A NEW SUPPORT FOR THE SYNTHESIS OF BIOACTIVE PEPTIDES

Description: (Applicant's abstract) Disulfide-bridged cyclic peptides form the base for many popularly used cancer-treatment drugs and hormones such as somatostatin, calcitonins, and oxytocin. However, the production of these peptides is difficult and expensive. One of the main problems faced during the production of disulfide-bridged peptides is the removal of the oxidant for the disulfide bond formation from the final product. Extensive subsequent purification steps lead to increased manufacturing costs and lower yields, resulting in annual production costs of about $300 million in the US. We propose a new procedure in which a resin with a directly attached oxidant is produced. This procedure will ease the synthesis of complex peptides in a very cost-effective manner by allowing for the final purification of disulfide-bridged cyclic peptides to involve only simple filtration. The CLEAR (cross-linked ethoxylate acrylate resin) base support is unique because it is compatible with both organic solvents (for the reagent linkage) and aqueous solutions (for the final peptide recovery). CLEAR has been successful as a support for peptide and organic synthesis and the proposed chemistry for oxidant linkage has been demonstrated elsewhere utilizing other solid supports. Our process will be evaluated in discrete steps beginning with the characterization of the resin-bound oxidant and culminating with its use in the synthesis of a bioactive drug. The final cyclic peptides will be characterized to evaluate purity, by-product formation, and yields in comparison with existing methods. Currently, no such commercial product exists. The commercial impact for this product could reach as much as $50 million just for the synthesis of hypothalamic peptides alone. The success of this proposal will significantly simplify the synthesis process of many cancer-treatment chemicals and hormones, and reduce medical costs. PROPOSED COMMERCIAL APPLICATION: Somatostatin analogs are important anti-cancer products with an estimated $900 million in annual sales. These and other disulfide bridged cyclic peptides can benefit from our resin-bound oxidant. Future derivatives can impact the diagnostics market which represents a far larger opportunity for this class of products.