Creation of New Antiviral Agents
Creation of New Antiviral Agents on the Basis of Substances Controlling Free-Radical Processes in Biosystems
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
- CHE-RAD/Photo and Radiation Chemistry/Chemistry
- CHE-SYN/Basic and Synthetic Chemistry/Chemistry
3 Approved without Funding
Belarussian State University, Belarus, Minsk
- Belarussian Research Institute for Epidemiology and Microbiology, Belarus, Minsk
- Consiglio Nazionale delle Ricerche / Istituto per la Sintesi Organica e la Fotoreattivita, Italy, Bologna\nFaculty of Chemistry and Mineralogy, Research Unit "Time Resolved Spectroscopy", Germany, Leipzig\nLudwig-Maximilians-Universität / Strahlenbiologisches Institut, Germany, Munich\nUniversitatsklinikum Jena, Germany, Jena\nUniversitat Leipzig / Institute of Medical Physics and Biophysics, Germany, Leipzig\nYork University, Canada, ON, Toronto\nUniversity of Kyoto/ Kinski Invention Center, Japan, Kyoto
Project summaryPurpose of the Project.
Development of new approaches to creation of antiviral medications prospective for introduction in medical practice on the basis of substances controlling the course of free-radical processes in biosystems.
Modern approaches to the development of novel antiviral agents are based on information about deep-seated virus-cell interaction processes and on biochemistry of the animate nature. A substantial number of antiviral agents effective against the most widespread infections (herpes, hepatitis, HIV) are represented by compounds of the nucleoside series [E. De Clercq (1997). In search of a selective antiviral chemotherapy. Clin. Microbiol. Rev. 10 (4), pp. 674-93]. Such substances, along with inhibitory action on viruses, can produce undesirable side effects due to possible negative influence on genetic system of a host cell. In this connection, stages of virus-cell interaction which are not directly coupled with the processes of coding and realization of viral genetic information appear to be very attractive for obtaining inhibitory effects on the virus reproduction cycle. Data are available in the literature indicating that free-radical reactions play an important role in realization of such stages [B.Halliwell and J.M.C.Gutteridge (1999) Free Radicals in Biology and Medicine. 3th Ed., Clarendon Press, Oxford].
Studies in the area of free-radical virology started relatively recently. However, it is already known that generation of reactive oxygen species (ROS) and activation of lipid peroxidation (LPO) processes accompany the course of various viral infections, including those caused by rhinovirus, HIV, cytomegalovirus, influenza and various neuroviruses, and chronic viral hepatitis viruses. Within recent years, a number of clinical and experimental investigations have been carried out providing evidence of expediency of including antioxidants into the collection of means for therapy of viral pathologies [B.Halliwell and J.M.C.Gutteridge (1999) Free Radicals in Biology and Medicine. 3th Ed., Clarendon Press, Oxford]. Nevertheless, the knowledge accumulated thus far does not permit to establish a correlation between antioxidant properties of substances and their antiviral activity. Difficulties in finding such a correlation arise from an ambiguous role of free-radical processes in the development of viral pathology. This is due to the fact that most of ROS reactions have a non-selective character, so their realization can cause damage to both viruses and healthy cells. For this reason, the issue as to which substances being introduced into biosystems could alter the course of free-radical reactions in favour of antiviral effects remains undecided. One of the possible approaches to the solution of this problem can be investigation of free-radical processes effectively taking place on the surface of cell membranes, where initial and final stages of virus reproduction cycle are known to proceed.
Studies performed by the Project participants [O.I.Shadyro (1997) Radiation-induced free-radical fragmentation of cell membrane components and the respective model compounds. In Free Radicals in Biology and Environment, Ed, F.Minisci, Kluwer Academic Publishers, Netherlands, pp.317-329; S.N.Muller, R.Batra, M.Senn, B.Giese, M.Kisel and O.Shadyro (1997), Chemistry of C-2 glycerol radicals: indications for a new mechanism of lipid damage, J.Am.Chem.Soc. 119, pp.2795-2803. O.I.Shadyro et al. (1997) The damage to phospholipids caused by free radical attack on glycerol and spingosine backbone. International Journal of Radiation Biology, 71, pp.555-560. O.I.Shadyro, I.L.Yurkova and M.A.Kisel (2002) Radiation-induced peroxidation and fragmentation of lipids in a model membrane. International Journal of Radiation Biology, 78, pp.211-217] revealed that in the course of interaction of active radical intermediates with lipids, carbohydrates, peptides, etc., free-radical fragmentation reactions are possible involving formation of carbon-centered radicals which produce destructive changes in biologically important compounds. In the case of lipids, the reactions take place in their hydrophilic sphingosine or glycerol moieties. Realization of processes of such kind can lead to dramatic biochemical and biophysical consequences ranging from alterations in barrier properties of biomembranes up to formation of apoptosis-inducing molecules.
