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

2011, Current Pharmaceutical Design

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 extracell ular protein receptors is just an example. Antibodies, however, suffer from clear limitations: they are expensive to produce, cannot be deli vered orally, show low tissue penetration and can not target intracellular targets, among other issues. The potential problems associated wit h 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 !-MVIIA (Prialt ®) received FDA approval in 2004 for the treatment of chronic pain. In Chapters XXX and XXX, Alewood and Craik, respectively, discuss the potential of "-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 associat ed with abnormal host responses to infection, chronic inflammatory diseases, and cancer. In Chapter XXX 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-inf lammatory 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. Plant defensins have also shown numerous biological activities, such as inhibiting protein synthesis, ion channel function and "-amylase and trypsin activity; impairing microbial, root hair and parasitic plant growth among others. In Chapter XXX Carvalho provides a very comprehensive review on the biological activities and roles of plant defensins as well as their application in the field of bio technology. Cyclotides are another family of highly constrained peptides found in plants with interesting pharmacological properties. In c hapter XXX, Camarero provides a complete review on recent findings of the biological diversity and therapeutic potential of natural and engineered cyclotides. Sunflower trypsin inhibitor (SFTI-I) is another backbone cyclized polypeptide isolated from sunflower seeds with potent trypsi n inhibitory activity. In chapter XXX, Legowska provides an extensive review on the molecular engineering of SFTI-I as a molecular scaffold for the introduction of novel biological activities. Genetically-encoded backbone cyclized polypeptides have been found in plants, fungi, bacteria and animals. The cyclization mechanisms associated with their post-translational synthesis, although not completely understood, are believed to involve a protease-catalyzed transpeptidation reaction. In chapter XXX, Anderson provides an updated revision on the biosynthesis of gene-encoded backbone cyclized polypeptides. Cystine knot miniproteins also known as knottins is another family of highly constrained peptides that are typically 30 residues in length containing three disulfides forming a cystine knot topology. They have been isolated from a plethora of natural sources, for example arthropods, insects, vertebrates, viruses, fungi, and plants. In Chapter XXX, Kolmar reviews the structural, biophysical and biological properties of natural and engineered knottins, discussing their potential diagnostic and therapeutic applications. In Chapter XXX, Gracy also reviews the structural characteristics of knottins as well as the different bioinformatics tools that can be used for the analysis and engineering of this interesting family of peptides. Animal venoms also provide a good source of highly constrained peptides with pharmacological properties that can be used for t he development of peptide-based therapeutics and/or diagnostics tools. In Chapter XXX, Rhadis-Baptista reviews the potential biotechnological Novel Peptide-Based Scaffolds for Drug Discovery