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In silico and in vitro Demonstration of Homoharrintonine’s Antagonism of RBD-ACE2 Binding and its Anti-inflammatory and anti-thrombogenic Properties in a 3D human vascular lung model

Shalini Saxena, Kranti Meher, Madhuri Rotella, Subhramanyam Vangala, Satish Chandran, Nikhil Malhotra, Ratnakar Palakodeti, Sreedhara R Voleti, Uday Saxena
doi: https://doi.org/10.1101/2021.05.02.442384
Shalini Saxena
AIn Silico Discovery Research Academic Services (INDRAS) Pvt. Ltd. 44-347/6, Tirumalanagar, Moula Ali, Hyderabad – 500040, TS, India
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Kranti Meher
Crd, Gachibowli, Hyderabad – 500046, TS, India
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Madhuri Rotella
Crd, Gachibowli, Hyderabad – 500046, TS, India
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Subhramanyam Vangala
Crd, Gachibowli, Hyderabad – 500046, TS, India
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Satish Chandran
Crd, Gachibowli, Hyderabad – 500046, TS, India
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Nikhil Malhotra
BTech Mahindra Gateway Building, Apollo Bunder, Mumbai-400001, Maharashtra, India
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Ratnakar Palakodeti
BTech Mahindra Gateway Building, Apollo Bunder, Mumbai-400001, Maharashtra, India
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Sreedhara R Voleti
AIn Silico Discovery Research Academic Services (INDRAS) Pvt. Ltd. 44-347/6, Tirumalanagar, Moula Ali, Hyderabad – 500040, TS, India
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  • For correspondence: sreedhara.voleti@indras.in udaysaxena@reagenebiosciences.com
Uday Saxena
Crd, Gachibowli, Hyderabad – 500046, TS, India
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  • For correspondence: sreedhara.voleti@indras.in udaysaxena@reagenebiosciences.com
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Abstract

Since 2019 the world has seen severe onslaught of SARS-CoV-2 viral pandemic. There is an urgent need for drugs that can be used to either prevent or treat the potentially fatal disease COVD-19. To this end, we screened FDA approved antiviral drugs which could be repurposed for COVID-19 through molecular docking approach in the various active sites of receptor binding domain (RBD). The RBD domain of SARS-CoV-2 spike protein is a promising drug target due to its pivotal role in viral-host attachment. Specifically, we focussed on identifying antiviral drugs which could a) block the entry of virus into host cells, b) demonstrate anti-inflammatory and/or anti-thrombogenic properties. Drugs which poses both properties could be useful for prevention and treatment of the disease. While we prioritized a few antiviral drugs based on molecular docking, corroboration with in vitro studies including a new 3D human vascular lung model strongly supported the potential of Homoharringtonine, a drug approved for chronic myeloid leukaemia to be repurposed for COVID-19. This natural product drug not only antagonized the biding of SARS-CoV-2 spike protein RBD binding to human angiotensin receptor 2 (ACE-2) protein but also demonstrated for the first time anti-thrombogenic and anti-leukocyte adhesive properties in a human cell model system. Overall, this work provides an important lead for development of rapid treatment of COVID-19 and also establishes a screening paradigm using molecular modelling and 3D human vascular lung model of disease to identify drugs with multiple desirable properties for prevention and treatment of COVID-19.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 03, 2021.
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In silico and in vitro Demonstration of Homoharrintonine’s Antagonism of RBD-ACE2 Binding and its Anti-inflammatory and anti-thrombogenic Properties in a 3D human vascular lung model
Shalini Saxena, Kranti Meher, Madhuri Rotella, Subhramanyam Vangala, Satish Chandran, Nikhil Malhotra, Ratnakar Palakodeti, Sreedhara R Voleti, Uday Saxena
bioRxiv 2021.05.02.442384; doi: https://doi.org/10.1101/2021.05.02.442384
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In silico and in vitro Demonstration of Homoharrintonine’s Antagonism of RBD-ACE2 Binding and its Anti-inflammatory and anti-thrombogenic Properties in a 3D human vascular lung model
Shalini Saxena, Kranti Meher, Madhuri Rotella, Subhramanyam Vangala, Satish Chandran, Nikhil Malhotra, Ratnakar Palakodeti, Sreedhara R Voleti, Uday Saxena
bioRxiv 2021.05.02.442384; doi: https://doi.org/10.1101/2021.05.02.442384

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