SC75741

SC75741 is a potent NF-κB inhibitor with EC50 value of 200 nM.
NF-kB is a protein complex that regulates the expression of immunoreceptors, inflammatory cytokines and chemokines and is commonly regarded as a major antiviral factor. However, it has been shown that influenza A viruses exploit this signaling pathway for efficient replication [1].
In MDCK cells, inhibitory potential of 5 uM SC75741 on virus replication is highest at later stages of infection. In the human alveolar type II epithelial cell line A549 infected with H5N1 and H7N7 viruses, SC75741 provoked an efficient reduction of virus titers in a dose-dependent way [1].
In the lung of infected mice, SC75741 reduces viral replication and H5N1-induced IL6 and IP-10 expression. In addition, SC75741 also reduced cytokine production in vivo that is involved in hypercytokinemia mediated by influenza virus infection. Importantly, SC75741 exhibits a high barrier for virus variants [1].
References:
[1]. Ehrhardt C, Rückle A, Hrincius ER, et al. The NF-κB inhibitor SC75741 efficiently blocks influenza virus propagation and confers a high barrier for development of viral resistance. Cell Microbiol, 2013, 15(7): 1198-1211.

The NF-kappaB inhibitor SC75741 protects mice against highly pathogenic avian influenza A virus.[Pubmed:23811282]

Antiviral Res. 2013 Sep;99(3):336-44.

The appearance of pandemic H1N1 and highly pathogenic avian H5N1 viruses in humans as well as the emergence of seasonal H1N1 variants resistant against neuraminidase inhibitors highlight the urgent need for new and amply available antiviral drugs. We and others have demonstrated that influenza virus misuses the cellular IKK/NF-kappaB signaling pathway for efficient replication suggesting that this module may be a suitable target for antiviral intervention. Here, we show that the novel NF-kappaB inhibitor SC75741 significantly protects mice against infection with highly pathogenic avian influenza A viruses of the H5N1 and H7N7 subtypes. Treatment was efficient when SC75741 was given intravenously in a concentration of 5mg/kg/day. In addition, application of SC75741 via the intraperitoneal route resulted in a high bioavailability and was also efficient against influenza when given 15 mg/kg/day or 7.5 mg/kg/twice a day. Protection was achieved when SC75741 was given for seven consecutive days either prior to infection or as late as four days after infection. SC75741 treatment showed no adverse effects in the concentrations required to protect mice against influenza virus infection. Although more pre-clinical studies are needed SC75741 might be a promising candidate for a novel antiviral drug against influenza viruses that targets the host cell rather than the virus itself.

The NF-kappaB inhibitor SC75741 efficiently blocks influenza virus propagation and confers a high barrier for development of viral resistance.[Pubmed:23320394]

Cell Microbiol. 2013 Jul;15(7):1198-211.

Ongoing human infections with highly pathogenic avian H5N1 viruses and the emergence of the pandemic swine-origin influenza viruses (IV) highlight the permanent threat elicited by these pathogens. Occurrence of resistant seasonal and pandemic strains against the currently licensed antiviral medications points to the urgent need for new and amply available anti-influenza drugs. The recently identified virus-supportive function of the cellular IKK/NF-kappaB signalling pathway suggests this signalling module as a potential target for antiviral intervention. We characterized the NF-kappaB inhibitor SC75741 as a broad and efficient blocker of IV replication in non-toxic concentrations. The underlying molecular mechanism of SC75741 action involves impaired DNA binding of the NF-kappaB subunit p65, resulting in reduced expression of cytokines, chemokines, and pro-apoptotic factors, subsequent inhibition of caspase activation and block of caspase-mediated nuclear export of viralribonucleoproteins. SC75741 reduces viral replication and H5N1-induced IL-6 and IP-10 expression in the lung of infected mice. Besides its virustatic effect the drug suppresses virus-induced overproduction of cytokines and chemokines, suggesting that it might prevent hypercytokinemia that is discussed to be an important pathogenicity determinant of highly pathogenic IV. Importantly the drug exhibits a high barrier for development of resistant virus variants. Thus, SC75741-derived drugs may serve as broadly non-toxic anti-influenza agents.

SC75741 is a broad and efficient NF-κB inhibitor with an IC50 of 200 nM for p65. SC75741 blocks influenza viruses (IV) replication in non-toxic concentrations. SC75741 impairs DNA binding of the NF-κB subunit p65, resulting in reduced expression of cytokines, chemokines, and pro-apoptotic factors. SC75741 subsequently inhibits caspase activation and blocks caspase-mediated nuclear export of viral ribonucleoproteins.

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