New inhibitors of cytomegalovirus replication: in vitro evaluation, mechanism of action, and in vivo activity.
Human cytomegalovirus (HCMV) infections are a major cause of mortality and morbidity in human transplant recipients and a serious problem in patients with AIDS. Furthermore, CMV is the most frequent viral cause of congenital abnormalities. Two drugs are currently licensed for the treatment of severe CMV infections, i.e. ganciclovir (Cymevene) and foscarnet (Foscavir). However, both compounds may give severe side-effects, and resistant strains may emerge during long-term therapy. Therefore, the development of new and more effective anti-CMV drugs is one of the top priorities in current antiviral drug research. The first goal of our study was to devise an assay for the rapid and automated screening of large series of compounds against CMV. The new method that we present is based on the enhanced esterase activity in the CMV-infected cell. The method significantly reduces labor time as compared to the microscopical method that is currently used. Secondly, we investigated the anti-CMV activity of the acyclic nucleoside phosphonate (ANP) analogue HPMPC [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine]. HPMPC was recently identified in our laboratory as the most potent and selective anti-CMV compound described so far. We found that HPMPC specifically inhibits viral DNA synthesis and that the compound is endowed with an unique long-lasting antiviral effect. We then compared the antiviral potencies of HPMPC and ganciclovir in murine models for murine CMV (MCMV) infections. As could be expected from our in vitro data, HPMPC was far superior over ganciclovir in preventing MCMV-induced mortality. In order to mimic more closely the HCMV disease progression in immunocompromised patients, we elaborated a model for MCMV infections in mice with severe combined immune deficiency (SCID). The anti-CMV activity of HPMPC and DHPS was compared in several clinical relevant treatment schedules in the SCIO mouse model. HPMPC appeared in all conditions to be much more effective than ganciclovir. We also found that PMEDAP [9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine], an ANP with potent antiretroviral activity, is highly efficacious in the treatment of MCMV-associated mortality in both immunocompetent and immunodeficient (SCID) mice. Our third aim was to determine the mechanism by which polyanionic polymers [sulfated polymers, polycarboxylates and polyoxometalates] exhibit anti-HCMV activity. All these compounds were found to inhibit the adsorption of HCMV to the cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Neyts
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven.
De Clercq
E
E
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000187:drug effects*; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D004279:DNA, Viral / Q000096:biosynthesis / Q000187:drug effects; D015774:Ganciclovir / Q000494:pharmacology; D006566:Herpesviridae Infections / Q000188:drug therapy; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D018146:Muromegalovirus; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C059499:9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; D003596:Cytosine; D000225:Adenine; D000077404:Cidofovir; D015774:Ganciclovir