The success of protein-based therapeutics is revolutionizing drug development. Unlike small molecule drugs, peptide and protein-based therapeutics can target with high selectivity and specificity defective protein-protein interactions involved in human disease. Despite their success, however, there are still numerous stability and delivery issues associated with their use as therapeutic agents. For example, monoclonal antibodies (one the most successful protein-based therapeutics with several blockbuster drugs on the market and many more in clinical development) can only target extracellular molecular targets due to their inability to cross biological membranes. They are also extremely expensive to produce and are not bioavailable due to their susceptibility to proteolytic degradation. These issues have led to the exploration of alternative protein scaffolds as a source for novel types of protein-based therapeutics. In response to this important challenge, the Camarero lab is using the ultra-stable cyclotide scaffold. Cyclotides are a new emerging family of large plant-derived backbone-cyclized polypeptides (?30 amino acids long) that share a 3 disulfide-stabilized core characterized by an unusual knotted structure. They have several characteristics that make them ideal drug development tools. The main features of cyclotides are a remarkable stability due to the cystine knot, a small size making them readily accessible to chemical synthesis, and excellent tolerance to sequence variations. For example, the first cyclotide to be discovered, kalataB1, is an orally effective uterotonic, and other cyclotides have been also shown to be orally bioavailable and capable of crossing cell membranes to efficiently target intracellular interactions. In addition, cyclotides have been shown to be poorly immunogenic due to their highly constrained nature. Cyclotides thus appear as highly promising leads or frameworks for peptide drug design. Within this context, the Camarero lab is also exploring the cell penetrating properties of these interesting microproteins as well as ways to improve it. Furthermore, his lab is also studying their pharmacokinetic (PK) and pharmacodynamic (PD) properties and explore different approaches to improve their PK profiles and oral bioavailability. In addition, we are also exploring the potential of bioactive cyclotides to be used as selective and specific bioimaging tools for early detection of cancer tumors.
This proposal describes the on-going efforts at the Camarero Lab to develop novel and innovative approaches for the screening and selection of a novel class of micro-protein-based therapeutics called cyclotides. Our lab has is developing both genetically- and chemically-encoded cyclotide-based libraries to screen intracellular and extracellular protein-protein interactions using novel high throughput screening methods. The Camarero is also studying the molecular pharmacology of bioactive cyclotides targeting autoimmune disorders and cancer. It is anticipated that the outcome of this research will have profound implications for human health and the way protein-based therapeutics can be used in the future to target specific extra- and intracellular protein-protein interactions involved in the development of several human diseases.
