Nucleotide analogs related to acyclovir and ganciclovir are effective against murine cytomegalovirus infections in BALB/c and severe combined immunodeficient mice

Abstract

Acyclovir phosphonate [9-(3-phosphono-propyloxymethyl)guanine; SR3722] and the S enantiomer (SR3772), R enantiomer (SR3773), and R,S enantiomeric mixture (SR3745A) of ganciclovir phosphonate {9-[((-'-)-1-hydroxymethyl-3-phosphono)propyloxymethyl]guanine} were evaluated for their antiviral activities against murine cytomegalovirus. In severe combined immunodeficient mice infected with murine cytomegalovirus, SR3773 and SR3745A (12.5, 25, and 50 mg/kg of body weight per day) were superior to ganciclovir in extending the mean time to death, whereas SR3722 and SR3772 was less potent than ganciclovir. In normal BALB/c mice, SR3773 and ganciclovir were approximately equally active in preventing death. SR3773 caused renal tubular damage when administered at 50 mg/kgday for 15 days. These results suggest that SR3773 may have potential for use in the treatment of human cytomegalovirus infections, but it may also exhibit renal toxicity.Two antiviral drugs are approved for the treatment of human cytomegalovirus (HCMV) disease, ganciclovir (GCV) and foscarnet. Both compounds have toxic side effects which limit their usefulness (3,19), and the emergence of drugresistant viruses is a concern (6, 7). Thus, the need for safer and more effective anti-HCMV agents is apparent. Newer anti-HCMV compounds still in preclinical development include acyclic phosphonate derivatives of nucleosides such as (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) (18).We and others reported that phosphonate derivatives of acyclovir and GCV inhibited HCMV and other animal CMVs (1, 5, 12, 13). Many of these nucleotide analogs were approximately as active as GCV in inhibiting HCMV in cell culture (causing 50% inhibition of viral plaques or cytopathology when used at between S and 20 ,uM, depending on the virus strain). Until recently, the most potent of these agents, {9-[((±)-1-hydroxymethyl-3-phosphono)propyloxymethyl]guanine; SR3745A or ganciclovir homophosphonate [5]} was available only as a mixture of R and S enantiomers. One of the two enantiomers (the R enantiomer) was believed to be responsible for the anti-HCMV activity and the other enantiomer (the S enantiomer) was presumed to be inactive. This hypothesis was based on earlier studies of ganciclovir homophosphonate phosphorylation (5). The R enantiomer approximates 2'-deoxyguanosine-5'-monophosphate in structure more closely than does the S enantiomer, and therefore should interact more readily with cellular enzymes. Methods have recently been devised to synthesize the chiral R (SR3773) and S (SR3772) enantiomers (11).This report describes antiviral evaluations of SR3745A, SR3772, and SR3773 in cell culture and in two murine CMV (MCMV) animal models (14, 17) of HCMV infection. Previously, SR3745A was shown to be beneficial against MCMV infection in mice (5), and so the likelihood that the chiral R

Nephrotoxicity induced by the R- and S-enantiomers of N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and their sulfate conjugates in male Fischer 344 rats

“…For example, L-serine is a beneficial, naturally occurring amino acid, but D-serine is a nephrotoxicant (Carone and Ganote, 1975;Willimas and Lock, 2005). The S-enantiomer of ganciclovir is a nephrotoxicant in mice at 50 mg/kg/day for 15 days, while the R-enatiomer is not a nephrotoxicant at twice the dose (Smee et al, 1994). We also previously reported the stereoselective nephrotoxicity induced by 2-NDHSA (Rankin et al, 2001b).…”

Cytomegalovirus antivirals and development of improved animal models

“…The BALB/c mouse is susceptible to wild type MCMV and is employed in most studies. The SCID mouse is ideally suited as a model to study CMV viral pathogenicity as well as the testing of the efficacy of antiviral CMV drugs in an immunesuppressed host [129, 130]. …”

Potent anti-murine cytomegalovirus activity and reduced nephrotoxicity of ganciclovir cyclic phosphonate

“…This nucleotide analog is reported to inhibit HCMV in the range of 2 to 4 M (8, 13) and MCMV in the range of 0.4 to 0.6 M (15,17) in cell culture. In addition, SR3773 is very effective against MCMV infections in healthy and immunosuppressed mice (17), being much more potent than ganciclovir in comparative studies. Similar to HPMPC, however, SR3773 causes nephrotoxicity in mice (17).…”

“…In addition, SR3773 is very effective against MCMV infections in healthy and immunosuppressed mice (17), being much more potent than ganciclovir in comparative studies. Similar to HPMPC, however, SR3773 causes nephrotoxicity in mice (17).…”

“…Fifty percent effective concentrations were estimated by plotting on semilogarithmic paper. The effects of these compounds on the proliferation of actively growing uninfected C127I cells (a mea-sure of cytotoxicity) were determined over 4 days by methods reported previously (17).…”