Forming stable helical peptides using natural and artificial amino acids

Considerable progress has been made in understanding the factors governing helical stability of short peptides and designing stable peptide helices, but the picture is not yet complete. Bioorganic chemists have an important contribution to make; the design of unnatural amino acids, peptide mimetics and helix templates that can be incorporated into short peptides enables the current hypotheses of the properties of amino acids that favour or disfavour helix formation to be rigorously tested. It is clear, when the discrepancies between helical propensities derived from Ala-based host peptides and from the Ac-Hel templates are considered, that s-values are more dependent on context, sequence and inter-residue interactions than previously predicted. It may well be that the different stabilising factors used in each model to produce a short, helical peptide suitable for study will inevitably impose their own set of helix preferences on the s-values determined. The ability to design unnatural amino acids, mimetics and templates that will produce short, stable helical peptides is also of crucial importance for medicinal chemists. A portfolio of techniques that could ensure that (almost) any sequence of amino acids adopted a helical structure would enable the interactions of the side-chains of the residues in protein or peptide helices with any biological receptor - protein, DNA, RNA - to be studied, independently of the possible role of those side-chains in stabilising the structure. Moreover, many of the stabilised peptide helices so far produced have had impressive biological properties, and may become therapeutically useful. One of the most promising approaches to this goal appears to be the design of artificial N-cap residues to stabilise the first torn of the helix, and templates to mimic the first turn of the helix: this reflects the importance of such motifs in stabilising helices in proteins. Formation of a covalent linkage between appropriate side-chains is also important for helix stabilisation: again, this reflects the importance of the various side-chain- side-chain interactions that stabilise naturally occurring peptide helices. However, it should be borne in mind that enhanced helical stability does not necessarily mean improved biological activity, or vice versa; the preferred conformation of a peptide at a receptor may well differ from the conformation predicted from its sequence, or determined in solution. Finally, the design of non-peptide scaffolds that will display amino acid side-chains in the spatial arrangements produced by helices will undoubtably generate many lead candidates for drug discovery programmes. The scope for biological and medicinal chemists to make an impact in this area is considerable.