Exploring Organosilane Amines as Potent Inhibitors and Structural Probes of Influenza A Virus M2 Proton Channel

Wang, Junyang; Ma, Chunlong; Wu, Yibing; Lamb, Robert A.; Pinto, Lawrence H.; DeGrado, William F.

doi:10.1021/ja2050666

Cited by 68 publications

(56 citation statements)

References 37 publications

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“…We synthesized over 300 amantadine analogues and other diverse cores, some of which have been published. 14,15,22,35-38 While we succeeded in inhibiting V27A and L26F, none of these compounds inhibited S31N. 15 …”

Section: Introductionmentioning

confidence: 82%

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.

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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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Section: Introductionmentioning

confidence: 82%

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.

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130

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“…Although the most frequent amantadine-resistant mutant M2-S31N remains partially sensitive to amantadine (Wang et al, 2013), the M2-V27A mutant was completely resistant to amantadine (Balannik et al, 2009), which makes it a challenging drug target. Nevertheless, propelled by an integrated approach involving molecular dynamics simulations, NMR, electrophysiology, and medicinal chemistry, we were able to design the first-in-class M2-V27A inhibitors (Wang et al, 2011a; Wang et al, 2011b). In this report, we further evaluated the in vitro and in vivo antiviral activity of the M2-V27A inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…Among this limited number of mutants, V27A was shown to be the predominant mutation under drug selection pressure (Furuse et al, 2009a; Furuse et al, 2009b). We therefore are interested in designing the second generation of M2 channel blockers by targeting the V27A mutant (Balannik et al, 2009; Rey-Carrizo et al, 2013; Wang et al, 2011a; Wang et al, 2011b). …”

Section: Introductionmentioning

confidence: 99%

An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses

Musharrafieh

et al. 2017

Antiviral Research

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Adamantanes such as amantadine (1) and rimantadine (2) are FDA-approved anti-influenza drugs that act by inhibiting the wild-type M2 proton channel from influenza A viruses, thereby inhibiting the uncoating of the virus. Although adamantanes have been successfully used for more than four decades, their efficacy was curtailed by emerging drug resistance. Among the limited number of M2 mutants that confer amantadine resistance, the M2-V27A mutant was found to be the predominant mutant under drug selection pressure, thereby representing a high profile antiviral drug target. Guided by molecular dynamics simulations, we previously designed first-in-class M2-V27A inhibitors. One of the potent lead compounds, spiroadamantane amine (3), inhibits both the M2-WT and M2-V27A mutant with IC50 values of 18.7 and 0.3 μM, respectively, in in vitro electrophysiological assays. Encouraged by these findings, in this study we further examine the in vitro and in vivo antiviral activity of compound 3 in inhibiting both amantadine-sensitive and -resistant influenza A viruses. Compound 3 not only had single to submicromolar EC50 values against M2-WT- and M2-V27A-containing influenza A viruses in antiviral assays, but also rescued mice from lethal viral infection by either M2-WT- or M2-V27A-containing influenza A viruses. In addition, we report the design of two analogs of compound 3, and one was found to have improved in vitro antiviral activity over compound 3. Collectively, this study represents the first report demonstrating the in vivo antiviral efficacy of inhibitors targeting M2 mutants. The results suggest that inhibitors targeting drug-resistant M2 mutants are promising antiviral drug candidates worthy of further development.

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“…However, numerous medicinal chemical efforts directed toward discovery of small-molecule inhibitors of resistant M2 mutants (18-21) have shown little progress until recently (4,22,23). For example, we designed a spiroadamantane inhibitor of V27A and L26F mutants (23), but this compound did not inhibit S31N.…”

Section: M2-s31n Inhibitormentioning

confidence: 99%

“…T he influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine (1)(2)(3), which bind directly to the pore of the channel (2)(3)(4). Although amantadine has been widely used for several decades, drug resistance has curtailed the use of this family of drugs.…”

Section: M2-s31n Inhibitormentioning

confidence: 99%

Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus

Wang

Ma³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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204

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The influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine, whose use has been discontinued due to widespread drug resistance. Among the handful of drug-resistant mutants, S31N is found in more than 95% of the currently circulating viruses and shows greatly decreased inhibition by amantadine. The discovery of inhibitors of S31N has been hampered by the limited size, polarity, and dynamic nature of its amantadine-binding site. Nevertheless, we have discovered smallmolecule drugs that inhibit S31N with potencies greater than amantadine's potency against WT M2. Drug binding locks the protein into a well-defined conformation, and the NMR structure of the complex shows the drug bound in the homotetrameric channel, threaded between the side chains of Asn31. Unrestrained molecular dynamics simulations predicted the same binding site. This S31N inhibitor, like other potent M2 inhibitors, contains a charged ammonium group. The ammonium binds as a hydrate to one of three sites aligned along the central cavity that appear to be hotspots for inhibition. These sites might stabilize hydronium-like species formed as protons diffuse through the outer channel to the proton-shuttling residue His37 near the cytoplasmic end of the channel.M2-S31N mutant structure | membrane protein structure | M2-S31N inhibitorT he influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine (1-3), which bind directly to the pore of the channel (2-4). Although amantadine has been widely used for several decades, drug resistance has curtailed the use of this family of drugs. Many amantadineresistant influenza viruses can be selected in cell culture (5, 6). A subset of these mutations is found in infected patients undergoing treatment with amantadine (7), and reverse-engineered viruses harboring various pore-lining mutations are competent to replicate in the mouse (8). However, many of these mutations give rise to somewhat attenuated viruses that are less transmissible than WT virus, and they tend to revert in the absence of drug pressure (6, 9). Indeed, large-scale sequencing of transmissible viruses isolated as early as 1918 showed that mutations to pore-lining residues are allowed only within the first turn of the transmembrane (TM) helix at positions 26, 27, and 31 (10). S31N has long been the predominant amantadine-resistant mutation in M2 (11)(12)(13)(14). It predominated in 98-100% of the transmissible amantadineresistant H1N1, H5N1, and H3N2 strains isolated from humans, birds, and swine in the past decade. V27A and L26F are less frequent mutations (10,11,15). Extensive studies of point mutations to the pore-lining residues of M2 have been conducted to understand the paucity of natural variants (16,17). Numerous mutants in the N-terminal aqueous pore retained the ability to conduct protons selectively over other ions, although the magnitude and pH dependence of their conduction varied. However, only a few mutations at the most distal sites, V27A,...

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Exploring Organosilane Amines as Potent Inhibitors and Structural Probes of Influenza A Virus M2 Proton Channel

Cited by 68 publications

References 37 publications

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

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

An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses

Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus

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