SYNTHESIS OF A NEW BIVALENT HIRUDIN ANALOG (HIRUFOS), WHICH INCLUDES A STABLE 4'-PHOSPHONO-L-PHENYLALANINE MIMIC OF (L-TYROSINE O-4-SULFATE)-63

The synthesis on solid phase of a new derivative of the anticoagulant protein hirudin is described (see Scheme and Fig. 1, I). The henicosap eptide is a bivalent conjugate of the C-terminus of hirudin and of the active-site-binding tetrapeptide D-Phe-Pro-Arg-Pro linked via a tetra glycine spacer. The peptide, for which the name hirufos was coined, in corporates a stable phosphono derivative of L-phenylalanine which, com bined with the other structural modifications, leads to a potent antic oagulant agent. Synthesis was readily achieved by the (9H-fluoren-9-yl )-methoxycarbonyl (Fmoc) strategy followed by acidolytic cleavage from the resin and deprotection, including the liberation of the crucial p hosphonic group on L-phenylalanine.