EMILIANA DE SANTIS^1,2, ALISON A. EDWARDS¹*
*Corresponding author
1. Medway School of Pharmacy, Universities of Kent and Greenwich at Medway Central Avenue, Chatham Maritime, Kent, ME4 4TB, United Kingdom
2. Diamond Light Source Ltd, Diamond House, Harwell Science and Innovation Campus, Didcot, Oxfordshire, OX11 0DE, United Kingdom

Abstract

Peptides are ideal drug candidates due to their selectivity, however the therapeutic use of peptides is limited by their poor bioavailability e.g. due to the sensitivity to proteolytic enzymes. Therefore the development of peptidomimetic compounds is an area of research which has been rapidly expanding. The ability of such compounds (also known as foldamers) to fold into defined secondary structures is well documented and facilitates mimicry of the active conformation of peptide and proteins. A certain degree of flexibility is also desirable for peptidomimetics due to the importance of disorder in functional proteins. However, the greater flexibility complicates conformational studies due to the presence of multiple conformers e.g. NMR can have extensive signal overlap. In this scenario, chiroptical techniques such as circular dichroism become an invaluable tool for conformational studies.

BACKGROUND
Natural proteins and peptides are formed from amino acids linked together by amide bonds. Most of their biological functions, such as molecular recognition and catalysis, are related to the amino acid sequence and their spatial conformation in solution. Modification of the three-dimensional conformation (e.g. misfolding or a change in the secondary structure) can result in loss of physiological activity and in the occurrence of pathological conditions. Their high activity and specificity makes peptides ideal drug candidates. In addition, peptides can target physiological and pathological conditions not easily treated with small molecular weight drugs, e.g. large surface protein-protein interactions (1). However, the clinical use of peptide-based drugs is limited by their sensitivity to proteolytic enzymes (2) which shorten their half-life (typically to a few minutes) and thus decrease their bioavailability.
Although biological function has traditionally been associated with ordered structures, a number of functional disordered or partially disordered proteins have been reported (3). These have been found to play a role in a variety of ...