Aniline-Based Inhibitors of Influenza H1N1 Virus Acting on Hemagglutinin-Mediated Fusion

Leiva, Rosana; Barniol‐Xicota, Marta; Codony, Sandra; Ginex, Tiziana; Vanderlinden, Evelien; Montes, Marta Pascual de; Caffrey, Michael; Luque, F. Javier; Naesens, Lieve; Vázquez, Santiago

doi:10.1021/acs.jmedchem.7b00908

Cited by 32 publications

(28 citation statements)

References 70 publications

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“…SA-19; chloroquine (an inhibitor of endosomal acidification); and two aniline-based influenza fusion inhibitors (80, 81, Fig. 2) which inhibit the conformational refolding of H1 HA at low endosomal pH [26]. With 63, the inhibition of pseudoparticle entry, as deduced from the reduction in GFP signal, was 92% at 10 mM and 56% at 2 mM.…”

Section: Resultsmentioning

confidence: 99%

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Structure-activity relationship studies of lipophilic teicoplanin pseudoaglycon derivatives as new anti-influenza virus agents

Szűcs

Kelemen

Thai

et al. 2018

European Journal of Medicinal Chemistry

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Six series of semisynthetic lipophilic glycopeptide antibiotic derivatives were evaluated for in vitro activity against influenza A and B viruses. The new teicoplanin pseudoaglycon-derived lipoglycopeptides were prepared by coupling one or two side chains to the N-terminus of the glycopeptide core, using various conjugation methods. Three series of derivatives bearing two lipophilic groups were synthesized by attaching bis-alkylthio maleimides directly or through linkers of different lengths to the glycopeptide. Access to the fourth and fifth series of compounds was achieved by click chemistry, introducing single alkyl/aryl chains directly or through a tetraethylene glycol linker to the same position. A sixth group of semisynthetic derivatives was obtained by sulfonylation of the N-terminus. Of the 42 lipophilic teicoplanin pseudoaglycon derivatives tested, about half showed broad activity against influenza A and B viruses, with some of them having reasonable or no cytotoxicity. Minor differences in the side chain length as well as lipophilicity appeared to have significant impact on antiviral activity and cytotoxicity. Several lipoglycopeptides were also found to be active against human coronavirus.

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Section: Resultsmentioning

confidence: 99%

“…The two test compounds, 1a and 63, were tested in parallel with four control compounds, i.e. SA-19, a lipophilic derivative of aglycoristocetin[16]; chloroquine; and two aniline-based influenza fusion inhibitors, 80 and 81[26]. Data are the mean ± SEM of four independent experiments.…”

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confidence: 99%

Structure-activity relationship studies of lipophilic teicoplanin pseudoaglycon derivatives as new anti-influenza virus agents

Szűcs

Kelemen

Thai

et al. 2018

European Journal of Medicinal Chemistry

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“…The sulphated sialyl lipid NMSO 3 was a generous gift from G. Wright (Microbiotix, Worcester, MA). an System-500 spectrometers operating at 300, 400, or 500 MHz for 1 H NMR, and at 75, 100, or at 125 MHz for 13 C NMR with Me 4 Si as an internal standard. The purity of novel compounds was also determined to be >95% by elemental analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Specific HA mutations were introduced by site-directed mutagenesis and verified by cycle sequencing. Plasmid transfection into HeLa cells was carried out in 12-well plates as described [13,33]. Two days later, surface-exposed HA0 was first activated for 15 min with TPCK-treated trypsin.…”

Section: Methyl (S)-4-((1-benzyl-4-(benzylcarbamoyl)piperidin-4-yl)(2mentioning

confidence: 99%

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N-benzyl 4,4-disubstituted piperidines as a potent class of influenza H1N1 virus inhibitors showing a novel mechanism of hemagglutinin fusion peptide interaction

