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Applications of Constrained Peptides to Various Biological Processes

Peptides play a crucial role in many cellular processes; however, short peptides are devoid of well-defined structures while in solution. In addition, their short half-life in vivo due to rapid proteolytic degradation and poor cell permeability remains a challenge to their therapeutic applications [1]. Thus common strategies aiming at improving receptor affinity, receptor efficacy, enzyme stability, and pharmacokinetic properties are an active field of research.

Standard sidechain to sidechain conjugation allows the synthesis of cyclized peptides. Lactam formation allows linking amino acid residues identified as not involved in receptor interactions [2]. Ring-closing metathesis is another method utilized to stabilize peptide structures [3]. Stabilized α-helical structures are known to play essential roles in protein-protein interactions (PPI).


For instance, hydrocarbon stapled peptides mimicking the BCL-2 domain (an important family of proteins that regulates apoptosis) showed increased protease resistance and cell permeability due to a stabilized helical conformation [4]. This modification was further applied to NOTCH 1 transcription factor resulting in peptides with an increased binding affinity towards NOTCH transactivation complex. NOTCH proteins have been shown to play a pivotal role in cellular differentiation, proliferation, and apoptosis, and their mutations have been linked with diseases like T-cell acute lymphoblastic leukemia.


These few examples illustrate the potential of constrained synthetic peptides in PPI’s [5].


References

[1]  A. Caporale, M. Sturlese, L. Gesiot, F. Zanta, A. Wittelsberger and C. Cabrele, J Med Chem 2010, 53, 8072-8079. [
ACS]

[2]  a) R. S. Harrison, G. Ruiz-Gomez, T. A. Hill, S. Y. Chow, N. E. Shepherd, R. J. Lohman, G. Abbenante, H. N. Hoang and D. P. Fairlie, J Med Chem 2010 [
PDF]; b) E. N. Murage, J. C. Schroeder, M. Beinborn and J. M. Ahn, Bioorg Med Chem 2008, 16, 10106-10112. [Eu PMC]

[3]  a) H. E. Blackwell and R. H. Grubbs, Angewandte Chemie International Edition 1998, 37, 3281-3284 [Angewandte]; b) J. F. Reichwein, C. Versluis and R. M. Liskamp, J Org Chem 2000, 65, 6187-6195 [ACS]; c) J. Illesinghe, C. X. Guo, R. Garland, A. Ahmed, B. van Lierop, J. Elaridi, W. R. Jackson and A. J. Robinson, Chem Commun (Camb) 2009, 295-297. [PDF]

[4]  L. D. Walensky, A. L. Kung, I. Escher, T. J. Malia, S. Barbuto, R. D. Wright, G. Wagner, G. L. Verdine and S. J. Korsmeyer, Science 2004, 305, 1466-1470. [PMC]

[5]  R. E. Moellering, M. Cornejo, T. N. Davis, C. Del Bianco, J. C. Aster, S. C. Blacklow, A. L. Kung, D. G. Gilliland, G. L. Verdine and J. E. Bradner, Nature 2009, 462, 182-188. [PMC]

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