Second-generation nitazoxanide derivatives: thiazolides are effective inhibitors of the influenza A virus

Aim: The only small molecule drugs currently available for treatment of influenza A virus (IAV) are M2 ion channel blockers and sialidase inhibitors. The prototype thiazolide, nitazoxanide, has successfully completed Phase III clinical trials against acute uncomplicated influenza. Results: We report the activity of seventeen thiazolide analogs against A/PuertoRico/8/1934(H1N1), a laboratory-adapted strain of the H1N1 subtype of IAV, in a cell culture-based assay. A total of eight analogs showed IC50s in the range of 0.14–5.0 μM. Additionally a quantitative structure–property relationship study showed high correlation between experimental and predicted activity based on a molecular descriptor set. Conclusion: A range of thiazolides show useful activity against an H1N1 strain of IAV. Further evaluation of these molecules as potential new small molecule therapies is justified

Dalle Madri di Plaza de Mayo alle figlie di Ciudad Juarez

Il volume, che raccoglie le riflessioni emerse a partire dal Seminario interdisciplinare “L’individualità femminile”, si interroga sui temi di genere, mantenendo un focus privilegiato sull’educazione, e coprendo un percorso sulla storia delle donne che si snoda dal 1700 ad oggi

Dalle Madri di Plaza de Mayo alle figlie di Ciudad Juarez

Il volume, che raccoglie le riflessioni emerse a partire dal Seminario interdisciplinare “L’individualità femminile”, si interroga sui temi di genere, mantenendo un focus privilegiato sull’educazione, e coprendo un percorso sulla storia delle donne che si snoda dal 1700 ad oggi

La riscrittura di Lourdes Ortiz tra storia e mito

Da Oreste alla Gorgone Medusa, da Stanislavskij a Grace Ellison, passando dalla storia dell'arte medievale e moderna alla musica, dalla storia del cinema all'archeologia, dalla lingua e letterature inglese, russa e tedesca alla letteratura teatrale italiana, dalla filosofia all'etnomusicologia alla storia del teatro, alla numismatica, alla museologia: la presente miscellanea, nata come libro di studi in onore di Edo Bellingeri, ruota intorno al tema del mito antico e moderno investigato dai diversi autori secondo il proprio ambito disciplinare. Centrale il mito moderno di Don Giovanni, personaggio particolarmente amato e studiato da Bellingeri, illustrato per questo motivo da molti degli autori. Miti antichi e moderni si presenta così come magico caleidoscopio, per svelare all'occhio del lettore l'avvincente vicenda della storia del mito nel pensiero, nella musica, nella scrittura e in tutte le forme visive e performative che durante i secoli la fantasia dell'uomo ha saputo rappresentare

Antiviral activity of proteasome inhibitors in herpes simplex virus-1 infection: role of nuclear factor-kappaB

BACKGROUND: Herpes simplex virus type 1 (HSV-1) is a potent inducer of nuclear factor-KB (NF-kappaB), a cellular transcription factor with a crucial role in promoting inflammation and controlling cell proliferation and survival. OBJECTIVES: On the basis of the recent demonstration that HSV-1-induced NF-kappaB is actively recruited to KB-binding sites in the HSV-1 infected-cell protein 0 (ICPO) promoter enhancing viral transcription and replication, we investigated the effect of proteasome inhibitors MG132, MG115 and epoxomicin, which block NF-kappaB function by preventing the degradation of the inhibitory proteins IkappaBalpha, on HSV-1-induced NF-kappaB activation and viral replication. METHODS: Antiviral activity of proteasome inhibitors was analysed in HSV-1-infected HEp2 cells by determining infective virus titres by CPE50%, viral RNA synthesis by RT-PCR, and viral protein synthesis by immunoblot analysis or immunofluorescence. ICPO transcription was studied in transient transfection experiments using the ICPO promoter-luciferase IE1-Luc construct. IkappaBalpha degradation and NF-kappaB activity were determined by immunoblot analysis and EMSA, respectively. RESULTS: Proteasome inhibitors were found to prevent HSV-1-induced NF-kappaB activation in the early phase of infection. Block of virus-induced NF-kappaB activation resulted in inhibiting HSV-1 ICPO gene expression, in decreasing the level of immediate-early and late viral proteins, and ultimately in greatly suppressing viral replication. The antiviral effect was lost if treatment was started after NF-kappaB activation, and appeared to be independent of the HSV-1-induced activation of the JNK pathway.CONCLUSIONS: Proteasome inhibitors possess NF-kappaB-dependent antiherpetic activity. The results described further identify the IKK/NF-kappaB pathway as a suitable target for novel antiherpetic drug

The second-generation thiazolide haloxanide is a potent inhibitor of avian influenza virus replication

The emergence of new avian influenza virus (AIV) strains able to infect humans represents a serious threat to global human health. In addition to surveillance and vaccine development, antiviral therapy remains crucial for AIV control; however, the increase in drug-resistant AIV strains underscores the need for novel approaches to anti-influenza chemotherapy. We have previously shown that the thiazolide anti-infective nitazoxanide (NTZ) inhibits influenza A/PuertoRico/8/1934(H1N1) virus replication, and this effect was associated with inhibition of viral hemagglutinin (HA) maturation. Herein we investigated the activity of the second-generation thiazolide haloxanide (HLN) against H5N9, H7N1 and H1N1 AIV infection in vitro, and explored the mechanism of the antiviral action. Using the A/chicken/Italy/9097/1997(H5N9) AIV as a model, we show that HLN and its precursor p-haloxanide are more effective than NTZ against AIV, with IC50 ranging from 0.03 to 0.1 μg/ml, and SI ranging from 200 to >700, depending on the multiplicity of infection. Haloxanide did not affect AIV entry into target cells and did not cause a general inhibition of viral protein expression, whereas it acted at post-translational level by inhibiting HA maturation at a stage preceding resistance to endoglycosidase-H digestion. Importantly, this effect was independent of the AIV-HA subtype and the host cell. Immunomicroscopy and receptor-binding studies confirmed that HLN-induced alterations impair AIV-HA trafficking to the host cell plasma membrane, a key step for viral morphogenesis. The results indicate that haloxanide could provide a new tool for treatment of avian influenza virus infections