CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity

Abstract

Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for the treatment of and prophylaxis against influenza. In this paper, the new potent NA inhibitor R-125489 is reported for the first time. R-125489 inhibited the NA activities of various type A and B influenza viruses, including subtypes N1 to N9 and oseltamivir-resistant viruses. The survival effect of R-125489 was shown to be similar to that of zanamivir when administered intranasally in a mouse influenza virus A/Puerto Rico/8/34 infection model. Moreover, we found that the esterified form of R-125489 showed improved efficacy compared to R-125489 and zanamivir, depending on the acyl chain length, and that 3-(O)-octanoyl R-125489 (CS-8958) was the best compound in terms of its life-prolonging effect (P < 0.0001, compared to zanamivir) in the same infection model. A prolonged survival effect was observed after a single administration of CS-8958, even if it was given 7 days before infection. It is suggested that intranasally administered CS-8958 works as a long-acting NA inhibitor and shows in vivo efficacy as a result of a single intranasal administration.

Influenza neuraminidase operates via a nucleophilic mechanism and can be targeted by covalent inhibitors

“…Two more recently developed NA inhibitors, laninamivir and peramivir, are approved for use in Japan and still under phase III clinical trials in the United States. All of these current NA inhibitors were designed based upon the structure of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en), a putative NA transition-state analogue 8,[10][11][12] . Insight into the NA catalytic mechanism and the proposed oxocarbenium ion transition-state intermediate were crucial for the design of Neu5Ac2en analogues with potent NA inhibitory activity 13,14 .…”

In-silico structural analysis of the influenza A subtype H7N9 neuraminidase and molecular docking with different neuraminidase inhibitors

“…Oseltamivir and zanamivir are commercially available NA inhibitors which are active against both group 1 and group 2 NA as well as influenza B NA [3]. Meanwhile, laninamivir is another long-acting NA inhibitor including oseltamivir-resistant viruses in adults [24,25]. Recently, peramivir has been approved in Japan for use in over 1 month of age [11].…”

Fluorescence polarization-based assay using N-glycan-conjugated quantum dots for screening in hemagglutinin blockers for influenza A viruses

“…Neuraminidase inhibitors, oseltamivir, zanamivir, peramivir, and laninamivir, are licensed for the treatment and prevention of seasonal influenza (Babu et al, 2000;Gubareva, 2004;Yamashita et al, 2009). These drugs also possess potential to reduce virus transmission and mortality during the next pandemic.…”