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Modern day medicinal chemistry is relying more and more on synthetic biomolecules designed and produced using biotechnology approaches. For example, synthetic peptides that specifically bind to proteins such as cytokines, protein hormones, and nuclear hormone receptors offer alternative approaches to small molecules for the modulation of protein and receptor signaling and subsequent gene expression. The hydrocarbon-stabled peptide modeled after the BIM BH3 helix is one example. This peptide broadly targeted BCL-2 family proteins with high affinity. In addition the peptide blocked inhibitory antiapoptotic interactions, thereby directly triggering proapoptotic activity, and inducing dose-responsive and BH3 sequence-specific cell death of hematologic cancer cells. This example illustrates that stapled peptides are useful protein-protein interaction mimics. In addition many of these stapled peptides been shown to increase activity, potency in vivo cancer cell death and enhance therapeutic properties. Furthermore, recent research indicates that stapled peptides can offer new ways to treat so called “undruggable” diseases since available drugs, primarily small molecules and therapeutic proteins, address only an estimated 10% to 20% of all identified therapeutic targets within the human body.
These findings indicate that there is a need to use short peptide mimics, such as custom stapled peptides, that enable the fine-tuning of regulation pathways that control important biological process as they are found in various types of diseases. Custom stapled peptides have a great potential as a new class of therapeutic candidates to do just this. Unfortunately, when isolated and introduced into aqueous solutions, peptide helices are highly susceptible to conformational changes and can be easily degraded by proteolysis. In addition un-optimized stapled peptides have difficulties to penetrate intact cells, often leading to a reduction in biological activity and thus diminishing potential therapeutic benefit.
This challenge can be overcome by chemically locking the peptide in a specific conformation which mimics the molecular structures typically found at the interface of protein-protein interactions. When locked into this stable configuration, some of these constrained or stapled peptides are able to penetrate cells efficiently allowing them to exert their effects on intracellular protein targets. In addition, the large surface area of proper designed stapled peptides makes them superior to small molecules in their ability to disrupt specific signaling pathways by inhibiting targeted protein-protein interactions.
Bio-Synthesis offers a new peptide conformation screening tool called positional cyclization scanning.
This technique involves
synthesis of constrained peptide structures in the form of lactam bridge for stapling at various positions to determine the overall structure conformation of the protein. This process not only provides peptides with desirable pharmacokinetic properties but also provides a conceptual approach towards applying peptidomimetics and small molecules for intracellular protein-protein interactions.