Macrocyclic Modalities Combining Peptide Epitopes and Natural Product Fragments

Stéphanie M. Guéret, Sasikala Thavam, Rodrigo J. Carbajo, Marco Potowski, Niklas Larsson, Göran Dahl, Anita Dellsén, Tom N. Grossmann, Alleyn T. Plowright, Eric Valeur, Malin Lemurell, Herbert Waldmann

Research output: Contribution to JournalArticleAcademicpeer-review


"Hot loop" protein segments have variable structure and conformation and contribute crucially to protein-protein interactions. We describe a new hot loop mimicking modality, termed PepNats, in which natural product (NP)-inspired structures are incorporated as conformation-determining and -restricting structural elements into macrocyclic hot loop-derived peptides. Macrocyclic PepNats representing hot loops of inducible nitric oxide synthase (iNOS) and human agouti-related protein (AGRP) were synthesized on solid support employing macrocyclization by imine formation and subsequent stereoselective 1,3-dipolar cycloaddition as key steps. PepNats derived from the iNOS DINNN hot loop and the AGRP RFF hot spot sequence yielded novel and potent ligands of the SPRY domain-containing SOCS box protein 2 (SPSB2) that binds to iNOS, and selective ligands for AGRP-binding melanocortin (MC) receptors. NP-inspired fragment absolute configuration determines the conformation of the peptide part responsible for binding. These results demonstrate that combination of NP-inspired scaffolds with peptidic epitopes enables identification of novel hot loop mimics with conformationally constrained and biologically relevant structure.

Original languageEnglish
Pages (from-to)4904-4915
Number of pages12
JournalJournal of the American Chemical Society
Issue number10
Early online date14 Feb 2020
Publication statusPublished - 11 Mar 2020


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