Drug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection

Loucera, Carlos; Esteban-Medina, Marina; Rian, Kinza; Falco, Matías M.; Dopazo, Joaquı́n; Peña‐Chilet, María

doi:10.1038/s41392-020-00417-y

Cited by 45 publications

(50 citation statements)

References 7 publications

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“…Thus, a role for famotidine in COVID-19 may stem from cellular mechanisms and signaling pathways quite unrelated to its classic therapeutic role in gastroenterology-that, in turn, is an important lesson as regards drug repurposing (from a systems pharmacology perspective), targeted therapeutics, and the general idea of a COVID-19 'disease map'. 5 As SARS-CoV-2 infection rates continue surging worldwide, we desperately need more data on potential therapies. The large, international, multi-center retrospective study reported here, sampling over 250,000 COVID-19 cases, hopefully helps clarify the potential benefit of clinically-approved histamine antagonists such as famotidine.…”

Section: Resultsmentioning

confidence: 99%

Real-world Evidence for Improved Outcomes with Histamine Antagonists and Aspirin in 22,560 COVID-19 Patients

Mura

Preissner

Nahles

et al. 2021

Preprint

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COVID-19 has spurred much interest in the therapeutic potential of repurposed drugs, such as acid-reducing drugs that act as histamine H2 receptor antagonists (H2RA). These compounds, exemplified by famotidine (e.g., Pepcid) and ranitidine (e.g., Zantac), bind the H2R and block the histamine-triggered stimulation of signal transduction cascades. Histamine and H2RAs, on the one hand, and downstream physiological pathways, on the other hand, form a dense web of disparate pathways and signaling networks; these networks are ultimately tied to the dysregulated inflammatory cascades (cytokine storm) that underlies the pathophysiology of COVID-19. Is famotidine beneficial in treating COVID-19? This question remains unresolved, despite much recent effort: over 10 studies have examined the potential value of famotidine in COVID-19, but have found largely contradictory results. Given the conflicting reports, we have undertaken a new analysis reported herein, drawing upon a cohort of 22,560 COVID-19 patients. Using electronic health records, we statistically analyzed outcomes for treatment with the H1RAs loratadine (e.g., Claritin) and cetirizine (e.g., Zyrtec), the H2RA famotidine, the general-purpose anti-inflammatory aspirin, and a famotidine & aspirin combination. For severe cases (requiring respiratory support), we found a significantly reduced fatality risk for famotidine treatment. Notably, famotidine combined with aspirin exhibited a significant synergistic survival benefit (odds ratio of 0.55). The relative risk for death decreased by 32.5%—an immense benefit, given the more than 2.6 million COVID-19-related deaths thus far. The large, multi-center retrospective study reported here, sampling over 250,000 COVID-19 cases internationally, hopefully helps clarify the possible value of clinically-approved histamine antagonists such as famotidine. Given these findings, alongside the cost-effectiveness and mild side-effects of common over-the-counter drugs like famotidine and aspirin, we suggest that further prospective clinical trials, perhaps utilizing the aspirin combination reported here, are advisable.

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Section: Resultsmentioning

confidence: 99%

Real-world Evidence for Improved Outcomes with Histamine Antagonists and Aspirin in 22,560 COVID-19 Patients

Mura

Preissner

Nahles

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…The inhibition of Mpro is a checkpoint preventing the viral replication and thereby making it an important therapeutic target constitutes one of the potential anti coronaviral strategies ( Shawky et al, 2020 ). Recently, a large number of studies have focused on the repurposing of old drugs as a plausible treatment for COVID-19 ( Louceraet al, 2020 , Mohapatraet al, 2020 , Singhet al, 2020 , Krishnaet al, 2021 ). The success of drug repurposing has gained large research interest ( Cusinato et al, 2020 , Rubinet al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Screening of drug databank against WT and mutant main protease of SARS-CoV-2: Towards finding potential compound for repurposing against COVID-19

