New Antiviral Agents
Development of Effective Antiviral Agents of a New Type
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
- CHE-RAD/Photo and Radiation Chemistry/Chemistry
- CHE-SYN/Basic and Synthetic Chemistry/Chemistry
8 Project completed
Senior Project Manager
Gremyakova T A
Belarussian State University, Belarus, Minsk
- Belarussian Research Institute for Epidemiology and Microbiology, Belarus, Minsk
- Robert-Koch-Institute, Germany, Berlin\nUniversitat Leipzig / Institut fuer Medizinische Physik und Biophysik, Germany, Leipzig
Project summaryThe Project goal is the development of effective antiviral agents of a new type, prospective for introduction into medical practice.
The problem setting.
The capability of viruses to acquire resistance towards action of drugs determines, under many aspects, the need for development of new effective antiviral agents with a specific, non-conventional mechanism of action.
Modern methods used in the development of new antiviral agents are based on information about the virus-cell interactions and regularities in biochemical processes that form the basis of vital functions. The main feature of the most effective inhibitors of various viral infections (herpes, influenza, HIV) is the possibility of their involvement in inhibition of some key ferments responsible for virus replication E. De Clercq (1997). In search of a selective antiviral chemotherapy. Clin.Microbiol.Rev. 10(4), pp.674-930]. However, these agents have, along with the useful virus-inhibiting properties, some undesirable side effects due to their potential of affecting the genetic machinery of the host cell. In this connection, it seems promising to perform the search for substances capable of inhibiting the virus replication in the stages not involved in processes of encoding and realization of genetic information of viruses. Such properties can belong to compounds capable of regulating the probability and directivity of free-radical processes occurring in biosystems.
Studies in the area of free-radical virology have started in relatively recent times, but it has already been shown that various viral infections (e.g. caused by rhinovirus, HIV, cytomegalovirus, influenza virus, and various neuroviruses) are accompanied by production of reactive oxygen species (ROS) and activation of lipid peroxidation (LPO) processes [B.Halliwell and J.M.C.Gutteridge (1999). Free Radicals in Biology and Medicine. 3-th Ed., Clarendon Press, Oxford]. Nevertheless, the information available to-date does not allow a correlation to be found between effects of substances on free-radical processes and antiviral activity. The complexity in establishing such relationships is due to an ambiguous role of free-radical processes in the development of viral pathology. This is associated with the generally non-selective character of ROS reactions, which can cause damage to both viruses and healthy cells. Therefore, at present, one cannot answer the question: what substances should be introduced into a biosystem in order to change the directivity of free-radical reactions in such a way that a predominantly antiviral effect is achieved. The search for such substances is the main task of the proposed Project. That the above mentioned task is realizable is confirmed by preliminary data obtained by the Project participants in cell cultures demonstrating that there are substances among derivatives of diphenols and aminophenols that effectively inhibit reproduction processes in viruses of herpes, influenza and HIV. The Project participants have discovered also that the named substances inhibit various processes in biosystems while being able to activate the production of ROS.
The influence of the proposed Project on the progress in the area of development of new antiviral agents consists in discovering viral infection inhibitors with a new mode of action, based on regulation of free-radical processes in biosystems.
The Project implementation will result in the development of novel effective, non-toxic and inexpensive antiviral agents, prospective for introduction into medical practice.
The Project participants.
Belarusian State University (BSU) and State Institution - Research Institute for Epidemiology and Microbiology of the Ministry of Health (SI RIEM).
The researchers from BSU taking part in the Project implementation have wide operational experience in the fields of synthesis and testing of antioxidants and stablilizers for materials used in armaments technology. At present, their scientific activities are focused on targeted synthesis of efficient inhibitors of various homolytic processes and investigation of physicochemical and medico-biological properties of these inhibitors.
The participant team from SI RIEM has more that twenty-year experience in studying new substances with potential antiviral properties, and in development of new antiviral drug products. In the past, this team took part in implementation of a number of classified integrated programs financed by the Ministry of Defense of USSR, associated with synthesis and investigation of antiviral properties of some organic compounds towards viral infectious agents that could potentially be used in bacteriological weapons.
