Preprint Article Version 1 This version is not peer-reviewed

Inhibition of Viral Macrodomain of COVID-19 and Human TRPM2 by losartan

Version 1 : Received: 30 March 2020 / Approved: 31 March 2020 / Online: 31 March 2020 (10:23:10 CEST)
Version 2 : Received: 22 April 2020 / Approved: 23 April 2020 / Online: 23 April 2020 (14:56:22 CEST)

How to cite: Sallari Jazzi, A.; Mahnam, K.; Hossein Hejazi, S.; Damavandi, M.S.; Sadeghi, P.; Zeinalian, M.; Tabesh, F.; Mirbod, S.M.; Khanahmad, H. Inhibition of Viral Macrodomain of COVID-19 and Human TRPM2 by losartan. Preprints 2020, 2020030457 (doi: 10.20944/preprints202003.0457.v1). Sallari Jazzi, A.; Mahnam, K.; Hossein Hejazi, S.; Damavandi, M.S.; Sadeghi, P.; Zeinalian, M.; Tabesh, F.; Mirbod, S.M.; Khanahmad, H. Inhibition of Viral Macrodomain of COVID-19 and Human TRPM2 by losartan. Preprints 2020, 2020030457 (doi: 10.20944/preprints202003.0457.v1).

Abstract

Background: The SARS-CoV-2 virus is a new highly contagious Coronavirus with a positive-sense RNA encoding 16 non-structural proteins (nsps16, nsp15, nsp3). In this study, the coronavirus pathogenicity and the losartan functional ligand for inhibiting TRPM2 and macrodomain have been molecularly evaluated.Material and method: In this study, the structures of macrodomain binding ADP ribose in CoVs and human Transient Receptor Potential Cation Channel Subfamily M Member 2 (TRPM2) protein were downloaded from protein data bank. Then, a virtual screening was done to recognize the hit compounds from GalaXi_2019-10, KnowledgeSpace_2019-05, and REALspace_2019-12 databases. This collection, then, was imported to the ligandScout software, on the base of Adenosine Diphosphate Ribose (ADPR) pharmacophore model. Result: Among seven compounds, five compounds were finally evaluated as the structural analogs of ADPR or other nucleotides, from which one compound was a non-FDA-approved sulphonamide and was removed. The other compound, losartan, was finally selected for molecular docking and molecular dynamic simulation. According to the virtual screening and docking, losartan was candidate as an effective ligand for TRPM2 and macrodomain. Conclusion: In the current study losartan earned a proper dock score and binding affinity to create the complexes with TRPM2 and macrodomain. The inhibitory effect of losartan on PARP has been shown and it could interfere positively in several points (PARP, PARG- macrodomain and TRPM2) and decreases oxidative stress and apoptosis in COVID-19.

Subject Areas

Viral Macrodomain; COVID-19; TRPM2; losartan; Bioinformatics

Comments (2)

Comment 1
Received: 1 April 2020
Commenter: Patrick Chambers
The commenter has declared there is no conflict of interests.
Comment: The below Link succinctly describes what’s happening with angiotensin II and COVID-19 and why Losartan Is such a good choice.

https://www.bmj.com/content/368/bmj.m406/rr-19
The virus destroys the cells that carry the membrane bound ACE2 receptors, leading to an imbalance in the RAS with more angiotensin II.

Increased angiotensin II in diabetics and hypertensives is precisely why these are the top two comorbidities for COVID 19 and stand to gain the most from an ARB approach, esp in those homozygous for the ACE deletion (D) allele (v the insertion allele I), which would be Iranians, Italians and the Spanish. That's why IMHO Asians have a lower COVID death rate.
That’s why children with lower ACE/ACE2 ratios do better than the elderly, who have much higher ratios.

Review Table 2
https://www.cambridge.org/core/journals/genetics-is such a good choice.research/article/geographic-distribution-of-the-aceii-genotype-a-novel-finding/6DC14A0774C181C37981E5E732E92E45/core-reader
It sure would be nice if we had some human recombinant ACE2 available for clinical application.
+ Respond to this comment
Response 1 to Comment 1
Received: 11 April 2020
Commenter: Gustavo Rezende
The commenter has declared there is no conflict of interests.
Comment: This is already under the way: Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2, Cell paper, https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00739.pdf.

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 2
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.