Discovery of cyclosporine A and its analogs as broad-spectrum anti-influenza drugs with a high in vitro genetic barrier of drug resistance

Abstract

As the number of drug-resistant influenza viruses continues to increase, antivirals with novel mechanisms of action are urgently needed. Among the two classes of FDA-approved antiviral drugs, neuraminidase (NA) inhibitors, oseltamivir, zanamivir, and peramivir, are currently the only choice for the prevention and treatment of influenza virus infection. Due to the antigenic drift and antigenic shift, it will only be a matter of time before influenza viruses become completely resistant to these NA inhibitors. In pursuing the next generation of antiviral drugs with complementary mechanisms of action to those of the NA inhibitors, we have identified a natural product, cyclosporine A (CsA) (1), as a desired drug candidate. In this study, we discovered that CsA (1) and its analogs have broad-spectrum antiviral activity against multiple influenza A and B strains, including strains that are resistant to either NA or M2 inhibitors or both. Moreover, CsA (1) displays a high in vitro genetic barrier of drug resistance than oseltamivir carboxylate Mechanistic studies revealed that CsA (1) acts at the intermediate step of viral replication post viral fusion. Its antiviral mechanism is independent of inhibiting the isomerase activity of cyclophilin A (CypA), and CsA (1) has no effect on the viral polymerase activity The potent antiviral efficacy of CsA (1), coupled with the high in vitro genetic barrier of drug resistance and novel mechanism of action, renders CsA (1) a promising anti-influenza drug candidate for further development.

An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses

“…Plaque assay were performed according to previous reports (Ma et al, 2016a; Ma et al, 2016b). M2-WT-expressing A/Udorn/72 (H3N2), A/WSN/33 (M2-N31S) (H1N1), A/Solomon Islands/3/2006 (H1N1), and M2-V27A-expressing A/WSN/33 (M2-N31S + V27A) (H1N1) were used to infect MDCK cells in the presence or absence of compounds to evaluate their antiviral activity.…”

Discovery of dapivirine, a nonnucleoside HIV-1 reverse transcriptase inhibitor, as a broad-spectrum antiviral against both influenza A and B viruses

“…A time-of-addition experiment was performed as previously described (Ma et al, 2016a). Briefly, MDCK cells were seeded at 2×10 5 cells/6 cm dish.…”

Drug repurposing for new, efficient, broad spectrum antivirals

“…CsA has been reported to have antiviral activity against a wide range of viruses including human papilloma virus (HPV) (Bienkowska-Haba et al, 2009), vesicular stomatitis virus (VSV) (Bose et al, 2003), vaccinia virus (VV) (Damaso and Moussatche, 1998), HIV-1 (Franke et al, 1994;Thali et al, 1994;Wainberg et al, 1988), and HCV (Kaul et al, 2009;Nakagawa et al, 2004;Yang et al, 2008). Although the immunosuppressive activity of CsA does not make it a good candidate for antiviral treatment, some CsA derivatives, like alisporivir, NIM811 and SCY-635, with reduced immunosuppressive properties that retain the ability to bind cyclophilin have been developed and proved to conserve the antiviral activity (Flisiak et al, 2008;Ma et al, 2016;Paeshuyse et al, 2006;Watashi et al, 2014). The replication of certain viruses like HIV, HCV, HPV, VSV, VV or influenza virus relies on their interaction with cyclophilins at certain steps of their replication cycle.…”

“…CsA-treated mice were administered a dose of influenza A virus that would be lethal for untreated mice, but they survived (Schiltknecht and Ada, 1985). CsA has also been reported to inhibit the propagation of several strains of influenza A virus in cell cultures blocking a late step of the replication cycle by mechanisms that might implicate CypA-dependent and -independent pathways (Hamamoto et al, 2013;Liu et al, 2012a;Ma et al, 2016).…”