Process for producing pentapeptides and intermediates for use in

Details Process for producing pentapeptides and intermediates for use in Process for producing pentapeptides and intermediates for use in

1992-09-04

1993-10-12

Robinson, Douglas W.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Enzymatic production of a protein or polypeptide

930DIG802, 530330, C12P 2100, C07K 700

Patent

active

052524647

ABSTRACT:
Pentapeptides having the formula H-Asp-Ser-C-Pro-Arg-OH, where Asp, Ser, Pro and Arg may have L- or D-configuration, and C denotes Asp or Asn in L or D configuration, are synthesized by reacting in an aqueous medium Y.sub.2 -Pro-OH, wherein Y.sub.2 is a protective group, with Arg-Ro, wherein Ro is OH or is as defined below for R.sub.1 below, to form Y.sub.2 -Pro-Arg-Ro, which is deprotected, if necessary under conversion to Pro-Arg-R.sub.1, wherein R.sub.1 is an enzymatically cleavable .alpha.- carboxy substituting group selected form esters, amides, anilides, hydrazides or L-amino acid esters, and thereafter reacting Y.sub.3 -C(Z.sub.3)-OH with Pro-Arg-R.sub.1 to form Y.sub.3 -C(Z.sub.3)-Pro-Arg-R.sub.1 which is deprotected to C-Pro-Arg-R.sub.1, and then reacting Y.sub.4 -Ser-OH with C-Pro-Arg-R.sub.1 to form Y.sub.4 -Ser-C-Pro-Arg-R.sub.1, which is deprotected to Ser-C-Pro-Arg-R.sub.1, and reacting Y.sub.5 -Asp(Z.sub.5)-OH with Ser-C-Pro-Arg-R.sub.1 to form Y.sub.5 -Asp(Z.sub.5)-Ser-C-Pro-Arg-R.sub.1, which is deprotected to the intermediate Asp-Ser-C-Pro-Arg-R.sub.1, and finally removing the group R.sub.1 with an enzyme, preferably trypsin to form Asp-Ser-C-Pro-Arg, or removing R.sub. 1 from Y.sub.5 -Asp(Z.sub.5)-Ser-C-Pro-Arg-R.sub.1 before deprotection to Asp-Ser-C-Pro-Arg-OH.
The groups Y.sub.2, Y.sub.3, Y.sub.4, Y.sub.5, Z.sub.3 and Z.sub.5 are protective groups which apart from Y.sub.2 are removable by catalytic hydrogenation. The employed synthesis strategy based on the combination hydrogenation/enzyme, both proceeding under mild conditions, leads to the peptides, in particular HEPP, in good yield without risk of formation of .beta.-aspartyl peptides and cleavage of Asp-Pro bonds.

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