Oral Presentation 9th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2023

The Effects of Fluoroalkene Dipeptide Isosteres on the Collagen Self-Assembly (96823)

Chihiro Iio 1 , Junko Fujimoto 1 , Daichi Toyama 1 , Kohei Sato 1 , Nobuyuki Mase 1 , Tetsuo NARUMI 1
  1. Shizuoka university, Hamamatsu, SHIZUOKA, Japan

The backbone modification of peptides can provide an opportunity to stabilize the conformation by forming effective non-covalent interactions[1] since those interactions play crucial roles in controlling the dihedral angle of the peptide backbone and its conformation. In particular, the installation of electron-withdrawing fluorine atoms has been studied as a powerful conformational control strategy, as exemplified by the fluorine gauche effect.[2] Among the fluorine-containing peptidomimetics, fluoroalkene dipeptide isosteres (FADIs) have been thought of as one of the ideal peptide bond surrogates, and there are many reports about their synthesis and application to bioactive peptides. However, there has been limited discussion of the stereoelectronic basis for the conformational control strategy of FADIs. In this presentation, the effect of FADIs on collagen self-assembly will be presented.

Fluoroalkene-type peptidomimetics of collagen model peptide containing a Gly-Pro-type (Z)-FADI were synthesized to investigate their substitution effects on the collagen self-assembly. Based on the CD spectra of synthesized peptidomimetics, the peptidomimetic in which the 10Gly-Pro11 peptide bond was replaced with a fluoroalkene isostereformed a self-assembled triple helix. On the other hand, the peptidomimetic in which the 16Gly-Pro17 peptide bond was replaced with a fluoroalkene isosteres appears to form a polyproline helix. Furthermore, thermal denaturation experiments revealed that fluoroalkene-type peptidomimetic forming triple helix is more stable than the corresponding (E)-alkene-type peptidomimetic reported by Etzkorn group.[3]

To investigate the origin of these conformational restriction effects, density functional theoretical calculations were carried out. Potential energy scans of dihedral angles revealed that Gly-Pro-type FADI has a geometrical preference for the N-terminus of collagen model peptide. In the most stable conformer, the mixing of σ*(C-F) orbital and adjacent σ(C-H) orbital leads to the restriction of the dihedral angles. This non-covalent interaction could contribute to stabilizing the N-terminus conformation in the triple helix.

  1. Jakovsche, C. E.; Choudhary, A.; Miller, S. J.; Raines, R. T. J. Am. Chem. Soc. 2010, 132, 6651-6653.
  2. Varhoork, S. J. M.; Killoran, K. M.; Coxon, C. R. Biochemistry 2018, 57, 6132-6143.
  3. Dai, N.; Wang, X. J.; Etzkorn, F. A. J. Am. Chem. Soc. 2008, 130, 5396-5397.