Sharma

Abohashrh

Baig

et al. 2021

Saudi Journal of Biological Sciences

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Although several pharmacological agents are under investigation to be repurposed as therapeutic against COVID-19, not much success has been achieved yet. So, the search for an effective and active option for the treatment of COVID-19 is still a big challenge. The Spike protein (S), RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro) are considered to be the primary therapeutic drug target for COVID-19. In this study we have screened the drugbank compound library against the Main Protease. But our search was not limited to just Mpro. Like other viruses, SARS-CoV-2, have also acquired unique mutations. These mutations within the active site of these target proteins may be an important factor hindering effective drug candidate development. In the present study we identified important active site mutations within the SARS-CoV-2 Mpro (Y54C, N142S, T190I and A191V). Further the drugbank database was computationally screened against Mpro and the selected mutants. Finally, we came up with the common molecules effective against the wild type (WT) and all the selected Mpro. The study found Imiglitazar, was found to be the most active compound against the wild type of Mpro. While PF-03715455 (Y54C), Salvianolic acid A (N142S and T190I), and Montelukast (A191V) were found to be most active against the other selected mutants. It was also found that some other compounds such as Acteoside, 4-Amino-N- {4-[2-(2,6-Dimethyl-Phenoxy)-Acetylamino]-3-Hydroxy-1-Isobutyl-5-Phenyl-Pentyl}-Benzamide, PF-00610355, 4-Amino-N-4-[2-(2,6-Dimethyl-Phenoxy)-Acetylamino]-3-Hydroxy-1-Isobutyl-5-Phenyl-Pentyl}-Benzamide and Atorvastatin were showing high efficacy against the WT as well as other selected mutants. We believe that these molecules will provide a better and effective option for the treatment of COVID-19 clinical manifestations.

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“…These may serve as a two edged sword by blocking the binding of SARS-CoV-2 to the host receptor as well as subsiding inflammatory responses. In a mechanistic modeling approach combined with virtual screening, Loucera et al identified sirolimus to have a strong impact over most of the specific signaling circuits in the COVID-19 [ 48 ]. Another study based on network proximity analyses of drug targets also identified sirolimus as potentially repurposable for COVID-19 [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

“…Since the global outbreak of COVID-19, there has been a plethora of reports on drug repurposing for the treatment of COVID-19. These studies have used virtual screening by molecular docking, molecular dynamics simulations or network based approaches to find potential remedies that target different proteins of SARS-CoV-2 [ [47] , [48] , [50] , [53] , [55] , [56] , [57] , [62] , [63] ]. Multiple proteins have been described as candidate drug targets, such as the human ACE2 receptor, viral RNA dependent RNA polymerase (RdRp), main protease (M pro , also called 3CL pro ) and papain-like protease (PL pro ).…”

Section: Discussionmentioning

confidence: 99%

Repurposing of approved drugs with potential to interact with SARS-CoV-2 receptor

Ahsan

Sajib

2021

Biochemistry and Biophysics Reports

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Respiratory transmission is the primary route of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Angiotensin I converting enzyme 2 (ACE2) is the known receptor of SARS-CoV-2 surface spike glycoprotein for entry into human cells. A recent study reported absent to low expression of ACE2 in a variety of human lung epithelial cell samples. Three bioprojects ( PRJEB4337 , PRJNA270632 and PRJNA280600 ) invariably found abundant expression of ACE1 (a homolog of ACE2 and also known as ACE) in human lungs compared to very low expression of ACE2. In fact, ACE1 has a wider and more abundant tissue distribution compared to ACE2. Although it is not obvious from the primary sequence alignment of ACE1 and ACE2, comparison of X-ray crystallographic structures show striking similarities in the regions of the peptidase domains (PD) of these proteins, which is known (for ACE2) to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Critical amino acids in ACE2 that mediate interaction with the viral spike protein are present and organized in the same order in the PD of ACE1. In silico analysis predicts comparable interaction of SARS-CoV-2 spike protein with ACE1 and ACE2. In addition, this study predicts from a list of 1263 already approved drugs that may interact with ACE2 and/or ACE1 and potentially interfere with the entry of SARS-CoV-2 inside the host cells.

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Drug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection

Cited by 45 publications

References 7 publications

Real-world Evidence for Improved Outcomes with Histamine Antagonists and Aspirin in 22,560 COVID-19 Patients

Real-world Evidence for Improved Outcomes with Histamine Antagonists and Aspirin in 22,560 COVID-19 Patients

Screening of drug databank against WT and mutant main protease of SARS-CoV-2: Towards finding potential compound for repurposing against COVID-19

Repurposing of approved drugs with potential to interact with SARS-CoV-2 receptor

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