Objective
A.GENERAL BACKGROUND
A1:Why a COST action on this topic?
As a result of the fact that every year more biological processes can be described in terms of molecules and molecular interactions, the importance of bio-organic studies for understanding health problems and drug development is steadily increasing. The result of this development is, amongst others, that interactions of bio-organic chemists with other scientists like biochemists, biologists and pharmacologists are becoming more and more intensive. In view of the scope of the field, international contacts are of vital importance, not only between academic groups, but also with appropriate R&D groups of (pharmaceutical) industries. Especially after the initial stages of research, development of useful new medicines means that the input of industrial know-how is indispensable. On the other hand, an important part of fundamental biochemical research should be carried out at universities, since for the pharmaceutical industries objectives are sometimes different from those of academic institutions. Industrial considerations are based on expected financial return on investments, which limits research interests for instance for low-incidence health disorders.
Owing to its multidisciplinary character, bio-organic chemistry would gain substantially from a European cooperation, since in one country scientists could not cover all relevant topics essential for adequate understanding of the complex principles, and for effective assistance to pharmaceutical industry in drug discovery and development and for other medicinal applications.
Although every research group in the field of bio-organic chemistry or pharmaco-chemistry has its own international contacts, a broader platform for discussions is essential for a multidisciplinary approach for urgent world-wide problems.
In view of the international recognition of bio-organic chemistry in the last ten years, a COST Action dealing with bio-organic chemistry for human health care is not only essential for scientific progress, but will also be beneficial for human health in the near future. The fact that COST recognition of a research group in a network can be used as an argument in some countries to obtain research funds, will be very important for stimulation of bio-organic research, directed towards development of new generations of drugs for very serious medical problems.
A2:Status of Research in the Field
Bio-organic chemistry is an extensive and expanding research area and has become very important for our understanding of the function of natural products and for the interaction of organic compounds with living organisms. The following list of recent research topics attempts to mark the boundaries of bio-organic chemistry in the context of this Action:
Studies on enzyme reaction mechanisms including recognition, activation and inhibition phenomena.
Molecular aspects of receptor mechanisms, including modelling, and control of life processes.
Investigation of biological activity of natural products (and synthetic analogues) which may be "lead substances" for new pharmacologically useful products.
Studies on neurodegenerative processes in order to allow new insight into the mechanism of ageing of neuronal functions.
Molecular approach for studies of antibodies in order to understand the complex of immune response and for applications of antibodies in catalysis and drug design.
Research on antisense oligonucleotides paves the way to introduce new concepts into drug discovery.
Research of pro-drug systems. Investigation of enzymatic and non-enzymatic transformations of compounds in vitro and in vivo.
The fact that approaches to the solution of many health problems fall within the field of bio-organic chemistry shall be highlighted. This may be illustrated by a few examples:
Studies of inhibition of typical bacterial or viral (encoded) enzymes for new approaches of chemotherapy. Inhibition of transpeptidase by penicillins and cefalosporins of different generations has been so successful during the last 50 years, that potential treatment via different types of inhibition of other bacterial enzymes has probably been underdeveloped. In fact, even the approach of overcoming resistance by combining penicillins with lactamase inhibitors is the result of rather traditional thinking. Thanks to a better understanding of molecular mechanisms and the development of new classes of enzyme inhibitors, total new approaches to selective attack of bacteria via enzyme inhibition must be possible. Since bacteria and viruses also affect plants or host micro-organisms, also natural product chemistry can again be of vital importance in the field of discovering and studying new antibiotics, based on new molecules produced by species for their own protection against bacteria. Treatment of malaria with herbs by traditional healers requires more attention and serious studies, possibly resulting into new lead compounds, comparable to Artemisinine, developed from Artensia annua in the 80's. The fact that traditional medicines have been "tested" on human beings, sometimes for centuries, gives them a clear advantage over newly developed drugs (if they are found active in test systems or double blind studies).
With respect to prions, questions exceed the answers by enormous factors. Bio-organic groups with expertise on protein-protein interactions or protein-(ant)agonist interactions should be capable of devising molecules which must be able to block essential functions on prions, thus inhibiting their multiplication via interaction with prion precursors. Although the size of this threat to human health is still unclear, studies toward prion-drug interactions should constitute an important part of bio-organic efforts as soon as possible.
Although information on multi-drug resistance of cancer cells is steadily increasing, the role of bio-organic chemists in studying the interaction with the different pumping mechanisms is still very important. Also membrane studies can play an essential role in this field, sometimes in combination with the development of suitable prodrugs, as has been shown in all cases of treatment of animals and human beings with drugs.
