Biologically Active Peptides Containing Proline

Many biologically active peptides contain one or more proline residues, including corticotropin, angiotensin II 1, bradykinin 2 and oxytocin 3. ^ Its prevalence may be due to the constraints that its structure imposes upon these hormones and neurotransmitters. Being more constrained, the peptides can bind more effectively to their receptors, and are less likely to adopt peptidase-bound conformations, resulting in increased stability and bioavailability. Peptidases frequently will not cleave cis peptide bonds, another advantage conferred by the presence of proline.

The most abundant protein in vertebrates, collagen, is also rich in proline and hydroxyproline residues which reinforce its stable structure. ^ 21,122

Proline is not the only //-alkyl amino acid found in biological systems. //-Methyl residues are prevalent in microbial peptides such as the fungal metabolite cyclosporin A 7. These have similar structural effects to those of proline, although thay lack the constraint on ({), so are somewhat more flexible. Cis-trans

isomérisation also occurs in peptides containing //-methylated residues. 1^3,124 1.3.2 C‘^“Disubstituted Amino Acids

The other common modification of amino acids besides //-alkylation is C®^-alkylation. This severely limits the conformational freedom of the residue, compressing the internal angle so that folded structures such as helices and turns are highly favoured over extended structures, 125

By far the most widespread of these amino acids is a-amino/5obutyric acid

(Aib, 9). The dihedral angles for this residue are fixed to helical values, but its lack of chirality means that both right and left-handed helices are of equal energy for Aib oligomers. These form fully developed Bjo-helices at the octamer level, and show high helicity even with only 4-7 residues in aqueous solution. 83,125,126,128-132 \Yhen present in peptides containing L-amino acid residues, the right handed helical forms are promoted. a-Helices are preferred in

these cases for peptides containing 9 or more residues, and for those with < 50% Aib content. Aib also favours type III p-turns (which are equivalent to a four-residue section of 3io helix).

NHg 9

Aib is commonly found in the pentaibol family of naturally occuning antibiotics which are produced by microbial sources. These alter the permeability of biological membranes by forming channels for ion transport. The presence of these structure-stabilising residues helps to direct folding of these molecules without other longer range forces, and may also be important in reduction of the entropie cost of receptor binding.

Other C®-disubstituted amino acids have come under study. Being chiral, (25)-a- methylvaline was found to favour right-handed helical forms.

a-Methylglutamic acid, a-methylaspartic acid and a-methylproline were all found to promote P-turns in short sequences.

1.4 Synthesis of Peptides Containing Hindered Residues