Laninamivir prodrug CS-8958, a long-acting neuraminidase inhibitor, shows superior anti-influenza virus activity after a single administration.
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.
Kubo
Shuku
S
Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan.
Tomozawa
Takanori
T
Kakuta
Masayo
M
Tokumitsu
Akane
A
Yamashita
Makoto
M
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005289:Ferrets; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects*; D009981:Influenza B virus / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000517:prevention & control / Q000821:virology; D053139:Oseltamivir / Q000008:administration & dosage / Q000627:therapeutic use; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D053243:Zanamivir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000998:Antiviral Agents; C546919:CS 8958; D011355:Prodrugs; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir