Peptidomimetics of β-secondary structure

Abstract

Of between 3,000-10,000 disease modifying proteins, only 400 have been targeted for clinical development. These 400 protein targets consist of hormone receptors, G-protein coupled receptors, ion channels, enzymes and other proteins that have predominantly been targeted by small molecules. For the advancement of therapeutics, it is therefore essential that new disease modifying proteins are targeted.[3]

Protein-protein interactions (PPIs) are defined as the physical contacts between two structured protein domains or peptides that allow one to selectively recognise the other.[4] These types of interaction are essential for nearly every aspect of cellular function and have been implicated in protein misfolding diseases such as AIDS,[5] cancer,[4] and Alzheimer’s.[6] PPIs therefore, are attractive targets but prove difficult to drug.[2]

The contact area for PPIs range from 750-4600 Ų, as opposed to the 300-500 Ų, observed in small molecule binding. This huge contact surface area, a flat protein interface, lack of defined binding pockets and complex binding epitopes consisting of (at the highest level) several tertiary structures, mean that small molecule drugs that target binding pockets are often incapable of interaction.[7] Of between 3,000-10,000 disease modifying proteins, only 400 are used for therapeutic development, usually by small molecules.[6] PPIs therefore, are attractive targets but prove difficult to drug.[8]

However, analysis of protein interfaces has shown that not all residues at the PPI interface are essential for the interaction, but rather, small ‘hot spots’ are responsible for most of the binding energy and are frequently found grouped on secondary structural elements.[7] PPIs between β-structures account for 16% of all PPIs,[7] secondary structure mimicry provides a promising route to PPI inhibition, either via conformational constraint of peptides or by non-peptidic mimicry.

Chapter 1 outlines the importance of PPIs in biology and medicine, the challenges associated with developing targeted therapeutics and how β-structure mimetics may provide a solution to these challenges.

Chapter 2 and 3 describe the design and development of two in-register β-sheet mimetics, rigidified by a central diphenylacetylene staple.

Chapter 4 develops non-peptidic β-strand mimetics with hydrophilic and mixed hydrophilic/hydrophobic side chains that are conformationally stabilised by dipolar repulsion. NOE NMR and CD studies demonstrate the conformational bias in the solution phase in a polar solvent.

Chapter 5 uses diphenylacetylenes in the synthesis of a long-lived singlet state probe for NMR diffusion experiments.

1.1 References

2. L. Jin, W. Wang and G. Fang, Annu. Rev. Pharmacol. Toxicol., 2014, 54, 435-456.

3. J. Munch, E. Rucker, L. Standker, K. Adermann, C. Goffinet, M. Schindler, S. Wildum, R. Chinnadurai, D. Rajan, A. Specht, G. Gimenez-Gallego, P. C. Sanchez, D. M. Fowler, A. Koulov, J. W. Kelly, W. Mothes, J. C. Grivel, L. Margolis, O. T. Keppler, W. G. Forssmann and F. Kirchhoff, Cell, 2007, 131, 1059-1071.

4. A. C. Joerger and A. R. Fersht, Annu. Rev. Biochem., 2008, 77, 557-582.

5. C. Haass and D. J. Selkoe, Nat. Rev. Mol. Cell. Biol., 2007, 8, 101-112.

6. M. R. Arkin, Y. Tang and J. A. Wells, Chem. Biol., 2014, 21, 1102-1114.

7. P.-N. Cheng, J. D. Pham and J. S. Nowick, J. Am. Chem. Soc., 2013, 135, 5477-5492.

8. J. S. Nowick, D. M. Chung, K. Maitra, S. Maitra, K. D. Stigers and Y. Sun, J. Am. Chem. Soc., 2000, 122, 7654-7661.

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Identifiers

ORCID for Sam Thompson: orcid.org/0000-0001-6267-5693

ORCID for Paul Skipp: orcid.org/0000-0002-2995-2959

ORCID for Rob Ewing: orcid.org/0000-0001-6510-4001

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