Bergofungin D, a peptaibol template for the introduction of chemical modifications, synthesis of analogs and comparative studies of their structures

• Published in: Journal of peptide science Vol. 30; no. 8; pp. e3598 - n/a
• Main Authors: Das, Sanjit, Salah, Khoubaib Haj Ben, Wenger, Emmanuel, Legrand, Baptiste, Didierjean, Claude, Inguimbert, Nicolas
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.08.2024; Wiley
• Subjects: 1,2,3‐triazole; Amino acid sequence; Amino acids; bergofungin; Chemical Sciences; Chemical synthesis; Comparative studies; Enantiomers; helical model; Hydrogen bonds; Hydroxyproline; peptaibols; peptides; Protein structure; Secondary structure; X‐ray structures; helical model; peptides; bergofungin; 1,2,3‐triazole; X‐ray structures; peptaibols
• ISSN: 1075-2617; 1099-1387; 1099-1387
• DOI: 10.1002/psc.3598

Bergofungin D is a helical peptide of the peptaibol family consisting of 14 amino acids, six of which are the helix inducer aminoisobutyric acid (Aib). In the second third of the sequence, a hydroxyproline causes a bending of the helix and a disruption of the hydrogen bond network, and Aib7 is the only amino acid in this region involved in the hydrogen bond network. Therefore, modification of this residue can serve as a probe to monitor the effect of introducing amino acid substitutions on this more fragile helical turn. To validate this approach, we simplified the original bergofungin D by reducing the number of non‐classical amino acids, replacing the (R)‐isovaleric acid by its enantiomer or an Aib and the hydroxyproline with a proline, respectively, without affecting its secondary structure. Within the modified structure, we replaced Aib7‐Aib8 by its 1,2,3‐triazolodipeptide equivalent or Aib7 by a serine or a dehydrobutyrine. We have reported and analyzed five crystal structures, three of which are new, demonstrating the usefulness of the modified bergofungin D as a probe for monitoring the introduction of amino acid substitutions within a helical structure. Peptaibol analogs derived from bergofungin D were generated by solid‐phase peptide synthesis and found to be easy to crystallize. Different substitutions of the aminoisobutyric acid (Aib) in position 7 produced new analogs, for which three structures were obtained by X‐ray diffraction.