Peptide Research Groups in Poland

Peptide Chemistry at the Faculty of Chemistry, University of Gdańsk

Peptide research in Poland commenced in early 50's at the Gdańsk University of Technology by Professor Emil Taschner. He was in fact one of the pioneers of peptide chemistry in Europe, belonging to the very exclusive club of the participants of 1st European Peptide Symposium called Symposium on Methods of Peptide Synthesis, Prague 1958. E. Taschner transferred his passion for peptides onto a group of young graduates of the Technical University of Gdańsk, who in the 60;s founded research groups that continued their mentor's research. Among his successors were the following professors: Andrzej Chimiak (Gdańsk University of Technology) Barbara Rzeszotarska (University of Opole), Teresa Sokołowska (Gdańsk University of Technology) and Czesław Wasielewski (Gdańsk University of Technology). Among his PhD students were also Bogdan Liberek and Gotfryd Kupryszewski who were appointed in 50. at the Higher Pedagogical School in Gdansk which combined with the Higher School of Economics in Sopot in 1970, founding the University of Gdańsk. B. Liberek and G. Kupryszewski established independent groups and focused their interest on peptide chemistry. Initially these operated within the Institute of Chemistry, and since 1991 within the newly-founded Faculty of Chemistry of the University of Gdansk. Till their retirement (B. Liberek in 1996, G. Kupryszewski in 1999) both scientists led respectively the Amino Acids Group and the Bioorganic Chemistry Group. They did not give up research activity as professor emeriti, either. Unfortunately, prof. Kupryszewski's research was terminated by his death last year.

G. Kupryszewski's achievements in the early stage include introducing the method of synthesising peptides using active pentachlorophenyl esters. This method found wide use and constitutes a permanent part of peptide chemistry. Later professor Kupryszewski turned his attention towards biologically-active peptides. At first these were N-acyl derivatives of lysine and ornitine exhibiting antimicrobial activity, analogues of thyrotropin releasing hormone (TRH), opioid peptides (enkephalins, kyotorphins, casomorphines) and analogues of tissue hormone angiotensin II. In the 80's and 90's professor Kupryszewski's interest started to include larger peptides of more complex structures, like cholecystokinine, gastrine, arginine vasopressine analogues, galanin and its analogues, immunoactive peptides, serine proteinase inhibitors or the plant peptide hormone systemin. G. Kupryszewski was also the organizer of the First National Conference "Chemistry of Amino Acids and Peptides" in Gdańsk in 1967. In time these conferences turned into Polish Peptide Symposia held regularly every two years. The next one, 19th eptide Symposium, will take place in Warsaw in 2007 and will be organized by professors Aleksandra Misicka and Andrzej Lipkowski.

18PPS Among the more important achievements of B. Liberek one should note the halolysis reaction for selective cleavage of the ester group using lithium halogenides, discovered in the late 60's. Of high acclaim is his later research in mechanisms of side reactions in peptide synthesis, in particular of dehydratation of amide group to nitrile group in asparagine and glutamine moieties. Bogdan Liberek investigated and proposed a detailed mechanism of racemisation of amino acid moieties by direct α-hydrogen abstraction. He also dealt with Z-E isomerism in N-nitroso-N-alkylamino acids and their derivatives.

Scientific achievements and respect of both researchers in the scientific society caused many talented young scientists to gather around them. Some of them passed all the steps of scientific career, winning professor titles. In Professor G. Kupryszewski's group these were: Bernard Lammek, Krzysztof Rolka, Zbigniew Maćkiewicz, Piotr Rekowski. Professor B. Liberek's successors are: Zbigniew Grzonka, Jerzy Ciarkowski, Leszek Łankiewicz and Franciszek Kasprzykowski. With the exception of the deceased L. Łankiewicz the others are leaders of research groups with main research interests focused on widely-understood investigation of biologically-active peptides, creating the strongest peptide research centre in Poland. At the same time this is the most strongly represented field of research at the Faculty of Chemistry of the University of Gdansk. Research areas of the individual teams are detailed below.

The research activities of Bernard Lammek group are broadly concentrated in two areas. The first one is centered on synthesis and pharmacological evaluation of new analogues of bradykinin and neurohypophyseal hormones (arginine vasopressin and oxytocin). He has provided useful information about structure-activity relationships and opened up new possibilities for designing potent agonists or antagonists. The other part of his group is focused on conformational studies of previously synthesized, biologically-active peptides using e.g. two-dimensional Nuclear Magnetic Resonance (2D NMR), Raman Spectroscopy (RS), Surface-Enhanced Raman Spectroscopy (SERS), as well as theoretical calculations. Theoretical calculations are based on quantum mechanics and molecular dynamics calculations in vacuo and in explicit full-atom solvation models. These cover receptor-ligand and receptor-cellular membrane interactions – possibly allowing for predicting the properties of new hormone analogues before theis synthesis and clinical tests. Because of the additive character of scientific approaches to the same technological problem, there is constant cooperation between these two groups in all possible fields of research.

