A European team of researchers has discovered that raltegravir, the drug sold by pharmaceutical firm Merck under the name Isentress and used to treat AIDS (acquired immune deficiency syndrome), could help treat the herpes virus. The study, funded in part by the SPINE2-COMPLEXES ('From receptor to gene: structures of complexes from signalling pathways linking immunology, neurobiology and cancer') project, which received EUR 12 million under the 'Life sciences, genomics and biotechnology for health' Thematic area of the EU's Sixth Framework Programme (FP6), could lead to the development of a drug capable of fighting the entire herpesvirus family. Led by the Institute for Research in Biomedicine (IRB Barcelona) in Spain, the researchers provide evidence that raltegravir can cancel the function of an essential protein for the replication of one kind of herpes virus. 'These results have a clear medical impact for three reasons,' explained Miquel Coll, coordinator of the IRB's Structural and Computational Biology Programme. 'First, humans do not have the viral protein that is affected, thus this would allow a highly specific drug that does not show the secondary effects that other drugs may have. Second, the inhibitor is not toxic for humans when administered at therapeutic concentrations because it is already on the market and thus toxicity tests are facilitated; and third, we have data that indicate that all herpes viruses have this protein. Therefore, it could be a valid target against all Herpesviridae.' Herpes viruses include pathogens such as herpes simplex 1 and 2 - the virus that causes chickenpox (otherwise known as zoster virus), the Epstein-Barr virus (which is associated with several types of cancer), the roseola virus, the cytomegalovirus and the herpes virus associated with the cancer Kaposi sarcoma. The human cytomegalovirus (HCMV) on which the study was performed causes neurological defects in 1% of neonates in developed countries. It also produces retinitis that deteriorates into blindness in 25% of people with AIDS, defects in the brains and central nervous systems of young adults, inflammation of the colon, mononucleosis - more commonly known as the 'kissing disease' - and serious diseases of the throat. Although 90% of adults carry HCMV this virus is opportunistic, acting in people with weakened immune systems including cancer and AIDS patients, recipients of organ transplants and neonates. To replicate, the herpes virus enters the nucleus of a cell where it uses the cell machinery to copy its DNA (deoxyribonucleic acid) several times into a single large chain. Once this copy has been made, a complex called terminase, formed by three protein subunits, cuts the new DNA into small fragments the size of a single viral genome and introduces these into empty shells (capsids) that have developed in the cell nucleus. The new viruses then leave the cell to continue infection. The researchers resolved the 3D (three-dimensional) structure of one part of the terminase using a state-of-the-art high-performance protein expression technique, with the collaboration with the European Molecular Biology Laboratory (EMBL) in Grenoble, France, and discovered that it resembled the integrase of the AIDS virus, for which drugs are available. The assays were performed directly on the protein in test tubes. 'Now we must do the assays on whole infected cells, improve the effect of the drug and validate that it is also effective for other kinds of herpes viruses,' said Dr Coll, whose laboratory has patented this second application for raltegravir. Contributions to this study were made by experts from the Czech Republic, France, Germany, Hungary, Israel, Italy, the Netherlands, Portugal, Spain, Sweden and the UK. The findings of which were published in the journal Proceedings of the National Academies of Sciences (PNAS).
Czechia, Germany, Spain, France, Hungary, Israel, Italy, Netherlands, Portugal, Sweden