It has been found [O.I.Shadyro et al. (2002) Quinones as free radical fragmentation inhibitors in biologically important molecules. Free Radical Research, 36 (8), pp.859-867] that quinone derivatives are efficient inhibitors of fragmentation, themselves being reduced in the course of their inhibitory action to semiquinone radicals. The latter are known to participate, depending on the respective structure, in generation or deactivation of such ROS as superoxide anion-radical (·O2-). Hence, quinones or substances disposed to form quinoid structures can control probability and final results of various free-radical reactions in biosystems.
Impact of the proposed project on the progress in the development of new antiviral agents. A substantial progress can be achieved by conducting the search among compounds capable of forming diphenol-quinone or aminophenol/quinonimine systems, and hence inhibiting the processes of fragmentation and peroxidation of cell membrane components, and forming, at the same time, intermediates being ROS generation regulators. Substantiation of this can be found in preliminary data obtained by the Project participants in cell cultures where evidence has been found of existence of substances among diphenol and aminophenol derivatives actively suppressing reproduction processes of influenza and herpes viruses. The same substances inhibit free-radical reactions proceeding in biosystems with participation of oxygen- and carbon-centered radicals.
The Project Participants.
Belarussian State University (BSU) and State Institution - Research Institute for Epidemiology & Microbiology (SI RIEM) of the Belarus Ministry of Health.
Researchers from BSU who will participate in the Project implementation have large experience in the area of free-radical chemistry and in synthetic organic chemistry. Their scientific activity is associated with determining the role of free-radical fragmentation reactions in cell membrane component damage, as well as with targeted synthesis of efficient inhibitors of various homolytic processes and investigation of physico-chemical and medico-biological properties of such inhibitors.
The team of participants from the part of SI RIEM has a more than twenty-year experience in studies of novel substances with anticipated antiviral properties, and in development of new antiviral medications. The team took part in implementation of a number of closed integrated scientific projects formerly financed by the Defense Ministry of the USSR which dealt with synthesis, pilot manufacture and investigation of antiviral properties of compounds active against viral infectious pathogens potentially applicable in bacteriological weapons.
The Project Manager is a leading specialist in the area of radiation chemistry and free-radical chemistry. He worked in many laboratories of the world (Basel University, Switzerland; University of Illinois, USA, a.o.) and has established good contacts with foreign scientists. He has experience of management in conducting integrated studies on creation of novel medications.
Anticipated results and their scientific novelty.
In the course of the Project implementation, eight tasks are to be performed, and the following results obtained:
– Development samples of diphenol and aminophenol derivatives, as well as complex compounds on their basis will be prepared.
– Structures, molecular masses, melting and boiling points, and redox potentials of the synthesized compounds will be determined.
– Anti-radical properties will be investigated in chemical and biological models.
– Antiviral activity will be investigated with respect to:
– herpes simplex virus;
– influenza virus;
– Interrelations of structure and physico-chemical, anti-radical and antiviral properties of the synthesized compounds will be determined.
The project implementation will result in development of new approaches to inhibition of viral reproduction. On this basis, targeted synthesis of compounds with antiviral properties and a potential for application in medical practice will be performed.
These results will have a significant impact on the development of a new scientific trend formed at the boundaries of chemistry, biology and medicine, and relating to determination of the role of free-radical processes in normal or pathological condition of an organism. For the first time, a substance class will be found capable of modifying the realization probability of free-radical processes taking place with participation of carbon-centered and oxygen-centered radicals in both lipophilic and hydrophilic moieties of the cell membranes. The data obtained will enable scientists to develop regulation principles of free-radical reactions responsible for the beginnings of various pathological states of an organism, including virus-induced pathologies. Hence, a basis will be created for extending the market of antiviral medications with an original action mechanism, capable of overcoming drug resistance of prevalent infection pathogens towards current medications and enhancing efficacy of the latter. The intellectual property resulting from the project implementation will be liable to legal protection and protected by patenting.
