Most naturally occurring constrained peptides maintain the rigidity of the peptide framework by disulfide bond or N- to C-termini backbone cyclization. Commonly known antimicrobial peptides like Gramidicin S, Bacitracin and Polymyxin B are an example of backbone cyclic peptides that are used clinically (Table 1).[1]
Table 1: Natural cyclic peptides
Parenthesis indicate amino acids that are cyclized, d the D-enantiomer; O, Ornithine; B, diaminobutyrate
Figure 1: Scheme showing reduction of disulfide bonds in cellular environment to acyclic thiol. In addition, availability of variety of protecting groups for amines and carboxylic acids which are cleavable under orthogonal conditions have made amide bond lactam bridges to be an alternative covalent linkage substituting disulfide bonds (Figure 2B).
Conotoxins are another class of small peptide ligands (typically 10-30 amino acids) highly crosslinked by disulfide bonds.[2] Despite their small size, these peptide ligands have very high affinities and selectivities to their cognate receptors and many of them have now become standard research tools in neuroscience.
Although cysteine bridges are quite common structural motifs in naturally occurring peptides like neurotoxins,[2] cyclotides,[3] somatostatin[4] and insulin superfamily[5}, disulfide bridges (Figure 1) are readily reduced to their acyclic thiol form in an intracellular environment. Thus scientists have derived new methods of inducing stable conformation constraint of many peptides. For instance, advancement of organometallic chemistry has led to use of phase transfer catalyst like Grubbs catalyst[6] in ring closing metathesis. This chemistry has been utilized by Gregory Verdine to synthesize stapled peptides which have been found with promising biological functions (Figure 2A, Table 2) [7].
Figure 2: (A) Hydrocarbon stapled peptides synthesized through ring closing metathesis, (B) amide bond lactam bridge.
As summarized in the table 2 below, several synthetic cyclic peptides have shown desirable biological properties over their linear counterparts.
References1. S. R. Woodward, L. J. Cruz, B. M. Olivera and D. R. Hillyard, EMBO J 1990, 9, 1015-1020.
2. B. M. Olivera, J. Rivier, C. Clark, C. A. Ramilo, G. P. Corpuz, F. C. Abogadie, E. E. Mena, S. R. Woodward, D. R. Hillyard and L. J. Cruz, Science 1990, 249, 257-263.
3. D. J. Craik, N. L. Daly, T. Bond and C. Waine, J Mol Biol 1999, 294, 1327-1336.
4. L. Pradayrol, H. Jornvall, V. Mutt and A. Ribet, FEBS Lett 1980, 109, 55-58.
5. S. J. Chan, Q. P. Cao and D. F. Steiner, Proc Natl Acad Sci U S A 1990, 87, 9319-9323.
6. G. C. Vougioukalakis and R. H. Grubbs, Chem Rev 2010, 110, 1746-1787.
7. 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.
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