Peptidic Drugs

Written by Dr. Martin Flegel

Since the early 1950s, the research of peptides at the Institute of Organic Chemistry and Biochemistry (IOCB) of the Czechoslovak Academy of Sciences has focused on the Neurohypofyseal hormones – their synthesis and biological effects. When Vincent du Vigneaud received his Nobel Prize in 1955 for his pioneering synthesis of Oxytocin and Vasopressin, the research in this field at the IOCB considerably progressed and almost reached the goal of being the first in the industrially applicable synthesis of Oxytocin.

In 1958, the industrial production of synthetic Oxytocin started at the Leciva-Pharmaceuticals company.

In about two years, Lysin-vasopressin (LVP) was put into production at the same pharmaceutical company.

Oxytocin was and still is used as the basic drug in gynecology during childbirth; Lysin-vasopressin was originally used in the treatment of diabetes insipidus, but its side effects (pressoric activity and myocardial toxicity) have prevented its broad utilization in this treatment. Nowadays, it is still used at low concentrations in dentistry (as an additive to local anesthesia).

The research which has continued at the IOCB’s peptide department and structure-activity studies have enabled the rational replacement of amino-acid residues in various positions of above-mentioned hormone structures and the preparation of new analogues of hormones without the undesirable effects.

Oxytocin could be replaced in obstetrics-gynecology applications by Metyloxytocin

which was safer in the cases when protracted delivery took place; unfortunately, due to marketing problems, the production of this drug was rather low and stopped.

Another excellent OT analogue, Carbetocin, was later synthesized. Despite its very promising biological activity profile and at the same time enhanced stability, this peptide was used for many years as a veterinary drug, and only in the last ten years have its very suitable properties been exploited in human medicine.

Deamino-carba1-2-O-metyltyrosine-Oxytocin (Carbetocin)

In the group of “vasopressin-like” peptides, the research has focused on both anti-diuretic and pressoric activities and their selectivity. The extension of the peptide chain by the LVP sequence in the N-terminal part has resulted in a compound named Glypressin or Terlipressin.

The very protracted and low pressoric activity of this analogue is currently being used for the treatment of bleeding from gastric and duodenal ulcers and also in the treatment of esophageal varices.

The most successful analogue of Arginin-vasopressin has been prepared by substitutions of L-Arg in position 8 by D-Arginin and at the same time in position 1, where Cysteine was substituted by 3-mercaptopropionic acid (Mpa). In this way, a compound having very high specific antidiuretic and very negligible pressoric activity was obtained:

1-deamino-8-D-arginin-vasopressin (DDAVP) Desmopressin

DDAVP is one of the broadly used drugs for the treatment of diabetes insipidus, enuresis nocturna, Hellebrand disease and other bleeding hemophilic-like disorders. The DDAVP has been the highlight of the IOCB and in many aspects (including economical) the most successful story of peptide research at the IOCB.

All of the above-mentioned peptide drugs were produced in Czechoslovakia at the Leciva SPOFA Pharmaceutical company and after 1989 at Czech subsidiaries of the Ferring and Polypeptide Laboratories companies.

It is necessary to note that Desmopressin, Terlipressin and Carbetocin were licensed by the Czechoslovak Academy of Sciences to the Swedish firm Ferring AB in the late sixties. All three compounds are nowadays produced as bulk pharmaceutical chemicals at the Polypeptide Laboratories group mainly in Scandinavia in very large several ten-kilo quantities, and without a doubt Desmopressin is the diamond and flagship among the peptide drugs produced.

Behind the peptide research at the IOCB, there were mainly three excellent peptide chemists, whose names should be mentioned here:
Prof. Josef Rudinger and Dr. Milan Zaoral and Dr. Karel Jost.

All three were excellent peptide as well as organic chemists, and peptide chemistry in our country reached the highest and internationally recognized level during their laboratory time.

Today, the European Peptide Society awards excellent peptide chemists with the Rudinger Award for lifelong work in the peptide field and they give a lecture during the European peptide symposium, which is held every two years in a nominated European country. The very first EPS was organized by Prof. Rudinger in Prague in 1958.