oa Editorial [Hot Topic: Novel Peptide-Based Scaffolds for Drug Discovery (Executive Guest Editor: Julio A. Camarero)]

Broadly speaking, there are only two major structural classes of approved drugs, small molecules and protein therapeutics (also known as biologics). Small molecules typically show good stability and good pharmacological properties, but their intrinsic small size (≤100 atoms) endows them with only a modest overall surface area available to contact a protein target, which seriously limits their ability to effectively target large surfaces involved in protein-protein interactions. Protein-based therapeutics, on the other hand, have been shown to possess high specificity/selectivity and high affinity for protein targets. The use of therapeutic monoclonal antibodies to target extracellular protein receptors is just an example. Antibodies, however, suffer from clear limitations: they are expensive to produce, cannot be delivered orally, show low tissue penetration and can not target intracellular targets, among other issues. The potential problems associated with the use of antibody fragments have led to the exploration of alternative protein scaffolds as a source for novel protein-based therapeutics. However, the utility of protein-based therapeutics has been typically limited by their generally poor stability and limited bioavailability. In response to this challenge a number of technologies are starting to emerge to address these issues. Special attention has been recently given to the use of highly constrained peptides, also known as micro- or miniproteins, as extremely stable and versatile scaffolds for the production of high affinity ligands for specific protein capture and/or development of therapeutics. The present special issue covers the discovery, structure-activity and biomedical applications, which includes therapeutics and diagnostics, of novel highly-constrained peptidebased scaffolds. Conotoxins are small bioactive highly structured peptides isolated from the venom of marine cone snails (genus Conus) that have great potential for the development of novel peptide-based therapeutics. The conotoxin ω-MVIIA (Prialt®) received FDA approval in 2004 for the treatment of chronic pain. In Chapters one and two, Alewood and Craik, respectively, discuss the potential of α-conotoxins to develop novel peptide-based therapeutics. Defensins are also an important family of cationic and highly-constrained host defense peptides that are widely distributed in plants, fungi, and animals. In mammals, defensins exert potent antimicrobial and immunomodulatory activities linking the innate and adaptive immune defenses. These peptides play critical roles in health and disease, and defects in their production are usually associated with abnormal host responses to infection, chronic inflammatory diseases, and cancer. In Chapter three, Seveau reviews the biological activities of human and murine defensins in the host immune response and their potential to be used for developing novel antimicrobial and anti-inflammatory peptide-based therapeutics. Of particular interest is the recent discovery of -defensins, which are so far the only backbone cyclized peptides found in animals. -Defensins have very strong anti-inflammatory and anti-HIV activities, which makes them very attractive leads for the development of novel peptide-based drugs.....