Conformationally constrained cyclic grafted peptidomimetics targeting protein–protein interactions.

Sunflower trypsin inhibitor‐1 (SFTI‐1) structure is used for designing‐grafted peptides as a possible therapeutic agent. The grafted peptide exhibits multiple conformations in solution due to the presence of proline in the structure of the peptide. To lock the grafted peptide into a major conformation in solution, a dibenzofuran moiety (DBF) was incorporated in the peptide backbone structure, replacing the Pro‐Pro sequence. NMR studies indicated a major conformation of the grafted peptide in solution. Detailed structural studies suggested that SFTI‐DBF adopts a twisted beta‐strand structure in solution. The surface plasmon resonance analysis showed that SFTI‐DBF binds to CD58 protein. A model for the protein‐SFTI‐DBF complex was proposed based on docking studies. These studies suggested that SFTI‐1 grafted peptide can be used to design stable peptides for therapeutic purposes by grafting organic functional groups and amino acids. However, when a similar strategy was used with another grafted peptide, the resulting peptide did not produce a single major conformation, and its biological activity was lost. Thus, conformational constraints depend on the sequence of amino acids used for SFTI‐1 grafting. [ABSTRACT FROM AUTHOR]