The Project Manager is a leading specialist in the field of radiation chemistry and free radical chemistry. He worked in many scientific laboratories of the world (the University of Basel, Switzerland; the University of Illinois, USA; the University of Leipzig, Germany) and maintains close scientific contacts with foreign researchers. He has experience in guidance and conducting integrated studies aimed at the development of new drug products.
Expected results and their scientific novelty.
In the course of fulfillment of the four Project Tasks, the following results will be obtained:
· experimental samples of diphenol and aminophenol derivatives will be synthesized and their physicochemical properties investigated;
· reactivity of the synthesized compounds towards various radicals will be studied in chemical and biological models;
· antiviral properties of the synthesized compounds towards herpes simplex virus, influenza virus and HIV will be investigated;
· interrelations of structure, anti-radical and antiviral properties of the synthesized compounds will be discovered.
Scientific significance of the Project consists in relationships to be discovered for the first time: between structures of the synthesized compounds and their reactivity towards various radicals - on the one hand - and virus-inhibiting activity – on the other.
The Project results will find application in the public health system of the Republic of Belarus for obtaining medical products based on the developed substances and performing their clinical trials.
Meeting ISTC Goals and Objectives.
The Project meets ISTC goals and objectives because:
· it will give the scientists, which formerly participated in realization of military programs, an opportunity to switch over to solving a purely humanistic problem: the development of new antiviral agents;
· the experimental data to be obtained will contribute to integration of scientists of the Republic of Belarus into the international scientific community because these data will be acquired in collaboration with foreign researchers – specialists in chemistry, biology and medicine;
· it is aimed at performing applied tasks for peaceful purposes;
· it will promote changes within the researcher community towards the market economy, due to the sale of licences for the “know-how” used in searching for new pharmacologically active agents, as well as licences for synthesis of these substances;
· introduction of the new antiviral products into medical practice will allow millions of dollars to be saved for national economy, and a future Project investor will have privileges in acquisition of licences for the new antiviral substances.
The Project effort.
The activities planned to be deployed in the framework of the Project have a multiple-discipline character, and require large-scale investigations to be performed in the field of targeted synthesis of a number of phenol, diphenol and quinone derivatives, as well as related compounds, and studies of their physicochemical, anti-radical and antiviral properties. These tasks will be performed by the research teams from BSU and SI RIEM. The Project duration is three years. The overall effort on the Project will amount to 6600 man-months.
The tasks to be performed by participants from BSU: Syntheses of diphenol and aminophenol derivatives and their preparation in experimental lots, investigation of physicochemical and anti-radical properties of the compounds synthesized and of a number of substances of natural origin.
The tasks to be performed by participants from SI RIEM: Studies of antiviral properties of the compounds synthesized with respect to herpes, influenza and HIV.
Investigations aimed at finding a relationship between structures and relevant characteristics of the compounds synthesized will be conducted by a joint effort of the both research teams.
The role of foreign Collaborators.
Agreements with the Collaborators have been reached on the following forms of participation in the Project:
· joint scientific research experiments,
· exchange of scientific information,
· participation in joint workshops and conferences,
· joint publications in scientific journals.
Technical approach and methodology.
The approach that will be used in the course of the Project implementation consists in conducting systematic and purposeful investigations allowing cause-effect relationships to be discovered between each pair of relevant properties of the compounds under study: namely their structures, their anti-radical properties and their anti-viral activity. Preliminary data obtained by the Project participants show that there are substances among derivatives of diphenols and aminophenols that effectively inhibit reproduction processes in viruses of herpes, influenza and HIV. The same substances produce changes in directivity and realization probability of various free-radical processes.
Technical realization of experiments will be provided by using up-to-date synthetic procedures and physicochemical investigation methods (chromatography, ESR-spectrometry, mass spectrometry).
Studies of antiviral properties will be conducted in experiments with viruses of herpes, influenza and HIV using monolayer cell structures. Substances displaying the most marked antiviral properties in cell cultures will also undergo trials with experimentally produced viral infections in laboratory animals. Standard methods of determination of antiviral properties will be used, for which the SI RIEM research team has been accredited by the Government Standard Agency of the Republic of Belarus. It should be pointed out that scientific collaboration between BSU and SI RIEM has already resulted in creation of a new antiviral product Butaminophen® effective for the treatment of herpes infections. This product is now manufactured by pharmaceutical industry of the Republic of Belarus.