910576-32-8

Peginesatide was approved by the US FDA in March 2012 to treat anemia in patients with chronic kidney disease (CKD) requiring dialysis. Peginesatide activates the erythropoietin receptor, but it is not structurally related to EPO, so it was proposed to avoid the liabilities associated with EPO. Peginesatide was discovered by screening of a recombinant >1010 membered-peptide library against the human erythropoietin receptor. The hits were optimized by introducing nonnatural amino acids (1-Nap-Ala), resulting in a dimeric peptide with little sequence identity to natural erythropoietin. To improve the circulating half-life of peginesatide, the modified peptide dimer was coupled to the NHS-activated ester of bis-N-PEG-carbamoylated lysine (PEG₂–Lys–NHS). The peptide coupling partner was synthesized via solid-phase peptide synthesis to construct 21-mer peptides that were coupled in 2:1 ratio to NHS-activated esters of Boc-b-alanine-N-diacetic diacid. Boc-deprotection produced the penultimate free amine for coupling to PEG₂–Lys–NHS to give peginesatide.

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