MODERN ETHIOTROPIC CHEMOTHERAPY OF HUMAN CYTOMEGALOVIRUS INFECTION: CLINICAL EFFECTIVENESS, MOLECULAR MECHANISM OF ACTION, DRUG RESISTANCE, NEW TRENDS AND PROSPECTS. PART 1
Modern chemotherapy of cytomegalovirus (CMV) infections has a very limited arsenal of first-line drugs. These are preparations of ganciclovir (GCV) belonging to the class of modified nucleosides and its metabolic precursor ganciclovir valine ester. After three-step phosphorylation, GCV, as a structural analogue of the natural nucleotide, competes with it for binding to DNA polymerase and, due to its structural features, inhibits its activity. However, with prolonged use of GCV, mainly under conditions of immunosuppression, the virus develops drug resistance associated in most cases with changes in pUL97 catalyzing the first stage of GCV phosphorylation, as well as in the catalytic subunit of DNA polymerase. When variants of viruses resistant to GCV appear, second-line drugs are used: pyrophosphate analog of foscarnet and nucleotide cidofovir. Resistance to second-line drugs is due to mutations in the pol-gene and in a number of cases leads to multiresistance, which makes it impossible to use traditional anti-CMV drugs. In addition, the use of all of the above drugs is accompanied by the development of severe side effects. All of the above determines the need to search for new compounds that can effectively inhibit the reproduction of the virus, harmless to the macroorganism, convenient to use, overcoming the drug resistance barrier in viruses. As a result of the search in international databases (PubMed, MedLine, eLIBRARY.RU, ClinicalTrials.gov, etc.), the main trends in the search for new anti-CMV agents were identified. In the first part of the review, we concentrated on compounds that are modifications of known antiviral agents currently used in clinical practice, the most promising for the development of drug anti-CMV drugs.