The Prague Institute That Redesigned a Hormone

They did it by changing two things in a nine-amino-acid hormone, and the changes were chosen, not stumbled upon. In 1967 chemists at the Institute of Organic Chemistry and Biochemistry in Prague removed the free amino group from the first residue of vasopressin and replaced its eighth residue, an arginine, with the mirror-image form of the same amino acid. The result, now called desmopressin, kept the antidiuretic activity of the natural hormone, lost almost all of its blood-pressure-raising activity, and lasted far longer in the body 1.

Peptide chemists had already shown that natural hormones could be made in the laboratory. What the Prague group showed was that a hormone could be rewritten, with intent, to separate its functions. It is a quiet milestone, and it happened in a country that Western scientists seldom thought about, in a year when the political ground was about to move.

An institute founded in 1953

The institute that made the compound was young. The Czechoslovak Academy of Sciences established the Institute of Organic Chemistry and Biochemistry in 1953, and it was led from the outset by František Šorm, a chemist with the political skill to build a large, well-equipped establishment under a state that valued science as a showcase 4. Šorm built a department of peptide chemistry with an international outlook and recruited able young chemists, among them Josef Rudinger and Milan Zaoral.

The period matters because the conditions were unusual. Funding for fundamental chemistry was relatively secure, journals and visiting scholars moved with some difficulty but did move, and the field was in a state where the central problem was clear. Vincent du Vigneaud had synthesised oxytocin and vasopressin in the 1950s, a feat recognised with the Nobel Prize in Chemistry in 1955, and had shown that a peptide hormone could be reproduced exactly in a flask. The obvious next question was what could be done with that capability.

Vasopressin: two jobs in one molecule

Vasopressin is made in the hypothalamus and released from the posterior pituitary gland. It has nine amino acids, with a loop closed by a sulphur bridge between residues 1 and 6, and two principal actions that physiologists measure separately. It acts on the kidney to reduce the volume of urine produced, which is why it is also called antidiuretic hormone, and at higher concentrations it narrows blood vessels and raises blood pressure, which is where the name vasopressin comes from.

Medicine had been using crude pituitary extracts since 1913 for diabetes insipidus, a rare condition in which the body cannot conserve water because it lacks the hormone or cannot respond to it. The extracts were short-acting, had to be given repeatedly, and carried the blood-vessel effects as an unavoidable companion. A cleaner, longer-lasting analogue would have been welcome to physicians, and for a chemist it posed a clean design problem: can the two actions be pulled apart?

The two changes of 1967

The Prague approach combined two ideas from the chemistry of peptides. The first was to remove the free amino group at the front of the molecule, leaving a residue of cysteine with no nitrogen attached at its end. Work on oxytocin analogues in the early 1960s had suggested that this change could make a hormone more active and more persistent, probably because enzymes that nibble peptides from the front end have nothing to grip.

The second was to change the eighth residue. Natural amino acids in proteins are almost all of one handedness, the L form. The D form is its mirror image, and enzymes built to cut L-containing chains tend to recognise a D residue poorly. In natural arginine vasopressin the eighth residue is L-arginine. Replacing it with D-arginine did two things the chemists wanted: it made the molecule more resistant to breakdown, and it shifted the balance of activity so that the effect on the kidney was retained while the effect on blood vessels fell dramatically 1.

The synthesis was reported in the Czechoslovak chemical literature in 1967 by Zaoral, Kolc and Šorm. The remarkable thing is how small the intervention was: of nine residues, one had a chemical group snipped off and another had its handedness reversed. Chemists describe the compound by a name that records exactly those two edits, and the name has been shortened over the years to desmopressin.

1968: a Lancet paper from the wrong side of the Curtain

The first account of the analogue's biological activity was published in The Lancet in 1968 under the title 'Effect of a synthetic analogue of vasopressin in animals and in patients with diabetes insipidus' 1. The authors were Czechoslovak researchers working with the institute chemists. The work spanned two evidence tiers, and the paper was clear about which was which: laboratory animals first, to measure the antidiuretic and pressor activities, and then a small number of patients with the condition, in whom the synthetic hormone's effects were observed.

The date is part of the story. The paper appeared in the spring of 1968, the months of reform in Czechoslovakia. In August of that year, Warsaw Pact forces entered the country, the reforms were reversed, and a period of enforced 'normalisation' began. Contact with the West narrowed, institutes lost staff who were politically unreliable or who chose to leave, and Rudinger left for Zurich. A piece of work that might have been followed by a decade of Prague-led development was, instead, picked up by others.

Why the design was a new kind of idea

To describe desmopressin as the first designed peptide analogue invites correction, and an honest account gives it. Analogues of oxytocin and vasopressin had been made in du Vigneaud's laboratory and others before 1967, and some showed altered activity. What distinguishes the Prague compound is that it combined two rational modifications, each justified by an understanding of how peptides are degraded, to reach a specific functional goal, and that it succeeded well enough to become a standard medicine.

The approach later became routine. The same two levers, protecting the ends of a chain and substituting unnatural or D-amino acids, run through the history of peptide drugs, from analogues of the hypothalamic hormones to the long-acting incretin medicines. The idea that a peptide's duration and selectivity can be engineered separately from its mechanism is now so familiar that its origins seem unremarkable. In 1967 it was not.

A medicine in 1978 and an essential one since

The route from Prague to the pharmacy ran through the West. The pharmaceutical company Ferring took the compound forward as a product, and by the early 1970s it was in use in Europe. Clinical studies in the following years described its use in central diabetes insipidus and, from the late 1970s, in certain bleeding disorders where its effect on clotting factors was exploited 23. The United States approved it in 1978. The dated record of those approvals and the clinical literature on them belong to the pharmacology articles, and in keeping with the scope of this site this piece does not describe how the compound is used.

It is today among the medicines on the World Health Organization's Model List of Essential Medicines. That is a reasonable measure of how far the idea travelled: a research result from a state-run institute in a closed country became a standard product in health systems that had no connection with the place where it was invented.

Where the pharmacology articles take over

What remains of the Prague story is institutional. The institute that Šorm founded continues as part of the Czech Academy of Sciences and still describes peptide chemistry among its historic strengths 4. Its Cold War years left a small and distinctive mark on the literature: Eastern European peptide laboratories produced a large share of the analogue work of the 1960s and 1970s, and some of it, like this, reached the world through a handful of well-chosen journals.

For a reader of the research literature, the lesson of desmopressin is one about structure and function. A change of two atoms' worth of chemistry in nine residues can change what a hormone does, how long it lasts, and where it acts. How and why belongs to receptor pharmacology, covered elsewhere on this network. How the idea arrived is covered here, and it arrived from Prague.