Laninamivir Prodrug CS-8958, a Long-Acting Neuraminidase Inhibitor, Shows Superior Anti-Influenza Virus Activity after a Single Administration

Abstract

Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for use for the treatment and prophylaxis of influenza. We have reported on laninamivir (code name, R-125489), a novel neuraminidase inhibitor, and have discovered that the laninamivir prodrug CS-8958 worked as a long-acting neuraminidase inhibitor in a mouse influenza virus infection model when it is intranasally administered. In this study, CS-8958 was administered just once 7 days before infection and showed significant efficacy in vivo. The efficacy of a single administration of CS-8958 after viral infection was then compared with that of repeated administrations of oseltamivir phosphate or zanamivir in mice and ferrets. CS-8958 showed efficacy superior or similar to the efficacies of the two licensed NA inhibitors. CS-8958 also significantly reduced the titers of an oseltamivir-resistant H1N1 virus with a neuraminidase H274Y substitution in a mouse infection model. These results suggest that since CS-8958 is characteristically long lasting in the lungs, it may be ideal for the prophylaxis and treatment of influenza.

The E119D neuraminidase mutation identified in a multidrug-resistant influenza A(H1N1)pdm09 isolate severely alters viral fitness in vitro and in animal models

“…NAIs target the active center of the influenza neuraminidase (NA) molecule, which is made of 8 functional (R-118, D-151, R-152, R-224, E-276, R-292, R-371, and Y-406; N2 numbering) and 11 framework and EÀ425;N2 numbering) residues that are largely conserved among influenza A and B viruses (Colman et al, 1993). Two NAI compounds (i.e., oseltamivir and zanamivir) have been commercially available worldwide for more than a decade whereas peramivir (Birnkrant and Cox, 2009;Press release, 2014) and laninamivir (Kubo et al, 2010;Watanabe et al, 2010) are licensed in a limited number of countries. As for the adamantanes, the emergence of NAI-resistant viruses is a serious threat that may compromise the clinical utility of these agents.…”

Discovery of Novel Antiviral Agents Directed Against the Influenza A Virus Nucleoprotein

“…2, the current treatments for influenza infections target two steps of the replication cycle: uncoating and budding. Six drugs are currently available (Table 1): the adamantanes and neuraminidase inhibitors, including amantadine, rimantadine, zanamivir, oseltamivir, peramivir, and laninamivir (Kubo et al, 2010;Vanvoris et al, 1981;Wingfiel et al, 1969, Yamashita, 2011. The adamantanes block the function of the M2 ion channel, preventing acidification-triggered uncoating.…”

“…Many reports have shown that both drugs are highly efficient in the treatment of influenza (Cooper et al, 2003;Hayden et al, 1997;Monto et al, 1999;Nicholson et al, 2000). In recent years, peramivir and laninamivir, which also target NA, have been licensed as anti-influenza drugs (Kubo et al, 2010;Yamashita, 2011). For oseltamivir, the appearance of drug-resistant mutants has significantly increased in many countries (Besselaar et al, 2008;Dharan et al, 2009;Hauge et al, 2009;Hurt et al, 2009).…”

“…Two classes of drugs including adamantanes (amantadine and rimantadine) and NA inhibitors (oseltamivir, zanamivir, peramivir, and laninamivir) are available for the treatment of the influenza infection (Kubo et al, 2010;Vanvoris et al, 1981;Wingfiel et al, 1969;Yamashita, 2011). Because the adamantanes exert several toxic effects on the central nervous system (Bryson et al, 1980;Keyser et al, 2000) and also because of the emergence of resistant variants (Bright et al, 2005(Bright et al, , 2006, the use of these drugs is limited.…”

Swine-origin influenza-virus-induced acute lung injury: Novel or classical pathogenesis?

“…NA inhibitors are currently preferred for influenza virus infections since they are less toxic and more effective than the M2 inhibitors. In mice, an A/ H1N1pdm strain CA04 was highly susceptible to oseltamivir phosphate, zanamivir, R-125489 [the active form of CS-8958 (laninamivir)], and viral RNA polymerase inhibitor T-705 (favipiravir) [75,76] . Peramivir is another NA inhibitor under development for the treatment and prevention of influenza [77] .…”