Expedient Synthesis of Gonadotropin Releasing Hormone (GnRH) Through a Combined Chemical-Enzymatic Approach

We have developed a chemical-enzymatic synthetic approach to gonadotropin releasing hormone Glp1–His-2–Trp3–Ser4–Tyr5–Gly6–Leu7–Arg8—Pro9–Gly10–NH2 (GnRH) which enables one to perform the synthesis efficiently according to minimal protection strategy with all reactive side chains of amino acids unprotected. Five peptide bonds His2–Trp3, Tyr5–Gly6, Leu7–Arg8 and Trp3–Ser4, Ser4–Tyr5 were formed by means of a-chymotrypsin and papain, respectively. The remaining four bonds Glp1–His2, Gly6–Leu7, Arg8—Pro9, Pro9—Gly10 were formed by chemical methods. The synthesis is simple to carry out and there are no problems in scaling up as demonstrated by the final coupling on 2 g scale affording highly pure GnRH in the yield of 84-90%.