Development of Anti-influenza Drugs: II. Improvement of Oral and Intranasal Absorption and the Anti-influenza Activity of Stachyflin Derivatives

Yoshimoto, Jun; Yagi, Shigenori; Ono, Junko; Sugita, Katsuji; Hattori, Naohiko; Fujioka, Toshihiro; Fujiwara, Tamio; Sugimoto, H.; Hashimoto, Naofumi

doi:10.1211/0022357001777225

Cited by 25 publications

(15 citation statements)

References 17 publications

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“…The results of the present study revealed that Stachyflin had subtype-specific antiviral activities against not only H1 and H2 viruses, but also H5, including highly pathogenic avian influenza viruses, and H6 viruses, as well as A(H1N1)pdm09 virus in MDCK cells and its IC 50 was 0.05-4.7 μM (Table 1). It is revealed that cytotoxicity of Stachyflin to the MDCK monolayers did not appear up to a concentration of 75 μM [13], however, for its insolubility [16], antiviral activity in vitro was assessed up to a concentration of 6.5 μM. In the present study, it was found that WSN strain was the most susceptible to Stachyflin, and then Ibaraki, an avian H5N2 virus isolated from chicken.…”

Section: Discussionmentioning

confidence: 68%

“…The antiviral activity of Stachyflin in mice challenged with A/Kumamoto/5/1967 (H2N2) was evaluated in previous study [15,16]. To confirm whether the antiviral activity in vitro can be applied to in vivo , the virus titers in the lungs of mice infected with WSN or A/chicken/Ibaraki/1/2005 (H5N2) (Ibaraki) 72 h post-inoculation were evaluated.…”

Section: Resultsmentioning

confidence: 99%

“…It was found that a sesquiterpene derivative, Stachyflin, inhibited replication of H1 and H2 influenza A viruses in vitro [13,14] and in vivo [15,16]. Although Stachyflin is postulated to inhibit the fusion step, its precise mechanism has not been clarified.…”

Section: Introductionmentioning

confidence: 99%

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Antiviral activity of stachyflin on influenza A viruses of different hemagglutinin subtypes

Motohashi

Igarashi

Okamatsu

et al. 2013

Virol J

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BackgroundThe hemagglutinin (HA) of influenza viruses is a possible target for antiviral drugs because of its key roles in the initiation of infection. Although it was found that a natural compound, Stachyflin, inhibited the growth of H1 and H2 but not H3 influenza viruses in MDCK cells, inhibitory activity of the compound has not been assessed against H4-H16 influenza viruses and the precise mechanism of inhibition has not been clarified.MethodsInhibitory activity of Stachyflin against H4-H16 influenza viruses, as well as H1-H3 viruses was examined in MDCK cells. To identify factors responsible for the susceptibility of the viruses to this compound, Stachyflin-resistant viruses were selected in MDCK cells and used for computer docking simulation.ResultsIt was found that in addition to antiviral activity of Stachyflin against influenza viruses of H1 and H2 subtypes, it inhibited replication of viruses of H5 and H6 subtypes, as well as A(H1N1)pdm09 virus in MDCK cells. Stachyflin also inhibited the virus growth in the lungs of mice infected with A/WSN/1933 (H1N1) and A/chicken/Ibaraki/1/2005 (H5N2). Substitution of amino acid residues was found on the HA2 subunit of Stachyflin-resistant viruses. Docking simulation indicated that D37, K51, T107, and K121 are responsible for construction of the cavity for the binding of the compound. In addition, 3-dimensional structure of the cavity of the HA of Stachyflin-susceptible virus strains was different from that of insusceptible virus strains.ConclusionAntiviral activity of Stachyflin was found against A(H1N1)pdm09, H5, and H6 viruses, and identified a potential binding pocket for Stachyflin on the HA. The present results should provide us with useful information for the development of HA inhibitors with more effective and broader spectrum.

