In Vitro Pharmacokinetic Optimizations of AM2-S31N Channel Blockers Led to the Discovery of Slow-Binding Inhibitors with Potent Antiviral Activity against Drug-Resistant Influenza A Viruses

Wang, Yuanxiang; Hu, Yanmei; Xu, Shuting; Zhang, Yongtao; Musharrafieh, Rami; Hau, Raymond K.; Ma, Chunlong; Wang, Jun

doi:10.1021/acs.jmedchem.7b01536

Cited by 46 publications

(96 citation statements)

References 34 publications

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“…and 15, which potently inhibited both M2 current activity by TEVC (75.5 and 84.3% at 100 µM) and adamantane-resistant viruses (EC 50 s = 1.2 and 0.3 µM, respectively; Li et al, 2017;Wang et al, 2018;Musharrafieh et al, 2018). Remarkably, unlike amantadine, which readily gave rise to resistance after a single passage in vitro, compounds 14 and 15 required 4-5 passages before two resistance mutations These observations may suggest that the viable evolutionary space of M2 in response to selection with these compounds may be limited.…”

Section: Adamantane-based Inhibitorsmentioning

confidence: 99%

“…For example, Compounds 5, 8, 10, and 16 have been reported to inhibited virus strains with resistance to the licensed neuramindase inhibitor oseltamivir (Hu et al, 2017a;Ma et al, 2016;Wang et al, 2018). In oseltamivir-sensitive viruses, 5 and 16 also synergized with oseltamivir, raising the possibility of combination therapies where lower doses of drugs can be used to minimize the risk of toxicities without sacrificing antiviral efficacy (Ma et al, 2016;Wang et al, 2018). Compound 16 also exhibited favorable in vitro pharmacokinetic properties such as half-life of at least 145 minutes in mouse and human liver microsome stability assays.…”

Section: Adamantane-based Inhibitorsmentioning

confidence: 99%

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Put a cork in it: Plugging the M2 viral ion channel to sink influenza

et al. 2020

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Highlights• The M2 protein of influenza A is a proton-gated proton channel that is required for viral replication • Current influenza strains are resistant to licensed M2 antivirals, so new therapies that target M2 are needed • The structure and function of M2, rise of drug resistance mutations, and current antiviral strategies are discussed AbstractThe ongoing threat of seasonal and pandemic influenza to human health requires antivirals that can effectively supplement existing vaccination strategies. The M2 protein of influenza A virus (IAV) is a proton-gated, proton-selective ion channel that is required for virus replication and is an established antiviral target. While licensed adamantane-based M2 antivirals have been historically used, M2 mutations that confer major adamantane resistance are now so prevalent in circulating virus strains that these drugs are no longer recommended. Here we review the current understanding of IAV M2 structure and function, mechanisms of inhibition, the rise of drug resistance mutations, and ongoing efforts to develop new antivirals that target resistant forms of M2.

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Section: Adamantane-based Inhibitorsmentioning

confidence: 99%

Section: Adamantane-based Inhibitorsmentioning

confidence: 99%

Put a cork in it: Plugging the M2 viral ion channel to sink influenza

et al. 2020

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“…Our drug discovery studies based on "strategic chemistry approaches" have been successful in the pharmaceutical science field. The achievements have further accelerated our researches and we are currently performing drug discovery studies on modulators for lysine-modifying enzymes based on enzyme inhibition kinetics [152][153][154][155] and in situ click chemistry. [156][157][158] The findings will be presented as articles in the near future.…”