Nucleic acid studies and the development of appropriate anti-sense oligonucleotides (which can play an important future role in so many subjects) might also be of vital importance in studying this problem.
Due to the (chemical) complexity of the CNS, treatment of diseases such as depression, Alzheimer's disease, Parkinson's disease, anxiety, migraine etc. remain difficult to treat effectively. The amount of neurotransmitters, receptor families and other molecules that play a role in the brain is increasing every day. Although fundamental studies thus become more and more promising, bio-organic efforts towards new drugs are often based on an already existing lead compound.
Both immunodeficiency and immuno response against "own" cells and other parts of the body are the cause of a vast amount of health problems. In the first category we find amongst others AIDS and insufficient control of Herpes viruses like Varicella Zoster, which leads to shingles. The amount of patients in the second group is even larger, with asthma, rheumatoid arthritis and multiple sclerosis as the main problems. Further fundamental studies towards the mechanism of action of the immune response are therefore essential for contributing to the treatment of health problems of many individuals.
Problems related to the immunological systems are common for various diseases like cancer, allergy, rheumatoid arthritis, wound-healing, various illnesses related to old age etc. A lot of the drugs available today have many side effects which are undesirable. It is of importance to find new compounds that can be leads for future drugs, and these can be found especially from natural sources like plants, algae, micro-organisms etc. that will have a better potential for stimulation of the immune system without side-effects.
A3:Relationship with other National European and international programmes
The established importance of bio-organic chemistry as a science and for human health stimulated the Organic Division of IUPAC to install a separate Bio-organic Committee in 1994. It is expected that in the near future the name of the Division will be changed into: "Division of Organic and Bio-organic Chemistry".
This development has resulted in a series of "IUPAC Symposia on Bio-organic Chemistry", ISBOC 4 being held in Biarritz, France, 1997. Previous conferences: Dagomyz, USSR, 1995, Fukuoka, Japan, 1993, New York, USA, 1985.
As to our knowledge at present, there exists no European programme devoted to the research in bio-organic chemistry.
The scientific developments described above have been partly covered by the previous COST Actions D2 "Selective Synthesis" (17 working groups involving 84 research teams) and D7 "Molecular Recognition" (10 working groups and 36 laboratories). Both of these actions ended in September 1997.
The future COST Action D13 will complement COST Action D8 "Chemistry of Metal in Medicine" (13 work groups, 102 research teams) and the recently launched COST Actions D11 "Supramolecular Chemistry" and D12 "Organic Transformations: Selective Processes and Symmetric Catalysis".
This complementarity of activity seems necessary due to the fact that bio-organic chemistry covers many more chemistry areas than those of the existing COST Actions. The description of a biological process in molecular terms is the start of a chain, leading to new molecules active biologically, after which molecular recognition might play a role in describing the interaction of target molecules with biopolymers like receptor proteins and nucleic acids.
This new COST Action D13 will permit, via joint research cooperation, the coordination of most European national efforts and programmes for bio-organic chemists. Fields of special interest are bio-organic chemistry studies on interactions to obtain a better understanding of the behaviours of prions in the areas of BSE (mad cow disease) and CJD (human Creuzfeld-Jacob Disease).
It is also to be stressed that this COST Action would fit very well within the 5th EC Framework Programme, where the first activity of the scientific and technological objectives comprises amongst others: The living world and the ecosystem, II and III: "Control of viral and other infectious diseases" and "The cell factory, antibiotics and anti-cancer agents", respectively.
B.OBJECTIVES OF THE ACTION
The main objective for the present COST Action is binding together established sciences of chemistry, biochemistry, biology and pharmacology and, by doing so, the new Action should develop knowledge relationships between the molecular structure and the biological activity of organic compounds including natural products.
This Action will stimulate the establishment of European research networks and contribute to provide the basis of knowledge for advanced applications in the pharmaceutical industry. The expected results are of high economic, industrial, social, and educational value. Understanding the chemistry in biological processes is central to this programme.
C.THE SCIENTIFIC PROGRAMME OF THE ACTION
As outlined in part A2, bio-organic chemistry is an extensive and expanding research area. The working groups (research networks) of this Action shall emerge from the abovementioned research topics.
Summarising these topics we can formulate five broad lines of research, which might describe the scientific scope of the COST Action:
1.Microbial resistance and its dramatic effect on bacterial infections like tuberculosis and staph. aureus infections, on viral infections like AIDS and herpes and on protozoa like plasmodium, responsible for malaria, e.g. development of new enzyme inhibitors and studies of natural products and their synthetic analogues to obtain new lead compounds for evaluation as drugs.
2.The stability and properties of prions and their role in BSE and CJD, i.e. e.g. bio-organic studies in the field of protein interactions to obtain a better understanding of the way prions behave.
