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Evolving geographic diversity in SARS-CoV2 and in silico analysis of replicating enzyme 3CLpro targeting repurposed drug candidates
Nitin Chitranshi
Macquarie University Faculty of Medicine and Health Sciences
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6508-9865
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Journal of Translational Medicine.
Background: Severe acute respiratory syndrome (SARS) has been initiating pandemics since the beginning of the century. In December 2019, the world was hit again by a devastating SARS episode that has so far infected almost four million individuals worldwide, with over 200,000 fatalities having already occurred by mid-April 2020, and the infection rate continues to grow exponentially. SARS coronavirus 2 (SARS-CoV-2) is a single stranded RNA pathogen which is characterised by a high mutation rate. It is vital to explore the mutagenic capability of the viral genome that enables SARS-CoV-2 to rapidly jump from one host immunity to another and adapt to the genetic pool of local populations.
Methods: For this study, we analysed 2,301 complete viral sequences reported from SARS-CoV-2 infected patients. SARS-CoV-2 host genomes were collected from The Global Initiative on Sharing All Influenza Data (GISAID) database containing 9 genomes from pangolin-CoV origin and 3 genomes from bat-CoV origin, Wuhan SARS-CoV2 reference genome was collected from GeneBank database. The Multiple sequence alignment tool, Clustal Omega was used for genomic sequence alignment. The viral replicating enzyme, 3-chymotrypsin-like cysteine protease (3CLpro) that plays a key role in its pathogenicity was used to assess its affinity with pharmacological inhibitors and repurposed drugs such as anti-viral flavones, biflavanoids, anti-malarial drugs and vitamin supplements.
Results: Our results demonstrate that bat-CoV shares >96% similar identity, while pangolin-CoV shares 85.98% identity with Wuhan SARS-CoV-2 genome. This in-depth analysis has identified 12 novel recurrent mutations in South American and African viral genomes out of which 3 were unique in South America, 4 unique in Africa and 5 were present in-patient isolates from both populations. Using state of the art in silico approaches, this study further investigates the interaction of repurposed drugs with the SARS-CoV-2 3CLpro enzyme, which regulates viral replication machinery.
Conclusions: Overall, this study provides insights into the evolving mutations, with implications to understand viral pathogenicity and possible new strategies for repurposing compounds to combat the nCovid-19 pandemic.
Keywords
SARS-CoV2, mutagenic capability
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CURRENT STATUS: Published
Version 2
Posted 22 Jun, 2020
Published
On 09 Jul, 2020
No community comments so far
Editorial decision: Accept
On 03 Jul, 2020
Review #1 received
Received 27 Jun, 2020
Editor assigned
On 18 Jun, 2020
Reviewers invited
Invitations sent on 18 Jun, 2020
Reviewer #1 agreed
On 18 Jun, 2020
Submission checks complete
On 17 Jun, 2020
Editor invited
On 17 Jun, 2020
No comments provided
Review #2 received
Received 11 Jun, 2020
Editorial decision: Minor revision
On 11 Jun, 2020
Review #1 received
Received 03 Jun, 2020
Reviewer #2 agreed
On 19 May, 2020
Reviewers invited
Invitations sent on 19 May, 2020
Reviewer #1 agreed
On 19 May, 2020
Editor assigned
On 18 May, 2020
Editor invited
On 17 May, 2020
Submission checks complete
On 09 May, 2020
First submitted
On 08 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Translational Medicine
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This preprint is under consideration at Journal of Translational Medicine. 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
Evolving geographic diversity in SARS-CoV2 and in silico analysis of replicating enzyme 3CLpro targeting repurposed drug candidates
Nitin Chitranshi
Macquarie University Faculty of Medicine and Health Sciences
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6508-9865
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: Published
Version 2
Posted 22 Jun, 2020
Published
On 09 Jul, 2020
No community comments so far
Editorial decision: Accept
On 03 Jul, 2020
Review #1 received
Received 27 Jun, 2020
Editor assigned
On 18 Jun, 2020
Reviewers invited
Invitations sent on 18 Jun, 2020
Reviewer #1 agreed
On 18 Jun, 2020
Submission checks complete
On 17 Jun, 2020
Editor invited
On 17 Jun, 2020
No comments provided
Review #2 received
Received 11 Jun, 2020
Editorial decision: Minor revision
On 11 Jun, 2020
Review #1 received
Received 03 Jun, 2020
Reviewer #2 agreed
On 19 May, 2020
Reviewers invited
Invitations sent on 19 May, 2020
Reviewer #1 agreed
On 19 May, 2020
Editor assigned
On 18 May, 2020
Editor invited
On 17 May, 2020
Submission checks complete
On 09 May, 2020
First submitted
On 08 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Translational Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Journal of Translational Medicine.
Background: Severe acute respiratory syndrome (SARS) has been initiating pandemics since the beginning of the century. In December 2019, the world was hit again by a devastating SARS episode that has so far infected almost four million individuals worldwide, with over 200,000 fatalities having already occurred by mid-April 2020, and the infection rate continues to grow exponentially. SARS coronavirus 2 (SARS-CoV-2) is a single stranded RNA pathogen which is characterised by a high mutation rate. It is vital to explore the mutagenic capability of the viral genome that enables SARS-CoV-2 to rapidly jump from one host immunity to another and adapt to the genetic pool of local populations.
Methods: For this study, we analysed 2,301 complete viral sequences reported from SARS-CoV-2 infected patients. SARS-CoV-2 host genomes were collected from The Global Initiative on Sharing All Influenza Data (GISAID) database containing 9 genomes from pangolin-CoV origin and 3 genomes from bat-CoV origin, Wuhan SARS-CoV2 reference genome was collected from GeneBank database. The Multiple sequence alignment tool, Clustal Omega was used for genomic sequence alignment. The viral replicating enzyme, 3-chymotrypsin-like cysteine protease (3CLpro) that plays a key role in its pathogenicity was used to assess its affinity with pharmacological inhibitors and repurposed drugs such as anti-viral flavones, biflavanoids, anti-malarial drugs and vitamin supplements.
Results: Our results demonstrate that bat-CoV shares >96% similar identity, while pangolin-CoV shares 85.98% identity with Wuhan SARS-CoV-2 genome. This in-depth analysis has identified 12 novel recurrent mutations in South American and African viral genomes out of which 3 were unique in South America, 4 unique in Africa and 5 were present in-patient isolates from both populations. Using state of the art in silico approaches, this study further investigates the interaction of repurposed drugs with the SARS-CoV-2 3CLpro enzyme, which regulates viral replication machinery.
Conclusions: Overall, this study provides insights into the evolving mutations, with implications to understand viral pathogenicity and possible new strategies for repurposing compounds to combat the nCovid-19 pandemic.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7