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Section: Discussionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

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Antiviral activity of stachyflin on influenza A viruses of different hemagglutinin subtypes

Motohashi

Igarashi

Okamatsu

et al. 2013

Virol J

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“…Therefore, stachyflin may be used as a tool for probing the molecular mechanism of HA conformational change at low pH, and as a pharmaceutical agent for the treatment of influenza. Further, stachyflin and its derivatives have been deeply discussed, including improvement of oral and intranasal absorption [73,74], isolation, synthesis, structure elucidation, biological activities, and preliminary structure activity relationships [75][76][77]. (Need one more sentence) It is interesting that diverse compounds have similar biological activities against the HA-mediated membrane fusion of influenza virus.…”

Section: Inhibitors Of Membrane Fusion-inducing Conformational Changementioning

confidence: 99%

Potential Targets and Their Relevant Inhibitors in Anti-influenza Fields

Gong¹,

Fang

Li³

et al. 2009

CMC

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Influenza is a disease for deeply affecting millions of people every year. Recently, there has been considerable concern regarding the highly pathogenic H5N1 avian influenza virus, and its human pandemic potential. With developments in viral biology, there are more novel antiviral strategies targeting these viruses. In this review, we will discuss several proven and potential anti-influenza targets, including viral factors (such as hemagglutinin (HA), M2 ion channel protein, RNA-dependent RNA polymerase (RdRp), nucleoprotein (NP), non-structural protein (NS) and neuraminidase (NA)) and host factors (such as v-ATPase, protease, inosine monophosphate dehydrogenase (IMPDH) and intracellular signalling cascades), and their relevant inhibitors.

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“…The mechanism of stachyflin action was shown to interfere with the low-pH induced conformational change of HA [42]. The same research group continued their effort in the development of stachyflin (I) derivatives (acetylstachyflin, II, III, and their phosphate esters, I-Phos, II-Phos and III-Phos) and found that intranasally administered III-Phos has anti-influenza-virus activity in animal studies [43][44][45][46]. Oral absorption properties were evaluated for stachyflin (I) and its derivatives (II, and their phosphate esters, I-Phos and II-Phos) with or without employing vehicles [43].…”

Section: Drug Discovery Based On Hamentioning

confidence: 99%

Strategies of Development of Antiviral Agents Directed Against Influenza Virus Replication

Hsieh

Hsu

2007

CPD

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In this review, we will discuss drug design based on proven and potential anti-influenza drug targets including viral hemagglutinin (HA), neuraminidase (NA), M2 ion channel, 3P polymerase complex, and host factors such as kinases. We have summarized influenza inhibitors based on their mode of actions. For instance, included are descriptions of (1) inhibitors of HA cleavage, such as nafamostat, camostat, gabexate, epsilon-aminocapronic acid and aprotinin, (2) inhibitors of fusion and entry, such as benzoquinones and hydroquinones, CL 385319, BMY-27709, stachyflin, and their analogues, (3) inhibitors of viral RNPs/polymerase/endonuclease, such as T-705, L-735,822, flutimide and their analogues, (4) inhibitors of MEK, such as PD 0325901, CI-1040 and ARRY-142886, and (5) inhibitors of NA such as DANA, FANA, zanamivir, and oseltamivir, etc. Although amantadine and rimantadine are not recommended for treating influenza virus infections because of drug resistance problem, these viral M2 ion channel blockers established a proof-of-concept that the endocytosis of virion into host cells can be a valid drug target because M2 protein is involved in the endocytosis process. The influenza polymerase complex not only catalyzes RNA polymerization but also encodes the "cap snatching" activity. After being exported from the nucleus to the cytoplasm, the newly synthesized vRNPs are assembled into virions at the plasma membrane. The progeny virions will then leave the host cells through the action of NA. The strategies for discovery of small molecule inhibitors of influenza virus replication based on each particular mechanism will be discussed. Finally, the lessons learned from the design of NA inhibitors (NAI) are also included. Many exciting opportunities await the cadre of virologists, medicinal chemists, and pharmacologists to design novel influenza drugs with favorable pharmacological and pharmacokinetic properties to combat this threatening infectious disease.

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Development of Anti-influenza Drugs: II. Improvement of Oral and Intranasal Absorption and the Anti-influenza Activity of Stachyflin Derivatives

Cited by 25 publications

References 17 publications

Antiviral activity of stachyflin on influenza A viruses of different hemagglutinin subtypes

Antiviral activity of stachyflin on influenza A viruses of different hemagglutinin subtypes

Potential Targets and Their Relevant Inhibitors in Anti-influenza Fields

Strategies of Development of Antiviral Agents Directed Against Influenza Virus Replication

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