Biology subjects

Kappler-Gratias, S.

Publications and source records attributed to Kappler-Gratias, S..

4 recordsLinked to original sources

bioRxiv2025

In vitro and in vivo Antiviral Activity of the Acyclic Nucleoside Phosphonate Prodrug LAVR-289 against Poxvirus and African Swine Fever Virus Replication

Poxviruses are double-stranded DNA viruses including relevant zoonotic pathogens with high morbidity. Although African swine fever virus (ASFV) belongs to the Asfarviridae family and is not strictly classified as a member of the Poxviridae, both fall within the same class of Pokkesviricetes that replicate in the cytoplasm, and some poxviruses pose potential biological warfare threats. Among compounds targeting these viruses, acyclic nucleoside phosphonate prodrugs are nucleoside analogues inhibitors of viral DNA polymerases that have been identified as promising agents. However, some limitations related to their toxicity and the rapid emergence of resistance highlight the need for new antiviral molecules. In this study, the new nucleoside analogue LAVR-289 was shown to effectively inhibit the viral replication by intervening early in the viral replication step, targeting a specific domain of the poxvirus DNA polymerase. Using monkeypox virus models, the subcutaneous or oral administration of LAVR-289 demonstrates protective efficacy in infected animal models without toxicity or behavioral modification. The stability in vivo, long shelf-life and efficacy make LAVR-289 a promising candidate for further development and stockpiling as a medical countermeasure against dsDNA virus outbreaks. Its broad-spectrum efficacy is a real asset in a context of recurrent viral epidemics, risk of bioterrorism and emergence of resistance strains in the population. HighlightsO_LILAVR-289 is a unique acyclic nucleoside phosphonate prodrug targeting viral DNA polymerases. C_LIO_LILAVR-289 displays antiviral activity against dsDNA viruses, ASFV and poxviruses. C_LIO_LIFirst report of in vivo evaluation of LAVR-289 against MPXV by subcutaneous and oral administration. C_LIO_LILAVR-289 reduces clinical signs and increase survival in animal models. C_LI

microbiology↗

bioRxiv2025

LAVR-289, a New Orally Bioavailable Inhibitor of Adenovirus Replication in vitro and in vivo.

Adenoviruses are responsible for a range of pathologies, including respiratory infections in children, accounting for 5-10% of such cases. Although most adenovirus infections are self-resolving, they can cause serious illness, particularly in immunocompromised individuals. There is currently no approved treatment for adenovirus infections, although various therapeutic approaches are under investigation, including nucleoside analog inhibitors of replication. However, these treatments have shown limited efficacy. In this study, we report on the antiviral activity of LAVR-289, a broad-spectrum acyclonucleoside phosphonate exhibiting potent in vitro efficacy against several adenovirus serotypes, comparable to that of brincidofovir. LAVR-289 specifically inhibits viral replication, blocking the formation of viral replication centers and preventing late protein expression without affecting viral entry or delivery of viral genomes to the nucleus. In vivo using immunocompromised Syrian hamsters infected with HAdV-C6, oral administration of LAVR-289 resulted in 100% animal survival. These results suggest that LAVR-289 holds promise as a potential therapy for adenovirus infections, particularly in immunocompromised patients. HighlightsO_LILAVR-289 is a unique acyclic nucleoside phosphonate prodrug. C_LIO_LILAVR-289 displays antiviral activity against Adenovirus with an EC50 of about 100 nM against HAdV-C5 ANCHOR. C_LIO_LILAVR-289 inhibits viral replication by targeting viral DNA polymerase, preventing DBP clustering and replication center formation. C_LIO_LIIn immunosuppressed Syrian hamsters, LAVR-289 is well tolerated and ensures 100% survival while effectively stopping virus replication. C_LIO_LILAVR-289's broad-spectrum activity positions it as a promising treatment for immunocompromised patients facing multiple viral infections. C_LI

microbiology↗

bioRxiv2025

LAVR-289, a new acyclo-nucleoside phosphonate having broad-spectrum activity against herpesviruses.

Human herpesviruses are latent opportunistic large dsDNA viruses that can have deleterious effect in immunocompromised patients by triggering life-threatening infections. Over the past years, different antivirals have been developed against a variety of herpesviruses, including Acyclovir for herpes simplex viruses (HSV1 and 2) and ganciclovir and letermovir for human cytomegalovirus (hCMV). However, broad-spectrum inhibitors of herpesvirus infections are still missing. Here we report the efficacy of LAVR-289, a new acyclic nucleoside analog, on a broad variety of herpesviruses from human and animal origin. LAVR-289 displays nanomolar efficiency in vitro, is active on viral strains resistant to gold standard antivirals and ex vivo on reconstituted human skin infected with HSV1. Combined with its anti-poxvirus and anti-adenovirus activity, LAVR-289 can become the next gold standard for the management of opportunistic virus infections in immunocompromised patient.

microbiology↗

bioRxiv2018

Real-time visualization and quantification of human Cytomegalovirus replication in living cells using the ANCHOR DNA labeling technology.

Human cytomegalovirus (HCMV) induces latent life-long infections in all human populations. Depending on geographic area and socio-economic conditions between 30 to nearly 100% of individuals are affected. The biology of this virus is difficult to explore due to its extreme sophistication and the lack of pertinent animal model. Here we present the first application of the ANCHOR DNA labeling system to a herpes virus, allowing real time imaging and direct monitoring of HCMV infection and replication in human living cells. The ANCHOR system is composed of a protein (OR) which specifically binds to a short, non-repetitive DNA target sequence (ANCH) and spreads onto neighboring sequences due to protein oligomerization. If OR protein is fused to GFP, this accumulation results in a site specific fluorescent focus. We have created a recombinant ANCHOR-HCMV harboring an ANCH target sequence and the gene encoding the cognate OR-GFP fusion protein. Infection of permissive cells with ANCHOR-HCMV enables visualization of the nearly complete viral cycle until cell fragmentation and death. Quantitative analysis of infection kinetics and of viral DNA replication revealed cell-type specific behavior of HCMV and sensitivity to inhibitors. Our results show that the ANCHOR technology is a very efficient tool for the study of complex DNA viruses and new highly promising biotechnology applications.\n\nIMPORTANCEThe ANCHOR technology is to date the most powerful tool to follow and quantify the replication of HCMV in living cells and to gain new insights into its biology. This technology is applicable to virtually any DNA virus or virus presenting a dsDNA phase, paving the way to infection imaging in various cell lines or even in animal models and opening fascinating fundamental and applied prospects. Associated to high content automated microscopy, this technology permitted rapid, robust and precise determination of Ganciclovir IC50 and IC90 on HCMV replication, with minimal hands-on investment. To search for new antiviral activities, the experiment is easy to up-grade towards efficient and cost-effective screening of large chemical libraries. The simple infection of permissive cells with ANCHOR-viruses in the presence of a compound of interest may even provide a first estimation about the stage of the viral cycle this molecule is acting upon.

microbiology↗