The research of Krzysztof Rolka's group is focused on synthetic inhibitors and substrates of serine proteinases. Initially, the leading structures for designing new inhibitors were low-molecular-weight inhibitors isolated from the seeds of the Cucurbitaceae family: CMTI (trypsin inhibitors isolated from pumpkin) and EETI-II (trypsin inhibitor isolated from jumping cucumber). More recently they have chosen as a starting structure the amino acid sequence of trypsin inhibitor SFTI-1 isolated from the sunflower seeds. Such investigations, carried out for years, led to discovering potent and selective inhibitors of trypsin, chymotrypsin and elastase. Some of these synthetic peptides belong to novel classes of serine proteinase inhibitors. A part of this long-term project is devoted to the design and synthesis of chromogenic substrates of serine proteinases. These investigations are carried out using both the classical approach and combinatorial chemistry methods. It is also worth to mention the other objects of this research group: neuropeptides such as opioids, tachykinins, nociceptin and its analogues and fragments of prion protein. This research includes both chemical synthesis of suitable analogues and determining space structures in solution of peptides exhibiting interesting pharmacological profiles.

The main interest of Zbigniew Maćkiewicz is the application of synthetic peptides in immunological investigations. The goal of this work is to develop synthetic vaccines and diagnostic tests. The objects of these studies are fragments of Hepatitis C Virus (HCV) proteins. More recently he turned his interest towards peptides with antimicrobial activity, such as histatin-5, statherin and parathormon. The analogues of these naturally-occurring polypeptides synthesized by his group are then evaluated for antimicrobial and immunogenicity activity in cooperation with biology groups.

Piotr Rekowski with his group designs and synthesises biologically-active peptides and their analogues: neuropeptides (galanin, P substance, and vasopressin) and the plant hormone systemin. A new area of research is interaction of peptides and proteins with nucleic acids (interaction models: zinc fingers from TFAIIIA transcription factor with 5S RNA, Tat protein of HIV-1 with TAR, peptides selected from a phage library with modified RNA fragments). Rekowski also began synthesizing nucleoside- and nucleobase-containing amino acids (NBAs) with the aim of researching peptide – nucleic acid interactions. Investigations of interactions of peptides and proteins with nucleic acids saw the marked presence of Piotr Mucha, who worked out an efficient method of analyzing protein – nucleic acid complex formation using capillary electrophoresis.

Professor Liberek's group was the place where the scientific activity of Zbigniew Grzonka, rector of the University of Gdansk in years 1990-1996, started. In the 60's and 70's Grzonka investigated the synthesis of nitrile-group-containing amino acids and peptides, as well as tetrazole mimetics of amino acids and peptide analogues containing them. In the 80's Grzonka's group participated in SAR investigations of biologically-active peptides: vasopressin, oxytocin, enkephalins, dynorphins and angiotensin. The 90's till now saw the gradual shift towards more complex problems like: lysosomal catepsin inhibitors, investigating the molecular mechanisms of Alzheimer's disease, searching for inhibitors of cystatin C oligomerisation, investigating the molecular mechanism of Finnish amyloidosis – creation of amyloid fibriles originating from gelsolin. Professor Grzonka's pupils – Leszek Łankiewicz and Franciszek Kasprzykowski – actively co-created the group's record in the area of chemistry of amino acids and peptides. The late Leszek Łankiewicz worked in assymetric synthesis of non-protein amino acids. At the moment the group is led by Franciszek Kasprzykowski, who continues the research directions. Kasprzykowski is involved in designing, synthesising and investigating the activity of azapeptide inhibitors of cysteine proteases and of copounds exhibiting anti-microbial activity. He has recorded great achievements in quantitative analysis of peptide mixtures using chromatography methods.

Within professor Grzonka's group there is independent research being conducted by Wiesław Wiczk. His activity is focused on physicochemistry of amino acids and peptides, including: synthesis and photophysical analyses of 3-(benzoksazol-5-yl)alanine, investigation of protein structures using Fluorescence Resonance Energy Transfer (FRET), investigation of inclusion complexes of amino acids and their derivatives as well as of peptides with cyclodextrins.

In the 70's in professor Liberek's group began the scientific activity of Jerzy Ciarkowski, who at first dealt with stereochemical aspects of N-alkyl-N-nitrosoamino acids, and in the 80's assembled databases for determining cyclodipeptide conformations. The last decade of his scientific activity involved application of molecular mechanics and molecular dynamics for investigating peptide and protein conformations, including uncovering the mechanisms of activation/inhibition of G Protein-Coupled Receptors (GPCR), which is the key to rational drug design.

In the late 80's in professor Ciarkowski's group theoretical studies of peptide and protein chemistry were undertaken by Adam Liwo. He deals with theoretical analysis of conformations of neurohypophyseal hormones employing molecular fields. Of great import is his method of searching the conformation space for forecasting the space structure of proteins on the basis of their amino acid sequences employing empirical force fields.

The last thirty years of peptide chemistry at the University of Gdansk can be circumscribed with a "symposium brace". In 1978 professor Gotfryd Kupryszewski organized the 15th European Peptide Symposium, which took place in Gdansk. About 150 peptide chemists participated, mostly from Europe and the USA. In September 2006 we, the pupuils of professor Kupryszewski, will be co-organizing the 29th European Peptide Symposium. We fervently hope that we will be able to greet in Gdansk as many colleagues – the participants of the 15th EPS from 28 years ago – as possible.

Contributed by Piotr Rekowski and Krzysztof Rolka