Towards Protein Surface Mimetics

Abstract

Proteins are generally poor drug candidates due to bioavailability problems that stem from conformational instability, susceptibility to proteolytic degradation, poor membrane penetration, and unfavourable pharmacokinetics. Since many proteins exert their biological activity through relatively small regions of their folded surfaces, their actions could in principle be reproduced by much smaller 'designer' molecules that retain these localised bioactive surfaces but have potentially improved pharmacokinetic/dynamic properties. Unlike proteins, smaller peptides generally lack well defined three dimensional structure in aqueous solution and tend to be conformationally mobile. Considerable progress has been made in recent years towards the use of molecular constraints to stabilise bioactive conformations. By affixing or incorporating templates that fix secondary and tertiary structures of small peptides, synthetic molecules (protein surface mimetics) can be devised to mimic the localised elements of protein structure that constitute bioactive surfaces. This is a promising growth area of medicinal chemistry that could impact significantly on biology and medicine. In this perspective review we summarise and prescribe methods for mimicking individual 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 understanding of the features that stabilise secondary and tertiary structures is the key to developing appropriate templates to support and correctly position residues in smaller folded surfaces. The goal is to direct critical amino acids (or surrogates) into the same conformational space and orientation as in bioactive surfaces of a native protein, yet retain sufficient flexibility to bind cooperatively, and with complementarity, to a given receptor. The requirements of size, shape, and directionality for templates to control peptide assembly and folding are discussed in relation to selected mimetics of secondary and tertiary structures. Particularly striking is the general tendency for protease inhibitors and MHC-binding peptides to adopt strand conformations; agonists 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.