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Innovative Antiviral Agents

#B-1746


Development of Innovative Antiviral Agents Based on Compounds of Natural Origin and Their Synthetic Analogues

Tech Area / Field

  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry
  • CHE-RAD/Photo and Radiation Chemistry/Chemistry
  • MED-DRG/Drug Discovery/Medicine

Status
8 Project completed

Registration date
20.04.2009

Completion date
02.04.2013

Senior Project Manager
Savinova N V

Leading Institute
Belarussian State University / Institute of Physical Chemical Problems, Belarus, Minsk

Supporting institutes

  • Belarussian Research Institute for Epidemiology and Microbiology, Belarus, Minsk

Collaborators

  • Universitat Leipzig / Institute of Medical Physics and Biophysics, Germany, Leipzig\nMedizinische Universitat Wien, Austria, Vienna

Project summary

The Project purpose is finding-out and/or designing new antiviral agents based on substances of natural origin and their synthetic analogues capable of controlling the processes involving reactive oxygen species (ROS) occurring in biosystems.

Problem statement

Virus resistance towards antiviral medicines determines the necessity of developing new effective antiviral agents with original mechanisms of action. Compounds characterized by a comparatively universal mechanism of microbiocidal action, for example, those capable of regulating probability and directivity of ROS-induced processes in biosystems, are expected to be less prone to provoke the development of resistant pathogen strains. Production of ROS by the cells of immune system is an important component of the processes aimed at controlling pathogenous microflora, e.g. generation of ROS accompanies the course of various viral infections. In recent time, the role of ROS as modulating factors with respect to redox-sensitive regulatory proteins is being extensively discussed. It is believed that ROS play an essential role in the signal transduction and are capable of modifying the regulatory proteins responsible for activation of gene expression, which leads to formation of products exerting a substantial influence on the development of viral infections. Being highly reactive, ROS are not selective, and they cause damage not only to viruses but also to various components of cells, including both infected and healthy ones. The result is the development of undesirable side effects. Thus far, the problem of finding-out the compounds, which, being introduced into biosystems, could modify the directivity of the ROS-induced processes in such a manner that the predominantly antiviral effects could be realized, remains unsolved.

The idea developed by Project participants originates from the key role of ROS in pathogenesis of viral infections, and it is aimed at finding-out the means ensuring a fine control of redox states of cells and the cell environment. Such control is one of the essential conditions determining the processes of penetration, reproduction and persistence of viruses.

The Project participants believe that the goal, namely the fine control of redox states of cells, can be attained using substances of natural origin and their synthetic analogues possessing variable oxidation-reduction properties. Depending on their redox state, the compounds of such type can either accumulate in the hydrophilic phase of cellular organellas and inactivate the viruses, or, being accumulated in the hydrophobic phase, they can impede the virus penetration into the cells.

The search for such substances among plant phenols, vitamins and coenzymes is the main goal of the proposed Project.

That the Project is feasible and the goal can be attained is confirmed by the data we have obtained in cell cultures and in laboratory animals. These data show that there are compounds among spatially hindered aminophenols and diphenols, which suppress quite effectively the replication of HIV, herpes and influenza viruses. It has been established that the highest antiviral activity was manifested by those of the named compounds, which effectively inhibited free-radical reactions involving organic radicals, while being indifferent towards ROS. Spatially hindered diphenol and aminophenol derivatives are membranotropic agents, which, being localized in cellular membranes, suppress free-radical processes of oxidation and fragmentation leading to the cell membrane injury. As a result, the agents are converted into the respective semiquinone and quinonimine radicals, and the named intermediates can be eliminated from biomembranes and react with oxygen. In that way, additional formation of ROS in the hydrophilic phase may occur, increasing thereby the probability of their direct or indirect interaction with viruses. This should ensure the build-up of antiviral effect.

Influence of the proposed Project on progress in the area of development of new antiviral products may be summarized as follows:

New antiviral agents characterized by original mechanisms of action will be found-out among readily available substances of natural origin and their synthetic analogues. Based on these agents, novel effective medicinal products will be developed for treatment of viral infections, including HIV.

The Project participants: Research Institute for Physico-Chemical Problems of the Belarusian State University (RI PCP BSU) and State Institution – Research Institute of Epidemiology and Microbiology (SI RIEM).

Research workers of RI PCP BSU have wide experience in the areas of synthesis and testing of antioxidants and stabilizers for materials used in weapon technologies. At present, their scientific work is focused on synthesis of inhibitors of various homolytic processes, as well as investigation of physico-chemical and pharmacological properties of the synthesized compounds. This work resulted in the development and launching on the pharmaceutical market of an antiviral product, Butaminophen®, as well as realization of a unique industrial technology for production of stabilized linseed oil.

