Poster Presentation 7th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2019

Probing the importance of cis-trans prolinyl conformation in bioactive peptides (#113)

Benjamin Husselbee 1 , William Jackson 1 , Andrea Robinson 1
  1. Department of Chemistry, Monash University, Clayton, VIC, Australia

Peptide mimetics aim to replicate the interaction between peptide and biological target while modifying non-essential regions to achieve desirable pharmacokinetic properties including enhanced stability, solubility and even potency. Replacement of cysteine bridges with synthetic isosteres1,2 and other forms of macrocyclisation have previously yielded peptide mimetics that have significant differences in biological activity.3 These analogues are important not only for the pharmaceutical development of the peptide but also for elucidation of the overarching biological importance of the target disulfide bond.2 In the native cystine-containing peptides, oxidative cyclisation of the linear sequence often appeared to be supported by suitably positioned proline residues. The peptide bond can exist in both cis and trans states, where the cis state is relatively abundant adjacent to a proline residue.4 There are remarkable examples of commercially significant peptides that have been shown to be activated by the singular cis-trans interconversion adjacent to a proline.5-7 Building upon this work, we want to explore the involvement of such transitions in new peptide classes including proline-rich antimicrobials and analgesic conotoxins with both established conformationally restricted proline analogues and novel pseudoprolines. Given our successful cyclisation approach to form sterically hindered 5,5-dimethylproline,8 interchanging our metathesis cross-partner presents a facile method of generating novel spirocyclic pseudoproline systems. In this context, there is a large scope to explore both the cis-trans directionality of novel proline analogues and the structural and biological effect that these unnatural amino acids have in target peptides.

 

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  2. Van Lierop, B. J.; Robinson, S. D.; Kompella, S. N.; Belgi, A.; McArthur, J. R.; Hung, A.; Macraild, C. A.; Adams, D. J.; Norton, R. S.; Robinson, A. J., Dicarba a-conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAb receptors. ACS Chemical Biology 2013, 8, 1815-1821.
  3. Keller, M.; Boissard, C.; Patiny, L.; Chung, N. N.; Lemieux, C.; Mutter, M.; Schiller, P. W., Pseudoproline-Containing Analogues of Morphiceptin and Endomorphin-2: Evidence for a Cis Tyr− Pro Amide Bond in the Bioactive Conformation. Journal of medicinal chemistry 2001, 44, 3896-3903.
  4. Dugave, C., cis-trans Isomerization in Biochemistry. John Wiley & Sons: 2006.
  5. Chierici, S.; Jourdan, M.; Figuet, M.; Dumy, P., A case study of 2,2- dimethylthiazolidine as locked cis proline amide bond: synthesis, NMR and molecular modeling studies of a δ-conotoxin EVIA peptide analog. Organic & Biomolecular Chemistry 2004, 2, 2437-2441.
  6. Garcia, J.; Dumy, P.; Rosen, O.; Anglister, J., Stabilization of the Biologically Active Conformation of the Principal Neutralizing Determinant of HIV-1IIIB Containing a cis-Proline Surrogate: 1H NMR and Molecular Modeling Study. Biochemistry 2006, 45 (13), 4284-4294.
  7. Wittelsberger, A.; Patiny, L.; Slaninova, J.; Barberis, C.; Mutter, M., Introduction of a cis-Prolyl Mimic in Position 7 of the Peptide Hormone Oxytocin Does Not Result in Antagonistic Activity. Journal of Medicinal Chemistry 2005, 48, 6553-6562.
  8. Elaridi, J., Jackson, W.R., Robinson, A.J., A catalytic asymmetric synthesis of 5,5-dimethylproline. Tetrahedron: Asymmetry, 2005, 16(11), pp.2025-2029.