Main Sector of relevance\IRC classification 5. Electronics, IT and Telecommunication

5.45 Computer-aided design of potential drugs for AIDS therapy: glycolipids against the gp120 V3 loop of HIV-1

Developers’ contact information

1) State Scientific Institution “The United Institute of Informatics Problems”
220012, Minsk, Surganov St., 6
Теl.: +375 (17) 284-21-75; e-mail: itekan@newman.bas-net.by; URL: http://uiip.bas-net.by/

doctor of physical and mathematical sciences Tuzikov Aleksandr Vasiljevich
Теl. +375 (17) 284-21-40; e-mail: tuzikov@newman.bas-net.by

2) State Scientific Institution “The Institute of Bioorganic Chemistry”
220141, Minsk, Kuprevich St., 5/2
Теl./Fax: +375 (17) 267-87-61

doctor of chemical sciences Andrianov Aleksandr Mihajlovich
Теl.: +375 (17) 264 82 63; e-mail: andrianov@iboch.bas-net.by

Summary

The aim of this project is to construct mathematical models describing the structure of atomic level and dynamic properties of the complexes formed by the V3 loop of HIV-1 subtype A, which is characteristic of the Republic of Belarus, with galactosylceramide, which water-soluble analogues inhibit viral replication by blocking the penetration of in susceptible cells by binding to a loop V3 according to the literature. The computer design of glycolipid’s modified forms is based on the calculated data. This forms will be able to more effectively block (compared with baseline lipid) of the main antigenic determinants of the virus with subsequent selection of the underlying structures of the most promising pharmacological substances to create an effective antiviral new generation.

Description

First applied approach to the prediction of structural,functional,energy characteristics of the immunogenic complexes "crown" of the V3 loop of HIV-1 provided hexapeptide Gly-Pro-Gly-Arg/Gln-Ala-Phe, glycolipids with GalCer and its water-soluble analogues in the absence of experimental data on principles of spatial organization is a combination of a number of modern computational methods.Based on the results of the calculations, the key role is played by residues of phenylalanine and arginine (glutamine) immunogenic "top" of HIV-1 upon binding to glycolipids.Close to the experimental data, the calculated values of free energy of formation of complexes of GalCer with peptides of the V3 loop showed the adequacy of the model and calculation scheme.Two theoretically constructed water-soluble analogs of GalCer are often close to the original molecule binding affinity to the central fragment of the V3 loop, and can serve as basic structures for the rational design of new effective antiviral drugs.
Despite the qualitative agreement of simulation results with published data,carrying out such calculations with an intact V3 loop is of interest to obtain more accurate information about the interaction of glycolipids with protein gp120. Similar studies should also be implemented for a wide variety of modified forms of GalCer with their subsequent synthesis, testing and selection of basic structures that represent promising pharmacological substances to create a new generation of antivirals.
In addition, the proposed model of structural complexes of the central fragment of the V3 loop with GalCer can serve as a basis for better understanding of the principles of the functioning of HIV-1, and can also be used in subsequent studies of the relationship between structure and function of the virus which is necessary for the successful implementation of protein-engineering projects which are aimed at developing of antiviral drugs with a wide range of therapeutic action.

Technology type

Technical advantages and economic benefits

  1. Nowadays the efforts of researchers is involved in the creation of antiviral drugs mainly focused on the studying of the structure of the V3 loop of HIV-1 subtype B ,which dominates in North and South America, Western Europe, Japan, Australia and Thailand, while similar studies of  subtype A virus, the predominant in Eastern Europe, including the Republic of Belarus has not yet been implemented and are therefore of great interest to us.
  2. Using of modern methods of computer simulation of three-dimensional structures will greatly streamline the procedure for extraction of structural data and eliminate the deficit of information which is necessary to conduct further work on the creation of antiviral drugs.

Technology differentiation and uniqueness

  1. The proposed solution of the problem preventing the use of glycosphingolipids as potential therapeutic agents is an alternative to the traditional approach. Induced to the V3 loop antibodies are involved to neutralize HIV in this approach. It has no analogue in world literature.
  2. The approach includes a number of modern computational methods for prediction of GalCer structure and its water-soluble analogues, as well as complexes formed with glycolipids loop V3.

Context in which technology was identified

Current research results were presented in reports at the conferences:
- Second International Conference on “Advanced Information and Telemedicine Technologies for Health” AITTH'2008, Minsk, October 1-3, 2008;
- Third International Conference “Supercomputer systems and applications” SSA'2010, Minsk, May 25-27, 2010;
- Third International Conference on “Mathematical Biology and Biophysics” ICMBB'2010, Pushchino (Russia), 10-15 October 2010.

Technological keywords

Biophysics, biochemistry, medicine, bioinformatics.

Development Stage

Intellectual property rights

Range of applications

- protein-engineering projects to develop medicines for the treatment of patients with AIDS;
- fundamental research aimed at studying the principles of functioning of HIV-1.

Classifier Used at the EU Innovation Relay Centres

Preferable Regions

Practical experience

Two of the calculated water-soluble analogs of GalCer were synthesized in the laboratory of Chemistry of lipids of the Institute of Bioorganic Chemistry of NAS of Belarus and tested for antiviral activity in RSPC Epidemiology and Microbiology. The activity of the synthesized compounds against HIV revealed during the tests.

Environmental impact

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Type of collaboration sought

Terms and restrictions

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Support provided at transfer of the technology