectivity.

Original languageEnglish
Pages (from-to)3273-3283
Number of pages11
JournalJournal of Medicinal Chemistry
Volume66
Issue number5
DOIs
Publication statusPublished - 21 Feb 2023

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