Castro

Ginex

Vanderlinden

et al. 2020

European Journal of Medicinal Chemistry

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The influenza virus hemagglutinin (HA) is an attractive target for antiviral therapy due to its essential role in mediating virus entry into the host cell. We here report the identification of a class of Nbenzyl-4,4,-disubstituted piperidines as influenza A virus fusion inhibitors with specific activity against the H1N1 subtype. Using the highly efficient one-step Ugi four-component reaction, a diverse library of piperidine-based analogs was synthesized and evaluated to explore the structureactivity relationships (SAR). Mechanistic studies, including resistance selection with the most active compound (2) demonstrated that it acts as an inhibitor of the low pH-induced HA-mediated membrane fusion process. Computational studies identified an as yet unrecognized fusion inhibitor binding site, which is located at the bottom of the HA 2 stem in close proximity to the fusion peptide. A direct π-stacking interaction between the N-benzylpiperidine moiety of 2 and F9 HA2 of the fusion peptide, reinforced with an additional p-stacking interaction with Y119 HA2 , and a salt bridge of the protonated piperidine nitrogen with E120 HA2 , were identified as important interactions to mediate ligand binding. This site rationalized the observed SAR and provided a structural explanation for the H1N1-specific activity of our inhibitors. Furthermore, the HA 1-S326V mutation resulting in resistance to 2 is close to the proposed new binding pocket. Our findings point to the N-benzyl-4,4,disubstituted piperidines as an interesting class of influenza virus inhibitors, representing the first example of fusion peptide binders with great potential for anti-influenza drug development. KEYWORDS Influenza virus, hemagglutinin, fusion peptide inhibitor, N-benzyl-4,4,-disubstituted piperidines 1. Introduction Each year, influenza A and B viruses are responsible for 3-5 million severe cases and 290,000-650,000 deaths worldwide [1]. The death toll rises sharply during influenza pandemics, like the 2009 pandemic that was caused by a novel swine-origin A/H1N1 virus [2]. Though widely used and recommended, influenza vaccination is limited by suboptimal effectiveness, the need for annual injection and possibility of antigen mismatch [3]. The complementary strategy, antiviral therapy, is crucial to treat and prevent complicated influenza infections, which typically develop in aged, chronically ill or hospitalized individuals [4]. Nowadays, neuraminidase inhibitors are the only effective drug class that is widely available. Hence, there is an urgent need for new influenza blockers with a distinct mode of action. Some of these are under early or advanced clinical evaluation [5,6]. The trimeric hemagglutinin (HA) glycoprotein is an attractive drug target due to its critical and dual role in virus entry [7]: i) the HA globular head recognizes sialylated cell surface glycans and mediates virus attachment [8], and ii) HA is required for membrane fusion after the virus particles have entered by endocytosis. Upon acidification of the early into late endosomes, t...

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Palladium Catalyzed Carbonyl Amination of Fluorinated Olefins for Synthesis of α‐CF₃‐Acrylamides

Li,

Jing,

Shi

et al. 2024

Eur J Org Chem

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Acrylamides are a class of important organic compounds that play key roles in biomedical chemistry, materials science, life science, and other fields. Due to the strong electron‐withdrawing effect of trifluoromethyl, the synthesis of trifluoromethylated acrylamides, especially those containing double bonds, has long been a challenge. Here, we report an example of the formation of trifluoromethyl acrylamides through palladium catalyzedcarbonylation of fluorinated olefins. By optimizing the reaction conditions, we can obtain different amide compounds, including alkyl acrylamides. aromatic acrylamides and heterocyclic acrylamides. This method has good substrate adaptability and functional group tolerance,so it is expected to be used in the synthesis of key amides in the fields of medicine and other fields.

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Aniline-Based Inhibitors of Influenza H1N1 Virus Acting on Hemagglutinin-Mediated Fusion

Cited by 32 publications

References 70 publications

Structure-activity relationship studies of lipophilic teicoplanin pseudoaglycon derivatives as new anti-influenza virus agents

Structure-activity relationship studies of lipophilic teicoplanin pseudoaglycon derivatives as new anti-influenza virus agents

N-benzyl 4,4-disubstituted piperidines as a potent class of influenza H1N1 virus inhibitors showing a novel mechanism of hemagglutinin fusion peptide interaction

Palladium Catalyzed Carbonyl Amination of Fluorinated Olefins for Synthesis of α‐CF₃‐Acrylamides

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Aniline-Based Inhibitors of Influenza H1N1 Virus Acting on Hemagglutinin-Mediated Fusion

Cited by 32 publications

References 70 publications

Structure-activity relationship studies of lipophilic teicoplanin pseudoaglycon derivatives as new anti-influenza virus agents

Structure-activity relationship studies of lipophilic teicoplanin pseudoaglycon derivatives as new anti-influenza virus agents

N-benzyl 4,4-disubstituted piperidines as a potent class of influenza H1N1 virus inhibitors showing a novel mechanism of hemagglutinin fusion peptide interaction

Palladium Catalyzed Carbonyl Amination of Fluorinated Olefins for Synthesis of α‐CF3‐Acrylamides

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Palladium Catalyzed Carbonyl Amination of Fluorinated Olefins for Synthesis of α‐CF₃‐Acrylamides