title: Broad range of inhibiting action of novel camphor-based compound with anti-hemagglutinin activity against influenza viruses in vitro and in vivo.
abstract: Influenza virus continues to remain one of the leading human respiratory pathogens causing significant morbidity and mortality around the globe. Due to short-term life cycle and high rate of mutations influenza virus is able to rapidly develop resistance to clinically available antivirals. This makes necessary the search and development of new drugs with different targets and mechanisms of activity. Here we report anti-influenza activity of camphor derivative 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene-aminoethanol (camphecene). In in vitro experiments it inhibited influenza viruses A(H1, H1pdm09, H3 and H5 subtypes) and B with EC50's lying in micromolar range. Due to low cytotoxicity it resulted in high selectivity indices (74-661 depending on the virus). This effect did not depend on susceptibility or resistance of the viruses to adamantane derivatives amantadine and rimantadine. The compound appeared the most effective when added at the early stages of viral life cycle (0-2h p.i.). In direct hemagglutinin inhibition tests camphecene was shown to decrease the activity of HA's of influenza viruses A and B. The activity of camphecene was further confirmed in experiments with influenza virus-infected mice, in which, being used orally by therapeutic schedule (once a day, days 1-5 p.i.) it decreased specific mortality of animals infected with both influenza A and B viruses (highest indices of protection 66.7% and 88.9%, respectively). Taken together, these results are encouraging for further development of camphecene-based drug(s) and for exploration of camphor derivatives as highly prospective group of potential antivirals.
authors.affiliation: Influenza Research Institute, Prof. Popova 15/17, 197376 St. Petersburg, Russia. Electronic address: zarubaev@influenza.spb.ru.
authors.forename: V V
authors.initials: VV
authors.lastname: Zarubaev
authors.affiliation: Influenza Research Institute, Prof. Popova 15/17, 197376 St. Petersburg, Russia.
authors.forename: A V
authors.initials: AV
authors.lastname: Garshinina
authors.affiliation: Influenza Research Institute, Prof. Popova 15/17, 197376 St. Petersburg, Russia.
authors.forename: T S
authors.initials: TS
authors.lastname: Tretiak
authors.affiliation: Influenza Research Institute, Prof. Popova 15/17, 197376 St. Petersburg, Russia.
authors.forename: V A
authors.initials: VA
authors.lastname: Fedorova
authors.affiliation: Influenza Research Institute, Prof. Popova 15/17, 197376 St. Petersburg, Russia.
authors.forename: A A
authors.initials: AA
authors.lastname: Shtro
authors.affiliation: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia; Novosibirsk State University, Pirogova St. 2, 630090 Novosibirsk, Russia.
authors.forename: A S
authors.initials: AS
authors.lastname: Sokolova
authors.affiliation: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia; Novosibirsk State University, Pirogova St. 2, 630090 Novosibirsk, Russia.
authors.forename: O I
authors.initials: OI
authors.lastname: Yarovaya
authors.affiliation: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia; Novosibirsk State University, Pirogova St. 2, 630090 Novosibirsk, Russia.
authors.forename: N F
authors.initials: NF
authors.lastname: Salakhutdinov
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D002164:Camphor / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004983:Ethanolamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D006388:Hemagglutinins / Q000378:metabolism*; D009980:Influenza A virus / Q000187:drug effects*; D009981:Influenza B virus / Q000187:drug effects*; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009976:Orthomyxoviridae Infections / Q000188:drug therapy; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D004983:Ethanolamines; D006388:Hemagglutinins; C000615699:camphecene; D002164:Camphor
keywords: Antivirals; Cage compounds; Camphor derivatives; Hemagglutinin; Influenza