The N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine is a potent and selective inhibitor of herpesvirus replication

Neyts, Johan; Andrei, Gracíela; Snoeck, Robert; Jähne, Gerhard; Winkler, Irvin; Helsberg, Matthias; Balzarini, Jan; Clercq, Erik De

doi:10.1128/aac.38.12.2710

Cited by 43 publications

(29 citation statements)

References 27 publications

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“…Cidofovir and S-2242 have similar in vitro activities against MAV-1, and the in vitro sensitivity of MAV-1 to cidofovir and S-2242 is comparable to those of several herpesviruses. Although the doses in our in vivo studies are comparable to those used in animal studies with herpesviruses, it seems that cidofovir and S-2242 are less effective in inhibiting mortality in the MAV-1/SCID model than in the herpesvirus models (40)(41)(42). It is rather unlikely that the limited effectiveness of cidofovir and S-2242 in our MAV-1 model is due to poor disposition, since both antiviral drugs are supposed to have different pharmacokinetics and organ distribution.…”

Section: Discussionmentioning

confidence: 78%

Mouse Adenovirus Type 1 Infection in SCID Mice: an Experimental Model for Antiviral Therapy of Systemic Adenovirus Infections

Lenaerts

Verbeken

Clercq

et al. 2005

Antimicrob Agents Chemother

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The importance of human adenovirus infections in immunocompromised patients urges for new and adequate antiadenovirus compounds. Since human adenoviruses are species specific, animal models for systemic adenovirus infections rely on a nonhuman adenovirus. We established mouse adenovirus type 1 (MAV-1) infection of BALB/c SCID mice as a model for the evaluation of antiadenovirus therapy. In vitro studies with mouse embryonic fibroblasts pointed to the acyclic nucleoside phosphonate cidofovir and the N-7-substituted acyclic derivative 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine (S-2242) as markedly active compounds against MAV-1. SCID mice, infected intranasally with MAV-1, developed a fatal disseminated infection after approximately 19 days, characterized by hemorrhagic enteritis. Several techniques were optimized to monitor viral, immunological, and pathological aspects of MAV-1 infection. Real-time PCR quantification of viral DNA revealed that after replication in the lungs, virus disseminated to several organs, including the brain, liver, spleen, intestine, heart, and kidneys (resulting in viruria). Immunohistochemical staining showed that MAV-1 was localized in the endothelial cells of the affected organs. Using reverse transcription-PCR, tissue levels of proinflammatory cytokines (i.e., interleukin-1␤ and tumor necrosis factor alpha) were found to be markedly increased. The MAV-1/SCID model appears to be an appropriate model for in vivo evaluation of antiadenovirus agents. Treatment with cidofovir or S-2242 at a dose of 100 mg per kg of body weight resulted in a significant delay in MAV-1-related death, although these antivirals were unable to completely suppress virus replication despite continued drug treatment. These findings suggest that complete virus clearance during antiviral therapy for disseminated adenovirus infection may require an efficient adaptive immune response from the host.

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Section: Discussionmentioning

confidence: 78%

Mouse Adenovirus Type 1 Infection in SCID Mice: an Experimental Model for Antiviral Therapy of Systemic Adenovirus Infections

Lenaerts

Verbeken

Clercq

et al. 2005

Antimicrob Agents Chemother

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“…Of particular interest is S2242, or 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine (Fig. 11), the only acyclic nucleoside analogue with the side chain substituted at the N-7 position of the purine ring that has proved to be antivirally active (83). This compound is a potent and selective inhibitor of virtually all herpesviruses (83) and inhibits VV replication at an IC 50 of 0.4 g/ml (Table 1).…”

Section: Nucleoside Analogues (Presumably) Targeted At Viral Dna Syntmentioning

confidence: 99%

Vaccinia Virus Inhibitors as a Paradigm for the Chemotherapy of Poxvirus Infections

