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 G lp '-H is2-T r p 3-S er4-T y r5-G ly 6-L e u 7-A r g 8-P r o 9G ly 10N H 2 (GnRH) which enables one to perform the synthesis efficiently according to minimal protection strategy with all reactive side chains o f amino acids unprotected. Five peptide bonds His2-T r p 3, Tyr5-G ly 6, Leu7-A r g 8 and Trp3-S er4, Sei^-Tyr5 were formed by means o f a-chymotrypsin and papain, respectively. The remaining four bonds G lp '-H is2, Gly6-L e u 7, Arg8-P r o 9, Pro9G ly 10 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 o f 84-90% .