Peptides are a consistent source of inspiration in drug discovery. However, they come with some strong limitations, regarding their physicochemical properties. At Symeres, our experienced scientists are well equipped to overcome these drawbacks by synthesizing peptidomimetics. These compounds are designed to eliminate a peptide’s weak spots, while maintaining the structural features responsible for its biological activity.[1][2] Two major classes of peptidomimetics that our chemists frequently work with are described below.
Amide isosteres
The amide functionality forms the backbone of peptides and is also often found in other early drug compounds. However, amide-rich compounds often show poor pharmacokinetic properties with respect to metabolic stability and permeability, making amide replacement desirable. At Symeres, we tackle this by applying the concept of (bio)isosteric replacements. These isosteres mimic the many specific properties of an amide group, e.g., size, rigidity, polarity, and H-bond acceptor/donor, but possess more favorable properties when it comes to, e.g., hydrolytic stability. For example, 1,4-disubstituted 1,2,3,-triazole can be used to replace a trans-amide bond, whereas 1,5-disubstituted 1,2,3,-triazoles are used to replace a cis-amide bond. Some more examples from our toolbox of amide isosteres can be found in the figure below.[3][2]
Peptide cyclization
Macrocyclization of linear peptides is shown to be another effective way to overcome some of the shortcomings of peptide-based drug leads.[1][2][4] For example, compounds aimed at targeting protein–protein interactions can benefit from decreased flexibility. Moreover, cyclization often also leads to improved proteolytic stability. Besides the classical head-to-tail amide formation (lactamization), peptides can also be cyclized in side-chain-to-tail, head-to-side-chain, or side-chain-to-side-chain formations. Within Symeres, we have extensive experience in preparing such cyclic peptidomimetics via, e.g., copper-catalyzed azide–alkyne cycloaddition (CuAAC), ring-closing metathesis (RCM), disulfide formation, thioether formation, disulfide stapling, and classical lactamization. Furthermore, our toolbox for preparing non-proteinogenic amino acids allows us to prepare tailor-made peptide building blocks for the various cyclization strategies.
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[1] Lenci, E., Trabocchi, A. Peptidomimetic Toolbox for Drug Discovery, Chem. Soc. Rev. 2020, 49, 3262 DOI: https://doi.org/10.1039/D0CS00102C
[2] MeanWell, N. The Influence of Bioisosteres in Drug Design: Tactical Applications to Address Developability Problems., Top. Med. Chem. 2015, 9, 283–382 DOI: https://doi.org/10.1007%2F7355_2013_29
[3] Kumari, S., Carmona, A. V., Tiwari, A. K. Tripper, P. C. Amide Bond Bioisosteres: Strategies, Synthesis, and Successes., J. Med. Chem. 2020, 63, 283–382 DOI: https://doi.org/10.1021/acs.jmedchem.0c00530
[4] Liskamp, R. M. J., Rijkers, D. T. S., Kruijtzer, J. A. W., Kemmink, J. Peptides and Proteins as a Continuing Exciting Source of Inspiration for Peptidomimetics., ChemBioChem. 2011, 12, 1626–1653 DOI: https://doi.org/10.1002/cbic.201000717
