A Novel Potent and Highly Specific Inhibitor against Influenza Viral N1–N9 Neuraminidases: Insight into Neuraminidase–Inhibitor Interactions

Sriwilaijaroen, Nongluk; Magesh, Sadagopan; Imamura, Akira; Ando, Hiromune; Ishida, Hideyuki; Sakai, Miho; Ishitsubo, Erika; Hori, Takuma; Moriya, Setsuko; Ishikawa, Takeshi; Kuwata, Kazuo; Odagiri, Takato; Tashiro, Masato; Hiramatsu, Hiroaki; Tsukamoto, Kenji; Miyagi, Taeko; Tokiwa, Hiroaki; Kiso, Makoto; Suzuki, Yasuo

doi:10.1021/acs.jmedchem.5b01863

Cited by 24 publications

(17 citation statements)

References 60 publications

(101 reference statements)

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“…The results are shown in Table 3. OSC showed very good inhibitory activity against the four 17,[32][33][34][35][36] and these findings served to verify the reliability of our assay.…”

Section: Inhibition Of Influenza Neuraminidasessupporting

confidence: 52%

Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant

et al. 2018

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Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five sub-series of oseltamivir derivatives were designed and synthesized to improve their activity towards drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6 and H5N8. Besides, 21h was 5-to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity and potent antiviral activity in vivo, and high metabolic stability. Overall, above excellent profiles make 21h a promising drug candidate for the treatment of influenza virus infection.

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“…The results are shown in Table 3. OSC showed very good inhibitory activity against the four 17,[32][33][34][35][36] and these findings served to verify the reliability of our assay.…”

Section: Inhibition Of Influenza Neuraminidasessupporting

confidence: 52%

Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant

et al. 2018

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“…By summing up these IFIEs calculated for individual fragments, overall binding energy between the ligand and protein can be estimated, which can be related to the resultant biological potency of the compound as measured in a biological assay. The correlated FMO calculation provides a complete list of interactions formed between the ligand and protein and so it is suitable for evaluating not only the electrostatic interactions (important in hydrogen-bonding) but also the van der Waals dispersion interactions (hydrophobic interactions) reliably and hence it has been successfully applied to study a lot of protein-ligand interactions by consistently evaluating their binding energies [17–21]. Recently, FMO calculations were made to study protein-peptide interactions to explain the experimental results [22].…”

Section: Introductionmentioning

confidence: 99%

Comparative Binding Analysis of Dipeptidyl Peptidase IV (DPP-4) with Antidiabetic Drugs – An Ab Initio Fragment Molecular Orbital Study

et al. 2016

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Dipeptidyl peptidase IV (DPP-4) enzyme is responsible for the degradation of incretins that stimulates insulin secretion and hence inhibition of DPP-4 becomes an established approach for the treatment of type 2 diabetics. We studied the interaction between DPP-4 and its inhibitor drugs (sitagliptin 1, linagliptin 2, alogliptin 3, and teneligliptin 4) quantitatively by using fragment molecular orbital calculations at the RI-MP2/cc-pVDZ level to analyze the inhibitory activities of the drugs. Apart from having common interactions with key residues, inhibitors encompassing the DPP-4 active site extensively interact widely with the hydrophobic pocket by their hydrophobic inhibitor moieties. The cumulative hydrophobic interaction becomes stronger for these inhibitors and hence linagliptin and teneligliptin have larger interaction energies, and consequently higher inhibitory activities, than their alogliptin and sitagliptin counterparts. Though effective interaction for both 2 and 3 is at subsite, 2 has a stronger binding to this subsite interacting with Trp629 and Tyr547 than 3 does. The presence of triazolopiperazine and piperazine moiety in 1 and 4, respectively, provides the interaction to the S2 extensive subsite; however, the latter’s superior inhibitory activity is not only due to a relatively tighter binding to the S2 extensive subsite, but also due to the interactions to the S1 subsite. The calculated hydrophobic interfragment interaction energies correlate well with the experimental binding affinities (KD) and inhibitory activities (IC50) of the DPP-4 inhibitors.

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“…Furthermore, most importantly, it does not inhibit human sialidases. 956 With such inhibitors, as well as vaccination, it is hoped that such severe and deadly influenza pandemics as had occurred just 100 years ago ("Spanish flu"), claiming many millions of casualties, 957 can be prevented.…”

Section: Sialidase Inhibitorsmentioning

confidence: 99%

Exploration of the Sialic Acid World

Schauer

Kamerling

2018

Advances in Carbohydrate Chemistry and Biochemistry

249

225

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The Sialic Acid World Table 1 Survey of Reported Structures of Naturally Occurring Members of the Sialic Acid Family-cont'd Name Abbreviation References5-N-Acetyl-8-O-acetyl-9-Olactyl-neuraminic acid Neu5,8Ac 2 9Lt 45 5-N-Acetyl-8-O-methylneuraminic acid Neu5Ac8Me 6,19,25,33,46 5-N-Acetyl-4-O-acetyl-8-Omethyl-neuraminic acid Neu4,5Ac 2 8Me 19 5-N-Acetyl-9-O-acetyl-8-Omethyl-neuraminic acid Neu5,9Ac 2 8Me 6,19,33,46 5-N-Acetyl-9-O-methylneuraminic acid Neu5Ac9Me 47 5-N-Acetyl-4-O-sulfoneuraminic acid Neu5Ac4S 48 5-N-Acetyl-8-O-sulfoneuraminic acid Neu5Ac8S 19,32,49,50 5-N-Acetyl-4-O-acetyl-8-Osulfo-neuraminic acid Neu4,5Ac 2 8S 19 5-N-Acetyl-9-O-phosphoneuraminic acid f,g Neu5Ac9P 51 5-N-Acetyl-2-deoxy-2,3didehydro-neuraminic acid g,h Neu2en5Ac 6,30,33,43,52-54 5-N-Acetyl-9-O-acetyl-2deoxy-2,3-didehydroneuraminic acid g Neu2en5,9Ac 2 55,56 5-N-Acetyl-2-deoxy-2,3didehydro-9-O-lactylneuraminic acid g Neu2en5Ac9Lt 55,565-N-Acetyl-2,7-anhydroneuraminic acid g,i

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A Novel Potent and Highly Specific Inhibitor against Influenza Viral N1–N9 Neuraminidases: Insight into Neuraminidase–Inhibitor Interactions

Cited by 24 publications

References 60 publications

Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant

Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant

Comparative Binding Analysis of Dipeptidyl Peptidase IV (DPP-4) with Antidiabetic Drugs – An Ab Initio Fragment Molecular Orbital Study

Exploration of the Sialic Acid World

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