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Effective Novel HIV Inhibitors

#B-984


A Search for Effective Novel HIV Inhibitors Based on the Polydisulfide Class Compounds

Tech Area / Field

  • BIO-CHM/Biochemistry/Biotechnology
  • MED-DRG/Drug Discovery/Medicine

Status
8 Project completed

Registration date
12.02.2003

Completion date
12.12.2008

Senior Project Manager
Visser H

Leading Institute
Belarussian State University, Belarus, Minsk

Supporting institutes

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

Collaborators

  • Johannes Gutenberg-Universitat Mainz / Institut für Physiologische Chemie, Germany, Mainz\nUniversita di Camerino / Dipartimento di Scienze Farmacologiche e Medicina Sperimentale, Italy, Camerino

Project summary

The principal purpose of the proposed project is a search for effective HIV inhibitor of the polydisulfide class as a base for the creation of nontoxic inexpensive home-produced medication for treatment of AIDS and HIV-infection.

Introduction and Overview. Priority of project activities.

At the present time more than 35 million people over the world are infected with human immunodeficiency virus (HIV) and this number is constantly growing. The number of HIV-infected registered in Belarus is currently about 4 thousand, exhibiting more than 26-times increase as compared to 1995.

A strategy of HIV-infection and AIDS treatment is associated with the use of highly active complex antiretroviral therapy (CAT) and specific HIV inhibitors. By their mechanism, these inhibitors may be pided into two large groups of compounds blocking the viral enzymes: reverse transcriptase (revertase) and protease leading to radical reduction of the HIV reproduction in human organism. However, these compounds are not free from some grave limitations. First, all them without exceptions are highly toxic and have pronounced side-effects. Second, they are very expensive. Third, what is more important, HIV rapidly acquires resistance, cross-resistance including, to their action.

Because of this, creation of nontoxic inexpensive inhibitors, having no side-effects and stable to the action of HIV is of vital importance. Presently, in the world practice such inhibitors of HIV infection are lacking.

Impact of the project proposed on the progress in the relevant field.

Based on the polydisulfide-class compounds,in the process of project realization it is expected to develop effective,nontoxic and inexpensive inhibitors,having no side effects and stable to HIV, for the first time in the world practice.

Participants of the project.

The proposed project is realized by the experts and specialists from the Belarusian State University (BSU) and Belarusian Research Institute of Epidemiology and Microbiology (BelRIEM).

At the Organic Chemistry and High Molecular Compounds Department of the BSU a team of researchers under the leadership of Chief Research Worker, Dr. Ph. Yu.P. Losev is planning to conduct synthesis and identification of the polydisulfide class compounds. Using advanced methods, the Research Laboratory for AIDS (BelRIEM) with Dr. Sc. Med., Prof. P.G. Rytik at the head will be engaged in tests of the polydisulfides as HIV infection inhibitors.

The team of Yu.P. Losev includes 3 workers possessing knowledge and skills related to rocket technologies.

The team of Prof. P.G. Rytik includes 4 project participants who possess knowledge and skills related to biological weapons.

Expected results.

  • As a consequence of the project activities directed to realization of its five goals, it is expected to obtain the following results:
  • Task 1 - synthesis and identification of 5 polydisulfides of amino acids.
  • Task 2 - synthesis and identification of 6 polydisulfides of oxy-acids.
  • Task 3 - synthesis and identification of 15 polydisulfides of phenols and their substitutes.
  • Task 4 - synthesis and identification of 13 polydisulfides of aromatic and aliphatic.
  • Polydisulfides synthesized when implementing tasks 1-4 will be tested as inhibitors of HIV-infection by the methods of formazan test (FTM), trepan blue staining and indirect immunofluorescence method (IFM).
  • Task 5 involves analysis of the obtained results and selection of a most effective HIV inhibitor.Working out of a scientifically substantiated approach to the creation of medicines for treatment of HIV-infection and AIDS on the basis of this effective inhibitor.Preparation of the final report on the project, technological regulations and order, specifications.
  • Certification of the obtained medicine.Search for investments to organize its production. Protection of the intellectual property by 6 patents.
  • Being a novel class of HIV-infection inhibitors, the synthesized compounds represent an object of intellectual property having a particular commercial value.

Development introduction.

It is planned to introduce the findings of the project in a public health system of the Republic of Belarus.

Meeting ISTC Goals and Objectives.

Being a new class of inhibitors, the synthesized inhibitors of HIV infection form an object of intellectual property having a particular commercial value. The outcome of project activities will find practical application in the establishments affiliated to the Belarusian Ministry of Public Health. BSU and BelRIEM were contractors of the Ministry of Defense and Ministry Weapons Industry.

Realization of the proposed project allows to redirect the knowledge and skills of weapons scientists and engineers in the CIS countries to peaceful activities, supporting the research for peaceful purposes in the interests of humanity, namely the development of substances with useful medicinal properties.

Marketing of licenses related to the know-how used in synthesis of new pharmacologically active substances will contribute to the integration of the research participants into the international scientific community and facilitate the transition to market-based economies.

Proceeding from the above, the proposed project conforms to the primary ISTC objective.

Scope of activities.

The length of time required for realization of the project is 36 months. Labor-intensity amounts to 6000 man/hours.Realization of the project includes 5 tasks performed in succession.

This period embraces synthesis of about 40 new compounds of the polydisulfide class and their identification by the research team from the Organic Chemistry and High Molecular Compounds Department, BSU, as well as testing of the synthesized compounds as HIV inhibitors by the project participants from the Research Laboratory for AIDS, BelRIEM, and also screening and analysis of the substances under study aimed at finding of the most effective one for the development of medicament for treatment of HIV infection and AIDS.

Role of Foreign Collaborators.

During the project activities it is planned to realize exchange of information and discussion of the results obtained with the collaborators. Based on these results, comments on the progress reports to the project will be given. Besides, together with the collaborators it is presumed to conduct scientific seminars and investigations for testing of the synthesized compounds using the methods and equipment supplied by the collaborator.

Technical Approach and Methodology.

The authors of the project proposal are adequately experienced in the related fields. To illustrate, by the project participants it has been found that some polydisulfides exhibit high efficiency as inhibitors of lipid peroxidation thus inhibiting the degradation of cell membranes characteristic for different pathologies. As has been shown previously, polydisulfide of gallic acid exhibits higher inhibiting activity to herpes simplex (resistant form including) as compared to acyclovir and acetophosphonic acid. Unlike acyclovir and acetophosphonic acid, this activity is insensitive to radiation. It has been demonstrated that polydisulfide of gallic acid is a preventive and medicinal agent on radiation damages of various severity. Its effectiveness in treatment of pneumonia and shock has been demonstrated also. Preclinical toxicological tests of the polydisulfide of gallic acid have revealed the absence of mutagenic, allergic, skin-irritation and - resorption effects.

This polydisulfide is characterized by low toxicity and produces no significant structural changes in vital systems of experimental animals.

Pilot tests of three polydisulfides have revealed the presence of APB-activity, whereas polydisulfide of 5-aminosalycilic acid exhibited a high chemicotherapeutic index of 100000. Besides, the extent to which these compounds may exert cytopathic effects has been indicated. Based on these results, there is a reason to believe that these compounds look promising as HIV infection inhibitors and require further investigation.


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