Design and synthesis of pinanamine derivatives as anti-influenza A M2 ion channel inhibitors

Zhao, Xin; Jie, Yanling; Rosenberg, Matthew; Wan, Junting; Zeng, Shaogao; Cui, Wei; Xiao, Yanhe; Li, Zhiyuan; Tu, Zhengchao; Casarotto, Marco G.; Hu, Wenhui

doi:10.1016/j.antiviral.2012.09.001

Cited by 51 publications

(35 citation statements)

References 47 publications

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“…1 Finding suitable antiviral drugs to treat influenza infection, particularly with the highly prevalent, amantadine-insensitive M2 (S31N), is a key field of influenza research, and M2 protein inhibitors are a significant class of anti-influenza agents. [2][3][4][5][6] The M2 proton channel of Influenza A is a critical protein in the viral replication cycle. When proton transport through the channel is inhibited, the cycle is arrested and infection of the host is halted.…”

Section: Introductionmentioning

confidence: 99%

“…What role does orientation play in amantadine insensitivity of N31 M2? 6 To better understand the influence of amantadine orientation in M2 inhibition, we explore not only its position but also its orientation with respect to the channel axis in the Influenza A M2 transmembrane domain (M2TM) using 2-dimensional umbrella sampling replica-exchange, steered, and classic molecular dynamics simulations. The principal amine binding positions identified by Wang et al (2013) 3 are seen to play an important role for amantadine binding, with the positions at carbonyls 31 and 34 being key to amantadine binding in S31 and the position at carbonyl 27 (which is also near the plane of the N31 side chain carbonyls) having an important, perhaps kinetic role for amantadine binding in N31.…”

Section: Introductionmentioning

confidence: 99%

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Resistance-Mutation (N31) Effects on Drug Orientation and Channel Hydration in Amantadine-Bound Influenza A M2

et al. 2015

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The mechanism of amantadine binding to the S31 variant of the M2 protein of Influenza A is well understood, but the reasons behind N31 M2 amantadine insensitivity remain under investigation. Many molecular dynamics studies have evaluated the influence of amantadine position within the channel pore on its ability to inhibit proton conductance in M2, but little is known about the influence of amantadine rotational orientation. Replica-exchange umbrella sampling, steered, and classic molecular dynamics simulations were performed on amantadine in the solid-state NMR structure of S31 M2 and an N31 M2 homologue, both in the homotetramer configuration, to explore the effects of the position and tilt angle of amantadine on inhibition of the M2 channel. Steered simulations show that amantadine rotates with the amine toward the bulk water as it passes into the hydrophobic entryway lined by Val27 side chains. Results from all simulation types performed indicate that amantadine has a strong, specific orientation with the amine turned inward toward the central cavity in the S31 M2 pore but has variable orientation and a strong propensity to remain outward pointing in N31 M2. Free energy profiles from umbrella sampling, measured relative to bulk water, show amantadine binds more strongly to the S31 M2 pore by 8 kcal/mol in comparison to amantadine in the N31 pore, suggesting that it can escape more readily from the N31 channel through the Val27 secondary gate, whereas it is captured by the S31 channel in the same region. Lower water density and distribution near amantadine in S31 M2 reveal that the drug inhibits proton conductance in S31 M2 because of its inward-pointing configuration, whereas in N31 M2, amantadine forms hydrogen bonds with an N31 side chain and does not widely occlude water occupancy in any configuration. Both amantadine's weaker binding to and weaker water occlusion in N31 M2 might contribute to its inefficacy as an inhibitor of the mutant protein.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Resistance-Mutation (N31) Effects on Drug Orientation and Channel Hydration in Amantadine-Bound Influenza A M2

et al. 2015

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“…At the same time of writing this article, a pinanamine bearing an imidazole derivative was reported to show weak inhibitory activity against the S31N M2 channel. 41 …”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Dual Inhibitors of the Wild-Type and the Most Prevalent Drug-Resistant Mutant, S31N, of the M2 Proton Channel from Influenza A Virus