3.Multidrug resistance of anti-cancer chemotherapeutic agents, e.g. development of new cytostatics.
4.Effective treatment of disorders of the Central Nervous System, e.g. development of new molecules for the study of the receptors of different neurotransmittors.
5.Fundamental bio-organic studies at a molecular level directed towards the functioning and disorders of the immune system.
6.Membrane studies in order to clarify many of the aspects of the topics 1. to 5.
7.New compounds with effect on the immunological system.
D.ORGANISATION AND TIMETABLE
D1:Organisation
The Management Committee of the Action will be responsible for:
stimulating and selecting the submitted working group proposals;
drawing up an inventory of research groups working in the field in the participating COST countries during the first year;
organising workshops;
coordinating activities with other COST Actions (joint meetings are likely to result from this activity);
exploiting wider participation and exchange of information with other fora (EC, ESF, CEFIC, etc.) as well as contacts to relevant industries;
establishing the intermediate report, the final report, and the concluding symposium.
The main part of the Action will be formed by working groups (collaborative research networks). They will be submitted by individual research teams and will be selected by the Management Committee. A working group shall consist of partners from at least 3 different COST countries. The successful working groups will be selected according to the subtopics described in section C.
The coordination of research shall be facilitated through annual workshops as well as working group seminars. A close collaboration with (pharmaceutical) industry will be essential for the success of this Action.
D2:Timetable
A 5-year programme is proposed consisting of 4 stages (each of 1-3 years).
Stage 1:After the first meeting of the Management Committee a detailed inventory of ongoing research and existing plans of the participating groups to begin joint projects will be made. This will result in a discussion document which will allow further planning to occur.
Stage 2:This stage will begin at the end of the first year. Then it will be evident which working groups are closely related and would benefit from joint activities. Researchers will set up (and continue) joint collaborative networks, and exchange their recent research results.
Stage 3:An intermediate progress report will be prepared after 3 years for review by the Technical Committee.
Stage 4:The final phase (after 4 years) will involve evaluation of the results obtained? It may include the organisation of a symposium for all the participants and co-workers.
E.ECONOMIC DIMENSION
20 countries have participated in the preparation of the Action or otherwise indicated their interest: Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Netherlands, Norway, Portugal, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom.
The overview given below represents a rough estimate of current research in some of the countries having participated in the preparation of this Action:
Greece:About 12 groups involved in this type of work with about 22 graduate students, 22 university professors and research scientists. Very approximately the involved funds amount to ECU 0,9 million/year.
Ireland:6 groups, totalling 10 scientists, including postdocs. Budget approximately ECU 0,5 million/year. Contacts with pharmaceutical industries represent approx. 20% of the budget. Total ECU 2 million/year.
Netherlands:15 academic groups, 2 industry undertakings; annual budget: research funds: ECU 1,5 million, labour input: ECU 2,5 million.
Norway:Academia: 3 groups, totally including 12 scientists, budget of approximately ECU 0,7 million/year. Industry: activities within some of the minor pharmaceutical and nutritional industries.
Portugal:Number of groups: 7. Number of permanent people: 18; PhD students: 15. Industry: 3 Portuguese pharmaceutical companies are doing R&D in this field. Research funds (no labour costs): ECU 480 000/year.
Slovenia:5 research groups with 10 full-time scientists, about 10 under-graduate students, 7 PhD students and 2 postdocs. The research budget amounts to ECU 300 000/ year (exclude salaries). Collaborations with pharmaceutical companies exist.
Sweden:Universities and academic institutions: 6 groups (25 scientists including graduate students). Annual research budget estimated at ECU 1,2 million; extensive activities in the pharmaceutical industry.
Extrapolating these figures to all 20 countries, the overall research funding of activities coordinated by this Action can be estimated at ECU 10 million.
F.DISSEMINATION OF SCIENTIFIC RESULTS
All publications arising from research carried out under COST Action D13 will credit COST support and the Management Committee will promote all co-authored papers.
Results of research carried out by the working groups under COST Action D13 will be submitted to international scientific journals and reviews (particularly in the field of bio-organic chemistry).
Joint meetings among different working groups in COST D13 and with working groups from other COST Actions will be organised in such a way as best to promote interdisciplinary communication.
The Management Committee (MC) will, in conjunction with the working groups (WG) of the Action, organise one meeting every year with the aim of presenting results to the MC as a whole and, where possible, the MC will invite potential users and interested parties to this meeting, and to set up a work plan for interdisciplinary events for the dissemination of results of the Action.
Programme(s)
Topic(s)
Call for proposal
Data not availableFunding Scheme
Data not availableCoordinator
Netherlands