Formerly, the research workers of SI RIEM took part in a number of classified research projects, financed by the Ministry of Defence of the USSR, dealing with synthesis and investigation of activity of compounds to be used against viral infectious agents that could potentially be regarded as bacteriological weapon. Prof. O.I. Shadyro, the scientific manager of the Project, is one of the leading specialists in the field of radiation chemistry and chemistry of free radicals. He has large experience in carrying out complex investigations aimed at developing novel pharmaceuticals.

Expected results and their novelty. After performing 4 tasks, the following results are expected:

  • Experimental samples of synthetic derivatives of plant phenols, vitamins and coenzymes will be prepared and their physico-chemical properties investigated.
  • Reactivity of the natural compounds and their synthetic analogues towards various free radicals will be investigated in chemical and biological models.
  • Antiviral properties of the compounds under study towards HIV, Herpes simplex and influenza viruses will be investigated.
  • Interrelations between structures of the test compounds and each antiradical and antiviral properties will be established.

Scientific relevance of the Project consists in the following:

For the first time, relationships will be established between structures of natural compounds or their synthetic analogues and the ability of these compounds to regulate the ROS-induced processes and replication of various viruses. This will allow novel antiviral agents with original mechanisms of action to be discovered.

Application of the Project results. It is expected that the Project results will be used in the Public Health system of the Republic of Belarus for preparation of dosage forms and clinical trials of the compounds found active as antiviral agents and eligible as potential antiviral medicinal products.

Meeting ISTC Goals and Objectives. The project conforms to the goals and objectives of ISTC as:

  • it gives an opportunity for the Project Participants formerly involved in studies related to weapon technologies to switch over to solving purely humanistic problems of creating new medicines;
  • the experimental data obtained together with foreign specialists working in the fields of chemistry, biology and medicine will promote integration of the participants of the project into the inernational scientific community;
  • it is aimed at solving practical problems for peaceful purposes;
  • it will facilitate a change-over of the Project participants to the market economy, due to sales of licenses for the “know-how”used in the search for novel pharmacologically active substances, as well as licenses for synthesis of such substances. Introduction of the new antiviral products into medicinal practice will allow millions of dollars to be saved for the national economy, and the Project investor will be given privileges as regards licenses for the new antiviral substances.

The effort on the Project implementation

To attain the Project goals, a substantial amount of multiple-discipline work should be carried out, including comprehensive studies in the area of targeted synthesis of derivatives of plant phenols, vitamins and coenzymes, as well as investigation of physico-chemical, radical-regulatory and antiviral properties of compounds of natural origin ant their synthetic analogues. The research teams of RI PCP BSU and SI RIEM will be enrolled in performing these tasks. The project duration is 3 years. The overall effort on the Project will amount to 6690 man-days.

The role of the RI PCP BSU Project Participants: synthesis and preparation of experimental samples of derivatives of plant phenols, vitamins and coenzymes in required quantities, as well as investigation of physico-chemical and anti-radical properties of natural substances and their synthetic analogues.

The role of the SI RIEM Project Participants: investigation of antiviral properties of natural substances and their synthetic analogues towards HIV, Herpes simplex and influenza viruses.

Establishing relationships between structures of the compounds under study and the properties to be investigated will be carried out by the effort of the both teams.

Role of foreign Collaborators

The following forms of participation in the Project have been agreed with the Collaborators: performance of research studies jointly with Collaborators; scientific information exchange; participation in joint seminars and conferences; preparation of joint publications.

Technical approach and methodology

Technical approach to the Project implementation is based on using up-to-date physico-chemical and medico-biological methods allowing the researchers to perform experimental work necessary for the development of novel antiviral agents with original mechanisms of action.

During realization of Task 1, regioselective methods will be used for modification of natural compounds with a view to produce changes in properties of pharmacophore groups of the compounds under study. Determination of structures and investigation of physico-chemical properties of the modified compounds will be performed using NMR spectroscopy and mass spectrometry techniques.

Reactivity of compounds of natural origin and their synthetic analogues towards various free radicals will be investigated by means of chromatographic and spectroscopic techniques using the approaches based on competitive kinetics. (Task 2).

Task 3. Investigation of antiviral properties will be carried out in cell cultures with HIV, Herpes simplex and influenza viruses. The compounds displaying the most marked antiviral properties in cell cultures will also be tested in laboratory animals experimentally infected with the above named viruses. The work with laboratory animals will be performed in accordance with “The main principles of care of laboratory animals and their use in ISTC projects”.

In order to establish interrelations between structures of the test compounds and each their anti-radical and their antiviral properties (Task 4), computer calculation methods will be used to obtain the key parameters responsible for generation of the required indices.


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