Wang¹,

Wang

et al. 2013

J. Med. Chem.

130

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Anti-influenza drugs, amantadine and rimantadine, targeting the M2 channel from influenza A virus are no longer effective because of widespread drug resistance. S31N is the predominant and amantadine-resistant M2 mutant, present in almost all of the circulating influenza A strains as well as in the pandemic 2009 H1N1 and the highly pathogenic H5N1 flu strains. Thus, there is an urgent need to develop second-generation M2 inhibitors targeting the S31N mutant. However, the S31N mutant presents a huge challenge to drug discovery, and it has been considered undruggable for several decades. Using structural information, classical medicinal chemistry approaches, and M2-specific biological testing, we discovered benzyl-substituted amantadine derivatives with activity against both S31N and WT, among which 4-(adamantan-1-ylaminomethyl)-benzene-1,3-diol (44) is the most potent dual inhibitor. These inhibitors demonstrate that S31N is a druggable target and provide a new starting point to design novel M2 inhibitors that address the problem of drug-resistant influenza A infections.

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“…The clinical application of anti-influenza drugs is limited by side effects and the emergence of resistant strains8. Consequently, it’s very necessary to explore new drugs for influenza virus control.…”

Section: Discussionmentioning

confidence: 99%

“…Vaccines must be continually updated to cover currently circulating viral strains, and their protective efficacy is limited in people over 65-year-old who are paradoxically susceptible to influenza7. M2 ion channel blockers, with potential neurotoxicity, inhibits influenza A virus only8. NAIs act by binding to the active site of the viral NA to prevent release and spread of progeny virions from infected cells during the replication cycle1, which is a promising target for anti-influenza drugs screening9.…”

mentioning

confidence: 99%

Antiviral activity of chlorogenic acid against influenza A (H1N1/H3N2) virus and its inhibition of neuraminidase

Ding

Cao

et al. 2017

Sci Rep

158

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Lonicera japonica Thunb, rich in chlorogenic acid (CHA), is used for viral upper respiratory tract infection treatment caused by influenza virus, parainfluenza virus, and respiratory syncytial virus, ect in China. It was reported that CHA reduced serum hepatitis B virus level and death rate of influenza virus-infected mice. However, the underlying mechanisms of CHA against the influenza A virus have not been fully elucidated. Here, the antiviral effects and potential mechanisms of CHA against influenza A virus were investigated. CHA revealed inhibitory against A/PuertoRico/8/1934(H1N1) (EC50 = 44.87 μM), A/Beijing/32/92(H3N2) (EC50 = 62.33 μM), and oseltamivir-resistant strains. Time-course analysis showed CHA inhibited influenza virus during the late stage of infectious cycle. Indirect immunofluorescence assay indicated CHA down-regulated the NP protein expression. The inhibition of neuraminidase activity confirmed CHA blocked release of newly formed virus particles from infected cells. Intravenous injection of 100 mg/kg/d CHA possessed effective antiviral activity in mice, conferring 60% and 50% protection from death against H1N1 and H3N2, reducing virus titres and alleviating inflammation in the lungs effectively. These results demonstrate that CHA acts as a neuraminidase blocker to inhibit influenza A virus both in cellular and animal models. Thus, CHA has potential utility in the treatment of the influenza virus infection.

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Design and synthesis of pinanamine derivatives as anti-influenza A M2 ion channel inhibitors

Cited by 51 publications

References 47 publications

Resistance-Mutation (N31) Effects on Drug Orientation and Channel Hydration in Amantadine-Bound Influenza A M2

Resistance-Mutation (N31) Effects on Drug Orientation and Channel Hydration in Amantadine-Bound Influenza A M2

Discovery of Novel Dual Inhibitors of the Wild-Type and the Most Prevalent Drug-Resistant Mutant, S31N, of the M2 Proton Channel from Influenza A Virus

Antiviral activity of chlorogenic acid against influenza A (H1N1/H3N2) virus and its inhibition of neuraminidase

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