TOWARDS PROTEIN SURFACE MIMETICS

Proteins are generally poor drug candidates due to bioavailability pro blems that stem from conformational instability, susceptibility to pro teolytic degradation, poor membrane penetration, and unfavourable phar macokinetics. Since many proteins exert their biological activity thro ugh relatively small regions of their folded surfaces, their actions c ould in principle be reproduced by much smaller 'designer' molecules t hat retain these localised bioactive surfaces but have potentially imp roved pharmacokinetic/dynamic properties. Unlike proteins, smaller pep tides generally lack well defined three dimensional structure in aqueo us solution and tend to be conformationally mobile. Considerable progr ess has been made in recent years towards the use of molecular constra ints to stabilise bioactive conformations. By affixing or incorporatin g templates that fix secondary and tertiary structures of small peptid es, synthetic molecules (protein surface mimetics) can be devised to m imic the localised elements of protein structure that constitute bioac tive surfaces. This is a promising growth area of medicinal chemistry that could impact significantly on biology and medicine. In this persp ective review we summarise and prescribe methods for mimicking individ ual elements of secondary structure (helices, turns, strands, sheets) and for assembling their combinations into tertiary structures (helix bundles, multiple loops, helix-loop-helix motifs). A detailed understa nding of the features that stabilise secondary and tertiary structures is the key to developing appropriate templates to support and correct ly position residues in smaller folded surfaces. The goal is to direct critical amino acids (or surrogates) into the same conformational spa ce and orientation as in bioactive surfaces of a native protein, yet r etain sufficient flexibility to bind cooperatively, and with complemen tarity, to a given receptor. The requirements of size, shape, and dire ctionality for templates to control peptide assembly and folding are d iscussed in relation to selected mimetics of secondary and tertiary st ructures. Particularly striking is the general tendency for protease i nhibitors and MHC-binding peptides to adopt strand conformations; agon ists and antagonists for G protein-coupled receptors to predominate in turn structures; transcription factors, cytokines and DNA/RNA-binding motifs to be helical; and antigen-recognition segments of antibodies to involve multiple loops.