Structure-based design of 5′-substituted 1,2,3-triazolylated oseltamivir derivatives as potent influenza neuraminidase inhibitors

Wang, Pengfei; Oladejo, Babayemi Olawale; Li, Chenning; Liu, Fu; Zhang, Shanshan; Qi, Jianxun; Lv, Xudong; Li, Xuebing

doi:10.1039/d1ra00472g

Cited by 12 publications

(3 citation statements)

References 53 publications

(36 reference statements)

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“…The standard ligand was redocked with neuraminidase enzyme active sites using Openeye software, and it was superimposed with its cocrystalized downloaded complex. 27 Both structures overlayed each other with the same binding mode and pose (Figure 5a). Santonin adopted a crooked shape in which the carbonyl of 1,4cyclohexene formed a hydrogen bond (HB) with Asp:151 A and two HBs with Arg:239 A as an acceptor.…”

Section: Chemoinformatic Studies 361 Molecular Docking Study With Neu...mentioning

confidence: 74%

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Robust Antiviral Activity of Santonica Flower Extract (Artemisia cina) against Avian and Human Influenza A Viruses: In Vitro and Chemoinformatic Studies

et al. 2022

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The evolution of drug-resistant viral strains following natural acquisition of resistance mutations is a major obstacle to antiviral therapy. Besides the improper prescription of the currently licensed anti-influenza medications, M2-blockers and neuraminidase inhibitors, to control poultry outbreaks/infections potentiates the emergence of drug-resistant influenza variants. Therefore, there is always a necessity to find out new alternatives with potent activity and high safety. Plant extracts and plant-based chemicals represent a historical antiviral resource with remarkable safety in vitro and in vivo to control the emerging and remerging health threats caused by viral infections. Herein, a panel of purified plant extracts and subsequent plant-derived chemicals were evaluated for their anti-avian influenza activity against zoonotic highly pathogenic influenza A/H5N1 virus. Interestingly, santonica flower extract (Artemisia cina) showed the most promising anti-H5N1 activity with a highly safe half-maximal cytotoxic concentration 50 (CC50 > 10 mg/mL) and inhibitory concentration 50 (IC50 of 3.42 μg/mL). To confirm the anti-influenza activity, we assessed the anti-influenza activity of the selected plant extracts against seasonal human influenza A/H1N1 virus and we found that santonica flower extract showed a robust anti-influenza activity that was comparable to the activity against influenza A/H5N1. Furthermore, the mode of action for santonica flower extract with strong inhibitory activity on the abovementioned influenza strains was elucidated, showing a virucidal effect. To go deeper about the activity of the chemometric component of the extract, the major constituent, santonin, was further selected for in vitro screening against influenza A/H5N1 (IC50 = 1.701 μg/mL) and influenza A/H1N1 (IC50 = 2.91 μg/mL). The oxygen of carbonyl functionality in the cyclohexene ring succeeded to form a hydrogen bond with the neuraminidase active site. Despite the fact that santonin revealed similarity to both reference neuraminidase inhibitors in forming hydrogen bonds with essential amino acids, it illustrated shape alignment to oseltamivir more than zanamivir according to Tanimoto algorithms. This study highlights the applicability of santonica flower extract as a promising natural antiviral against low and highly pathogenic influenza A viruses.

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Section: Chemoinformatic Studies 361 Molecular Docking Study With Neu...mentioning

confidence: 74%

“…The standard ligand was redocked with neuraminidase enzyme active sites using Openeye software, and it was superimposed with its co-crystalized downloaded complex . Both structures overlayed each other with the same binding mode and pose (Figure a).…”

Section: Resultsmentioning

confidence: 99%

Robust Antiviral Activity of Santonica Flower Extract (Artemisia cina) against Avian and Human Influenza A Viruses: In Vitro and Chemoinformatic Studies

et al. 2022

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“…The discovery of the 150-cavity in group-1 NAs provides a new strategy for the development of novel NA inhibitors with increased specificity and potency. In recent years, several N -substituted oseltamivir derivatives JMC32 , JMC20I [ 27 ], JMC21h , JMC21g , JMC17f [ 28 ], EJMC5c , EJMC13c [ 29 ] and JMC23d [ 30 ] , BMC17 [ 31 ] , EJMC8a [ 32 ] , JMC2 [ 33 ] and RSC2j [ 34 ] ( Figure 3 ) targeting the 150-cavity have been reported. Most of these inhibitors displayed better or similar inhibitory activities than OSC against both wild-type and mutant NAs.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Boron-Containing N-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant

Jia

Zhang

et al. 2022

Molecules

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To address drug resistance to influenza virus neuraminidase inhibitors (NAIs), a series of novel boron-containing N-substituted oseltamivir derivatives were designed and synthesized to target the 150-cavity of neuraminidase (NA). In NA inhibitory assays, it was found that most of the new compounds exhibited moderate inhibitory potency against the wild-type NAs. Among them, compound 2c bearing 4-(3-boronic acid benzyloxy)benzyl group displayed weaker or slightly improved activities against group-1 NAs (H1N1, H5N1, H5N8 and H5N1-H274Y) compared to that of oseltamivir carboxylate (OSC). Encouragingly, 2c showed 4.6 times greater activity than OSC toward H5N1-H274Y NA. Moreover, 2c exerted equivalent or more potent antiviral activities than OSC against H1N1, H5N1 and H5N8. Additionally, 2c demonstrated low cytotoxicity in vitro and no acute toxicity at the dose of 1000 mg/kg in mice. Molecular docking of 2c was employed to provide a possible explanation for the improved anti-H274Y NA activity, which may be due to the formation of key additional hydrogen bonds with surrounding amino acid residues, such as Arg152, Gln136 and Val149. Taken together, 2c appeared to be a promising lead compound for further optimization.

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Challenges in designing antiviral agents

Nascimento

Silva

Silva-Júnior

2023

Viral Infections and Antiviral Therapies

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Structure-based design of 5′-substituted 1,2,3-triazolylated oseltamivir derivatives as potent influenza neuraminidase inhibitors

Abstract: Exploring influenza neuraminidase inhibitors by targeting the charged residues near the entrance of the 150-cavity.

Cited by 12 publications

References 53 publications

Robust Antiviral Activity of Santonica Flower Extract (Artemisia cina) against Avian and Human Influenza A Viruses: In Vitro and Chemoinformatic Studies

Robust Antiviral Activity of Santonica Flower Extract (Artemisia cina) against Avian and Human Influenza A Viruses: In Vitro and Chemoinformatic Studies

Discovery of Novel Boron-Containing N-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant

Challenges in designing antiviral agents

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