2001

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Poxviruses continue to pose a major threat to human health. Monkeypox is endemic in central Africa, and the discontinuation of the vaccination (with vaccinia virus) has rendered most humans vulnerable to variola virus, the etiologic agent of smallpox, should this virus be used in biological warfare or terrorism. However, a large variety of compounds have been described that are potent inhibitors of vaccinia virus replication and could be expected to be active against other poxviruses as well. These compounds could be grouped in different classes: (i) IMP dehydrogenase inhibitors (e.g., EICAR); (ii) SAH hydrolase inhibitors (e.g., 5′-noraristeromycin, 3-deazaneplanocin A, and various neplanocin A derivatives); (iii) OMP decarboxylase inhibitors (e.g., pyrazofurin) and CTP synthetase inhibitors (e.g., cyclopentenyl cytosine); (iv) thymidylate synthase inhibitors (e.g., 5-substituted 2′-deoxyuridines); (v) nucleoside analogues that are targeted at viral DNA synthesis (e.g., Ara-A); (vi) acyclic nucleoside phosphonates [e.g., (S)-HPMPA and (S)-HPMPC (cidofovir)]; and (vii) polyanionic substances (e.g., polyacrylic acid). All these compounds could be considered potential candidate drugs for the therapy and prophylaxis of poxvirus infections at large. Some of these compounds, in particular polyacrylic acid and cidofovir, were found to generate, on single-dose administration, a long-lasting protective efficacy against vaccinia virus infection in vivo. Cidofovir, which has been approved for the treatment of cytomegalovirus retinitis in immunocompromised patients, was also found to protect mice, again when given as a single dose, against a lethal aerosolized or intranasal cowpox virus challenge. In a biological warfare scenario, it would be advantageous to be able to use a single treatment for an individual exposed to an aerosolized poxvirus. Cidofovir thus holds great promise for treating human smallpox, monkeypox, and other poxvirus infections. Anecdotal experience points to the efficacy of cidofovir in the treatment of the poxvirus infections molluscum contagiosum and orf (ecthyma contagiosum) in immunosuppressed patients

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“…We have shown previously that S2242 selectively inhibits the replication of herpesviruses (17,18). The compound is phosphorylated intracellularly first by deoxycytidine kinase and then further by cellular kinases to its 5Ј-triphosphorylated metabolite, which is expected to inhibit in a selective manner the viral DNA polymerase (19).…”

Section: Discussionmentioning

confidence: 99%

“…The NMRI mouse model allows the monitoring of pox lesion development on the tail in a nonlethal infection; the SCID mouse model allows the determination of protective effects on virus-induced mortality. Compound S2242 is a potent and selective inhibitor of the replication of herpesviruses (human cytomegalovirus, thymidine kinase-inducing and thymidine kinase-deficient strains of herpes simplex virus, and varicella-zoster virus) (17,18). VV is, like variola virus, an orthopoxvirus; it has been used as a smallpox vaccine for the past 200 years, and there are no known natural hosts for this virus.…”

mentioning

confidence: 99%

Efficacy of 2-Amino-7-(1,3-Dihydroxy-2-Propoxymethyl)Purine for Treatment of Vaccinia Virus (Orthopoxvirus) Infections in Mice

Neyts

Clercq

2001

Antimicrob Agents Chemother

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We have previously shown that the N-7 substituted acyclic nucleoside analog 2-amino-7-[1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) is, both in vitro and in animal models, a potent inhibitor of the replication of several herpesviruses (Neyts et al., Antimicrob. Agents Chemother. 39:56-60, 1995). Here we report on the potent and selective antiviral activity of S2242 against vaccinia virus (VV), an orthopoxvirus. The 50% effective concentrations for inhibition of VV-induced cytopathic effect and viral DNA synthesis in cell culture were 2.4 and 0.2 g/ml, respectively. We next studied the efficacy of S2242 in VV-infected mice. Immunocompetent NMRI mice that had been inoculated intravenously with VV developed tail lesions. Mice that had been treated for 5 consecutive days via the subcutaneous (s.c.) route with 100 mg of the diacetate ester prodrug of S2242 (compound H961) per kg of body weight did not develop any lesions and demonstrated no adverse effects. Severe combined immunodeficient (SCID) mice that had been inoculated intraperitoneally with VV became sick and died within 1 month after infection. Following treatment with H961 at 100 mg/kg for 10 consecutive days (either via oral gavage or s.c. injection) VV-inoculated SCID mice were completely protected, for at least 3 months, against virus-induced morbidity and mortality. At that time, no virus could be recovered from the organs of these mice (as assessed by titration for infectious virus, a DNA hybridization assay, and a PCR for VV-specific sequences). Compound S2242 and its oral prodrug H961 could be useful in treatment of orthopoxvirus infections.

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The N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine is a potent and selective inhibitor of herpesvirus replication

Cited by 43 publications

References 27 publications

Mouse Adenovirus Type 1 Infection in SCID Mice: an Experimental Model for Antiviral Therapy of Systemic Adenovirus Infections

Mouse Adenovirus Type 1 Infection in SCID Mice: an Experimental Model for Antiviral Therapy of Systemic Adenovirus Infections

Vaccinia Virus Inhibitors as a Paradigm for the Chemotherapy of Poxvirus Infections

Efficacy of 2-Amino-7-(1,3-Dihydroxy-2-Propoxymethyl)Purine for Treatment of Vaccinia Virus (Orthopoxvirus) Infections in Mice

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