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Antiviral Drugs with Nucleotide Analogs

#1244


Design of Viral Inhibitors on the Base of Nucleotide Analogs

Tech Area / Field

  • MED-DRG/Drug Discovery/Medicine

Status
8 Project completed

Registration date
10.04.1998

Completion date
01.04.2004

Senior Project Manager
Pobedimskaya D D

Leading Institute
State Research Center of Virology and Biotechnology VECTOR / Institute of Molecular Biology, Russia, Novosibirsk reg., Koltsovo

Supporting institutes

  • Engelhardt Institute of Molecular Biology, Russia, Moscow

Collaborators

  • Cardiff University, UK, Cardiff\nKatholieke Universiteit, Belgium, Leuven\nPhilipps Universität / Institute of Virology, Germany, Marburg\nEuropean Commission / Research Directorate-General / International Scientific Cooperation, Belgium, Brussels

Project summary

Nucleoside analogs is one of the most perspective and widespread group of the antiviral drugs. The approved antiviral drugs of nucleoside origin (acyclovir, azidothymidine, D4T, DDI, DDC, ribovirin) suffer a number of disadvantages. The most essential one is necessity of their transformation to an active form by phosphorylation with cell enzymes – nucleoside- and nucleotide kinases. Therefore, designing of principally new types of antiviral drugs that do not require the phosphorylation procedure is a actual problem of the day. On the basis of our early studies we plan to investigate nucleoside 5'-triphosphates modified at the sugar and phosphate residues as potential antivirals of the second generation. Although the types of modifications for the sugar residue imparting the nucleoside with antiviral properties are well described, little is still known about phosphate modifications. Scientists from “Vector” have a great experience to work with dangerous viral pathogens such as Marburg virus (MBV), Ebola virus (EBV), HIV and other. The integration of their experience with that of the researchers from EIMB dealing with synthesis and biochemical and cellular evaluation of potential antivirals could result in development of new drugs useful for treatment of serious infections including AIDS. The technological basis for Phosphazide (AZT 5’-hydrogenephosphonate) synthesis is developed now. This first Russian anti-AIDS drug is under clinical trials on HIV-infected and AIDS patient now. It is patented in Russia, USA, Europe,. Japan and South Korea.

The goals of the present Project are: design of new types of nucleotide analogs that do not require the phosphorylation for their antiviral activity. To reach the goal, it is necessary: (a) to synthesize and study nucleoside 5'-triphosphates with modification in triphosphate residue and in some cases in sugar part; (b) to study the antiviral activity of synthesized nucleosides against HIV, MBV, EBV , herpes simplex virus, cytomegalovirus, adenoviruses, and hepatitis B virus (HBV) using cell cultures and laboratory animals; (c) to study the appearance of nucleoside-resistant mutants of viruses (HIV); d) to select most promising application scheme of antivirals and their combination with other known antiviral preparations in order to avoid the selection of drug-resistant variants; (d) to evaluate stability of the most effective antiviral preparations in human blood, cellular cytoplasm and properties of selective inhibition of HIV reverse transcriptase in comparison with the major human DNA polymerases; (e) to perform large-scale synthesis of 2-3 most promising compounds.


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