Description
Ecallantide, also known as DX-88, was approved in 2009 in the
United States for treatment of hereditary angioedema (HAE), a condition
characterized by episodic attacks of localized edema in cutaneous
and mucosal tissues. HAE results from deficiencies or disorders of C1-esterase inhibitor protein (C1-
1NH). Mutation of the gene that encodes C1-1NH causes the lack or
altered activity of the serine protease, C1-1NH. C1-1NH regulates the
kallikrein–kinin (contact activation) and complement cascade systems.
Ecallantide (DX-88) was designed to inhibit the action of
plasma kallikrein. Ecallantide is a potent and selective inhibitor of
plasma kallikrein with a Ki= 25 pM. The discovery program that
identified ecallantide used phage display technology and a library of
designed variants of the first Kunitz domain of TFPI. Ecallantide, a
60-amino acid peptide, with 3-disulfide bonds, differs from TFPI by
7-amino acids. Ecallantide has been developed as a subcutaneous
administered formulation.
Originator
Dyax Corp. (United States)
Uses
Treatment of hereditary angioedema; reduction of blood loss during cardiothoracic surgery (plasma kallikrein inhibitor).
Synthesis
Dissolve 150 g of the linear crude peptide of eicosapentin in 150 L of buffer system, which was an aqueous solution of 0.1 mM ammonium acetate, 3 times the amount of DTT of the linear crude peptide (in substance), pH 7.8, and place it in the open mouth at the room temperature with stirring for 36 hours, and quench it by adding glacial acetic acid to adjust the pH=3-5, then the eicosapentin crude peptide solution was obtained, and purify it with reference to the method of Example 12. It was prepared and lyophilized, and 35.7 g of white peptide solid was obtained, the cyclization yield was 23.8%, and the mass spectral signal was 8387.654.