Application of results of the Project follows from the anticipated creation of efficient and commercially profitable antiviral agents. Later on, manufacture of various antiviral medications is planned on their basis. Quite probably, the substances capable of controlling free-radical reactions proceeding at the interface of two phases may have, besides the antiviral properties, many other useful qualities, the most interesting of which are immuno-modulating, wound-healing and radiation-protecting activity. This opens up possibilities for the development of medical products urgently need for the population of territories affected by the Chernobyl disaster. The development of new medicines on the basis of synthesized compounds will result in creation of products competitive on the world market.
The project results could be used by scientists and scientific institutions of the world’s leading countries as new scientific information that broadens modern concepts about the role of free-radical processes in the development of viral infections. Moreover, the data obtained will be of interest to pharmaceutical companies, of CIS countries first of all, because they will allow them to broaden the range of products offered and to enrich substantially the present-day market of antiviral medications.
It should be noted that the cooperation between BSU and SI RIEM researchers has already resulted in creation a new antiviral medication effective against herpes infection marketed under the name of Butaminophen.
Meeting ISTC Goals and Objectives.
In the course of the Project implementation, the following principal tasks will be performed complying with goals and objectives of ISTC:
– the scientists formerly engaged in military-oriented research will now be involved in solving a purely humanistic problem - creation of new medications;
– the experimental results obtained will promote integration of researchers of the Republic of Belarus into the world scientific community, because these results will be obtained in cooperation with foreign specialists in the areas of free-radical biology and medicine;
– the project implementation will contribute to solving national and international scientific and technical problems associated with creation of new medical products;
– antiviral agents developed in the course of the project implementation will be of interest to pharmaceutical industry. Sale of licences associated with the “know-how” used in the search for new pharmacologically active substances, as well as of licences for syntheses of such compounds, will contribute to the development of market economy, enabling the project participants to find a purchaser of the technology and to become a self-financed entity;
– introduction of the developed antiviral products into medical practice will enable millions of dollars to be saved for Belarus. At the same time, the Project investor will enjoy a privileged status in obtaining licences for manufacture of the new antiviral products.
The Project Effort.
The tasks planned in the framework of the Project are of a multiline nature and require extended studies to be performed in such areas as targeted synthesis of a large number of derivatives of diphenols, quinones and related compounds, and investigation of their physico-chemical, antiradical and antiviral properties. This work will be performed by the research teams from both BSU and SI RIEM.
The Project duration is 3 years. The total effort on the Project will be 626 person/months.
Synthesis and preparation of development samples of diphenol and aminophenol derivatives, including complex compounds on their basis, and investigation of physico-chemical and anti-radical properties of the synthesized compounds and polyphenol compounds of natural origin in chemical and biological models will be performed by the BSU research team.
Investigation of antiviral properties of the synthesized compounds and polyphenol compounds of natural origin with respect to herpes, influenza, enteroviruses and HIV will be performed by the research team of SI RIEM.
The task of determining interrelations of structure, physico-chemical, antiradical and antiviral properties of the substances studied will be fulfilled by joint effort of BSU and SI RIEM researchers.
The Role of Foreign Collaborators.
During the period of Project implementation, foreign collaborators will be involved in the following activities:
– information exchange;
– participation in joint workshops and conferences;
– carrying-out joint scientific research.
Technical Approach and Methodology.
The approach used for implementation of the Project is a systematic and targeted realization of research experiments enabling cause-effect relations to be determined between structure, physico-chemical and antiviral properties of the compounds studied. Preliminary results are already available indicating that there are compounds among diphenol and aminophenol derivatives that suppress effectively influenza and herpes viruses. These compounds modify the course and probability pattern of various free-radical processes.
Technical solution of the problems will be ensured by involving up-to-date synthetic methods, as well as by using physico-chemical methods of investigation of free-radical processes (chromatography, ESR-spectrometry, mass spectrometry).
Studies of antiviral properties will be performed in experiments on monolayer cell structures with viruses of herpes and influenza, enterovirus and HIV. Substances manifesting the most pronounced antiviral properties in cell cultures will also be tested under conditions of experimental viral infections in laboratory animals. Standard methods of determination of antiviral properties will be used, certified by Belarus National Agency of Standards, and officially authorized for SI RIEM.