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Research Article
Discovery of Potent Sialic Acid Inhibitors Against the Hemagglutinin of Influenza A Virus
Chih-Hao Lu
The Ph.D. Program of Biotechnology and Biomedical industry, China Medical University, Taichung
Corresponding Author
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Influenza A virus (IAV) is hard to eradicate due to its genetic drift and reassortment ability. Neuraminidase (NA), frequently the target protein, cleaves the sialic acid (SA) and discharges virions to complete the infectious cycle. However, the increasing use of NA inhibitors aroused drug resistance in recent years. Hemagglutinin (HA), on the opposite, initiates the infectious cycle and sticks virions to cells by connecting to the host SA so that HA might be a tempting target. In this study, HA was chosen for SA-binding site model preparation to screen more than 200,000 compounds by molecular docking method in silico. According to the post-screening analysis by iGemdock and SiMMap, nine of the top twenty compounds based on the ranking score were purchased and evaluated. NSC85561 was initially identified from the compounds through the bioassays. Next, the twelve derivatives of NSC85561 were selected to consolidate the primary results. NSC85561 and two of its derivatives were finally identified as potent HA inhibitors by cell proliferation, plaque reduction, and hemagglutination inhibition assays in vitro. These results suggested that virtual screening may be a powerful tool to concise the compounds from the massive database and reduce the complicated bioassays.
Keywords
Influenza A virus, Virtual screening, Hemagglutinin, Sialic acid inhibitors
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Posted 18 Dec, 2020
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Editorial decision: Major revision
On 20 Jan, 2021
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Received 07 Jan, 2021
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Received 07 Jan, 2021
Review #3 received
Received 07 Jan, 2021
Review #1 received
Received 07 Jan, 2021
Reviewer #4 agreed
On 28 Dec, 2020
Reviewer #6 agreed
On 28 Dec, 2020
Reviewer #1 agreed
On 28 Dec, 2020
Reviewer #5 agreed
On 28 Dec, 2020
Reviewer #3 agreed
On 28 Dec, 2020
Reviewer #2 agreed
On 28 Dec, 2020
Reviewers invited
Invitations sent on 28 Dec, 2020
Editor assigned
On 20 Dec, 2020
Editor invited
On 17 Dec, 2020
Submission checks complete
On 17 Dec, 2020
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On 10 Dec, 2020
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Bioinformatics
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This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Discovery of Potent Sialic Acid Inhibitors Against the Hemagglutinin of Influenza A Virus
Chih-Hao Lu
The Ph.D. Program of Biotechnology and Biomedical industry, China Medical University, Taichung
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Revision
Version 1
Posted 18 Dec, 2020
No community comments so far
Editorial decision: Major revision
On 20 Jan, 2021
Review #2 received
Received 07 Jan, 2021
Review #4 received
Received 07 Jan, 2021
Review #3 received
Received 07 Jan, 2021
Review #1 received
Received 07 Jan, 2021
Reviewer #4 agreed
On 28 Dec, 2020
Reviewer #6 agreed
On 28 Dec, 2020
Reviewer #1 agreed
On 28 Dec, 2020
Reviewer #5 agreed
On 28 Dec, 2020
Reviewer #3 agreed
On 28 Dec, 2020
Reviewer #2 agreed
On 28 Dec, 2020
Reviewers invited
Invitations sent on 28 Dec, 2020
Editor assigned
On 20 Dec, 2020
Editor invited
On 17 Dec, 2020
Submission checks complete
On 17 Dec, 2020
First submitted
On 10 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Bioinformatics
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Influenza A virus (IAV) is hard to eradicate due to its genetic drift and reassortment ability. Neuraminidase (NA), frequently the target protein, cleaves the sialic acid (SA) and discharges virions to complete the infectious cycle. However, the increasing use of NA inhibitors aroused drug resistance in recent years. Hemagglutinin (HA), on the opposite, initiates the infectious cycle and sticks virions to cells by connecting to the host SA so that HA might be a tempting target. In this study, HA was chosen for SA-binding site model preparation to screen more than 200,000 compounds by molecular docking method in silico. According to the post-screening analysis by iGemdock and SiMMap, nine of the top twenty compounds based on the ranking score were purchased and evaluated. NSC85561 was initially identified from the compounds through the bioassays. Next, the twelve derivatives of NSC85561 were selected to consolidate the primary results. NSC85561 and two of its derivatives were finally identified as potent HA inhibitors by cell proliferation, plaque reduction, and hemagglutination inhibition assays in vitro. These results suggested that virtual screening may be a powerful tool to concise the compounds from the massive database and reduce the complicated bioassays.
Figure 1
Figure 1
Figure 1
Figure 1
Figure 1
Figure 1
Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the latest manuscript can be downloaded and accessed as a PDF.