New inhibitors of cytomegalovirus replication: in vitro evaluation, mechanism of action, and in vivo activity.

摘要: Human cytomegalovirus (HCMV) infections are a major cause of mortality and morbidity in human transplant recipients serious problem patients with AIDS. Furthermore, CMV is the most frequent viral congenital abnormalities. Two drugs currently licensed for treatment severe infections, i.e. ganciclovir (Cymevene) foscarnet (Foscavir). However, both compounds may give side-effects, resistant strains emerge during long-term therapy. Therefore, development new more effective anti-CMV one top priorities current antiviral drug research. The first goal our study was to devise an assay rapid automated screening large series against CMV. method that we present based on enhanced esterase activity CMV-infected cell. significantly reduces labor time as compared microscopical used. Secondly, investigated acyclic nucleoside phosphonate (ANP) analogue HPMPC [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine]. recently identified laboratory potent selective compound described so far. We found specifically inhibits DNA synthesis endowed unique long-lasting effect. then potencies murine models (MCMV) infections. As could be expected from vitro data, far superior over preventing MCMV-induced mortality. In order mimic closely HCMV disease progression immunocompromised patients, elaborated model MCMV mice combined immune deficiency (SCID). DHPS several clinical relevant schedules SCIO mouse model. appeared all conditions much than ganciclovir. also PMEDAP [9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine], ANP antiretroviral activity, highly efficacious MCMV-associated immunocompetent immunodeficient (SCID) mice. Our third aim determine mechanism by which polyanionic polymers [sulfated polymers, polycarboxylates polyoxometalates] exhibit anti-HCMV activity. All these were inhibit adsorption cells.(ABSTRACT TRUNCATED AT 400 WORDS)