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Synthetic Conformationally Constrained Peptides

Synthetic Conformationally Constrained Peptides

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: Naturally occurring backbone cyclized peptides

Peptide

Structure

Gramicidin S

Cyclic (LOVPFdLOVPFd)

Bacitracin

Cyclic I(C )LEdI(KOdIFHD)Dd-NH2

Polymyxin B

Cyclized Octanoyl BTBB(BFdLBBT)

Parenthesis indicate amino acids that are cyclized, d represents the D-enantiomer; O, Ornithine; B, diaminobutyrate

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].



Synthetic Conformationally Constrained Peptides

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 has made amide bond lactam bridges to be an alternative covalent linkage substituting disulfide bonds (Figure 2B).


Polypeptides Synthesis

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.

Table 2: Examples of constrained peptides with attractive biological properties

Peptide

Type of Modification

Properties

References

a-Conotoxin

N- to C- terminus  cyclization

Increased stablility in human plasma

Clark et al.

Proc Natl Acad Sci USA 2005, 102, 13767–13772.

 

BID BH3

Hydrocarbon stapling using ring closing metathesis

Increased protease resistance and serum stability

 

Walensky et. al., Science, 2004, 3, 1466-1470

NOTCH1

Hydrocarbon stapling using ring closing metathesis

Increase binding affinity  towards NOTCH transactivation complex

Raymond E. M., Melanie C., Tina N. D., Cristina Del Bianco, Jon C. A., Stephen C. B., Andrew L. K., D. Gary G., Gregory L. V., James E. B., Nature 2009, 462, 182-188.

Glucagon-like Peptide-1

Side chain to side chain i, i+4 lactam bridge formation

Increased receptor efficacy and enzyme stability

 

Murage E. N. Gao G., Bisello A., Ahn J-M. J. Med. Chem. 2010, 53, 6412-6420

 

DP178 (HIV35)

Side chain to side chain i, i+7 lactam bridge formation

Increase HIV inhibitory activity as a result of stabilized a-helical conformation

Judice et. al., Proc. Natl. Acad. Sci. USA. 1997, 94, 13426-13430

 

 References

[1] 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.