Section: Resultsmentioning

confidence: 99%

Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches

Itoh

2020

CHEMICAL & PHARMACEUTICAL BULLETIN

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Enzymatic and post-translational modifications (PTMs) such as ubiquitination, acetylation, and methylation occur at lysine residues. The PTMs play critical roles in the regulation of the protein functions, and thus, various cellular processes. In addition, aberrations of the PTMs are associated with various diseases, such as cancer and neurodegenerative disorders. Therefore, we hypothesized that modulation of the PTMs and normalization of the PTM abnormalities could be useful as methods to control various cellular mechanisms and as a therapeutic strategy, respectively. To modulate the PTMs, we have focused on lysine-modifying enzymes and have pursued drug discovery researches on ubiquitination inducers, lysine deacetylase (KDAC) inhibitors, and lysine demethylase (KDM) inhibitors. For the identification of the modulators, we have used not only conventional drug design, such as structure-based drug design (SBDD) and ligand-based drug design (LBDD), but also "strategic chemistry approaches," such as drug design based on enzyme catalytic mechanism. As a result, we have identified several modulators which have pharmacological effects in animal models or in cellular studies. In this review, focusing on the drug design based on enzyme catalytic mechanism, our drug discovery researches have been discussed.

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“…Modified adamantane compounds have been shown to inhibit M2-N31 activity (Li et al, 2017;Wang et al, 2011;Wang et al, 2013a;Wang et al, 2018;Wu et al, 2014). Thus, to validate the assay we tested Eng195 peptides versus a small collection of similar prototypic molecules that included inhibitors of rimantadineresistant hepatitis C virus (HCV) p7 (Foster et al, 2011).…”

Section: Robust Identification Of Specific M2-n31 Inhibitors In Vitromentioning

confidence: 99%

“…This is due to a near-ubiquitous S31N polymorphism within M2 (other rarer variants also occur) generating resistance at little or no associated fitness cost to the virus. Targeting rimantadine resistant M2 has been a long-standing priority yet progress targeting M2-N31 is limited compared to other minor variants (Drakopoulos et al, 2018;Li et al, 2017;Li et al, 2016a;Li et al, 2016b;Musharrafieh et al, 2019; Thomaston & DeGrado, 2016;Wang et al, 2013a;Wang et al, 2018;Wu et al, 2014). The majority of studies have focused upon adamantane derivatives with various chemical groups linked via the primary amine.…”

Section: Introductionmentioning

confidence: 99%

Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza

Scott

Kankanala

Foster

et al. 2019

Preprint

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Pandemic influenza A virus (IAV) remains a significant threat to global health. Preparedness relies primarily upon a single class of neuraminidase (NA) targeted antivirals, against which resistance is steadily growing.The M2 proton channel is an alternative clinically proven antiviral target, yet a near-ubiquitous S31N polymorphism in M2 evokes resistance to licensed adamantane drugs. Hence, inhibitors capable of targeting N31 containing M2 (M2-N31) are highly desirable. Rational in silico design and in vitro screens delineated compounds favouring either lumenal or peripheral M2 binding, yielding effective M2-N31 inhibitors in both cases. Hits included adamantanes as well as novel compounds, with some showing low micromolar potency versus pandemic "swine" H1N1 influenza (Eng195) in culture. Interestingly, a published adamantane-based M2-N31 inhibitor rapidly selected a resistant V27A polymorphism (M2-A27/N31), whereas this was not the case for non-adamantane compounds. Nevertheless, combinations of adamantanes and novel compounds achieved synergistic antiviral effects, and the latter synergised with the neuraminidase inhibitor (NAi), Zanamivir. Thus, site-directed drug combinations show potential to rejuvenate M2 as an antiviral target whilst reducing the risk of drug resistance. Alame MM, Massaad E, Zaraket H (2016) Peramivir: A Novel Intravenous Neuraminidase Inhibitor for Treatment of Acute Influenza Infections. Front Microbiol 7: 450 Andreas LB, Eddy MT, Pielak RM, Chou J, Griffin RG (2010) Magic angle spinning NMR investigation of influenza A M2(18-60): support for an allosteric mechanism of inhibition. Journal of the American Chemical

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In Vitro Pharmacokinetic Optimizations of AM2-S31N Channel Blockers Led to the Discovery of Slow-Binding Inhibitors with Potent Antiviral Activity against Drug-Resistant Influenza A Viruses

Cited by 46 publications

References 34 publications

Put a cork in it: Plugging the M2 viral ion channel to sink influenza

Put a cork in it: Plugging the M2 viral ion channel to sink influenza

Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches

Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza

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