Drugs Synthesis for AIDS
Perspective in synthesis of new pharmaceutical compounds based on phosphilipids and nucleosides, possessing anti-HIV and immunoadjuvant activity, and investigation of their interaction with cellular membranes.
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
8 Project completed
Senior Project Manager
Tyurin I A
State Research Institute of Organic Chemistry and Technology, Russia, Moscow
- Gamalei Institute of Epidemiology and Microbiology, Russia, Moscow\nLomonosov Academy of Fine Chemical Technologies, Russia, Moscow
- Universiteit Leiden, The Netherlands, Leiden\nLeiden/Amsterdam Center for Drug Research / Sylvius Laboratories, The Netherlands, Leiden\nUniversity of California, USA, CA, Davis\nUniversity of Exeter, UK, Exeter\nUniversity of Liverpool, UK, Liverpool
Project summaryThe goal of the present project is searching for new compounds as perspective anti-AIDS drugs.
Though the illness is devastating, the number of anti-AIDS drugs is limited. The most efficient agents affect the vital step of the viruses replication - the reverse transcription. Most of them are nucleoside derivatives capable of becoming chain-terminating inhibitors of HIV reverse transcriptase. AZT known also as Retrovir and 2',3'-dideoxynucleoside analogues are among the most promising ones.
Analysis of recent literature data shows that combination of two biologically active components in one substance (nucleoside analog and immunostimulator) could give substantial increase of the anti-viral properties (AZT conjugates with retinoic acid, amino acids and 1,4-dihydro-l-methyl-3-[(pyridylcarbonyl)oxy]ester, antineoplastic nucleosides conjugates with phospholipids).
Utilising this approach we suggest a new type of nucleoside conjugates with phospholipids that could easily penetrate the cellular membrane and transport the active nucleoside analog inside the infected cell.
We suggest two types of nucleoside conjugates:
Where Nu - nucleoside (AZT, 2', 3'-dideoxynucleosides and acyclic nucleosides)
R = alkyi C16-C18,
R' = acyl, alkyl or carbamoyl
X = O or OCO
We suppose to use different structural analogs of PAF (platelet activation factor)as the phospholipid fragment. It should be noted that some phospholipids-PAF analogues, for example ET-18-OCH3-possesses profound anti-HIV and antineoplastic activity.
State Research Institute of Organic Chemistry and Technology has developed methods of full chemical synthesis for PAF and its analogues that possess high biological activity, as well as elucidated some aspects of structure-activity relationship for this class of compounds This experience will be used in the frames of this project for developing methods of transport biologically active nucleosides into the cell.
Thus this project addresses the ITSC objectives, namely supporting basic and applied research for peaceful purposes and promoting integration of chemical weapon scientists of the CIS into the international scientific community.
Three nucleoside analogs will be used as nucleoside component:
two well-known anti-AIDS agents AZT and 2',3'-dideoxynucleosides and a new type of acyclic nucleosides, recently developed in Lomonosov Academy of Fine Chemical Technology. In the last case, deoxyribose is substituted for hydroxypentene fragment, and it was shown that triphosphates of these nucleosides are highly efficient and selective inhibitors of HIV reverse transcriptase.
Vital part of the present project is development of liposomal test-systems for characterising antiviral agents penetration of the cellular membrane. Using NMR-spectroscopy and model membranes gives such an opportunity.
In vitro testing of the new compounds will be conducted at Gamalei Institute of Epidemiology and Microbiology, namely investigation of anti-HIV activity basing on the agent's ability to inhibit virus replication in the cell. Besides that a mixture of the parent compounds should be tested also to show the necessity of chemical bong between the phospholipid and nucleoside fragments.
All the suggested compounds are new and if any biological activity is found, a detailed technological scheme could be developed for the compound with the best properties.
Final result of the proposed project could be the substance for a new generation of antiviral agents (if the proposed substances show significant anti-HIV activity and low toxicity).