PotM: Methanoprolines and Dimethylprolines - Constraining the Conformation of Peptides

Published on 13/07/2021

Interested in structure-activity studies of your Proline-containing peptide drug? Find out more about the use of Methanoprolines and Dimethylprolines as conformational amide locks.

PotM: Methanoprolines and Dimethylprolines - Constraining the Conformation of Peptides

The cyclic amino acid Proline (Pro) represents unique features in terms of its conformational properties as its incorporation into peptide sequences leads to an equilibrium mixture of approximately isoenergetic cis and trans conformers at AAA-Pro bonds, whereas peptide bonds of secondary amino acid amides adopt predominantly the trans C_alpha/C_alpha conformation.

As many biological cascades are driven by the cis-trans isomerization process of a peptidic ligand within its binding pocket, the analysis of the bioactive conformation – whether cis or trans – represents a versatile strategy to improve a drug’s affinity, its binding properties, and activity.

To analyze the role of both proline isomers separately, substituted proline derivatives can be inserted to lock the AAA-Pro peptide bond either in cis or trans. As reported in the literature, rigid bicylic 2,4-Methanoprolines adopt preferably the trans amide conformation and are thus behaving more like primary alpha-amino acids, whereas 5,5-Dimethylprolines (Dmp) lock the cis conformation. These findings suggest that both derivatives are useful Proline analogues for structure activity studies and the molecular design of peptide drugs, as the desired active conformation can be selectively stabilized.

Iris Biotech offers several Dimethyl- (3,3 and 5,5) as well as Methanoproline building blocks which can easily be incorporated by using standard peptide synthesis protocols. Interested? See the related products at the end of this page!

References:

Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character; B. Cox, V. Zdorichenko, P. B. Cox, K. I. Booker-Milburn, R. Paumier, L. D. Elliott, M. Robertson-Ralph, and G. Bloomfield; ACS Med. Chem. Lett. 2020; 11: 1185-1190. https://doi.org/10.1021/acsmedchemlett.0c00039.
A Peptidyl-Prolyl Model Study: How Does the Electronic Effect Influence the Amide Bond Conformation? P. K. Mykhailiuk, V. Kubyshkin, T. Bach, N. Budisa; J. Org. Chem. 2017; 82: 8831-8841. https://doi.org/10.1021/acs.joc.7b00803.
Bradykinin and angiotensin II analogs containing a conformationally constrained proline analog; P. Juvvadi, D. J. Dooley, C. C. Humblet, G. H. Lu, E. A. Lunney, R. L. Panek, R. Skeean, G. A. Marshall; Int. J. Peptide Protein Res. 1992; 40: 163-170. https://doi.org/10.1111/j.1399-3011.1992.tb00289.x.
Conformational Properties of 2,4-Methanoproline (2-Carboxy-2,4-methanopyrrolidine) in Peptides: Evidence for 2,4-Methanopyrrolidine Asymmetry Based on Solid-State X-ray Crystallography, 1H NMR in Aqueous Solution, and CNDO/2 Conformational Energy Calculations; S. Talluri, G. T. Montelione, G. van Duyne, L. Piela, J. Clardy, H. A. Scheraga; J. Am. Chem. Soc. 1987; 109: 4473-4477. https://doi.org/10.1021/ja00249a008.
Conformational Properties of 2,4-Methanoproline (2-Carboxy-2,4-methanopyrrolidine) in Peptides: Determination of Preferred Peptide Bond Conformation in Aqueous Solution by Proton Overhauser Measurements; G. T. Montelione, P. Hughes, J. Clardy, H. A. Scheraga; J. Am. Chem. Soc. 1986; 108: 6765-6773. https://doi.org/10.1021/ja00281a051.
Potential Nicotinic Acetylcholine Receptor Ligands from 2,4-Metanoproline Derivatives; A. B. Patel, J. R. Malpass; J. Med. Chem. 2008; 51(21): 7005-7009. https://doi.org/10.1021/jm800537a.
Modification of 1-Substituents in the 2-Azabicyclo[2.1.1]hexane Ring System; Approach to Potential Nicotinic Acetylcholine Receptor Ligands from 2,4-Methanoproline Derivatives; J. R. Malpass, A. B. Patel, J. W. Davies, S. Y. Fulford; J. Org. Chem. 2008; 68(24): 9348-9355. https://doi.org/10.1021/jo035199n.
A convenient incorporation of conformationally constained 5,5-dimethylproline into the ribonuclease A 89-124 sequence by condensation of synthetic peptide fragments; V. Cerovský, E. Welker, H. A. Scheraga; J. Pept. Res. 2003; 61(3): 140-151. https://doi.org/10.1034/j.1399-3011.2003.00041.x.
5,5-Dimethylproline dipeptides: an acid-stable class of pseudoproline; B. J. van Lierop, W. R. Jackson, A. J. Robnson; Tetrahedron 2010; 66(29): 5357-5366. https://doi.org/10.1016/j.tet.2010.05.068.