A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin

Hasan, Anwarul; Paray, Bilal Ahamad; Hussain, Arif; Qadir, Fikry Ali; Attar, Farideh; Aziz, Falah Mohammad; Sharifi, Majid; Derakhshankhah, Hossein; Rasti, Behnam; Mehrabi, Masoumeh; Shahpasand, Koorosh; Saboury, Ali Akbar; Falahati, Mojtaba

doi:10.1080/07391102.2020.1754293

Cited by 272 publications

(250 citation statements)

References 76 publications

(92 reference statements)

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“…Seven of the predicted drug targets are upstream regulators of AR signaling and are targeted by multiple drug candidates that reduce ACE2 ( Figure 3C). Furthermore, peptidases such as FURIN and TMPRSS2 which are important players in ACE2 regulation and thereby SARS-CoV-2 viral entry 21,22 , are amongst the downstream targets of AR. These receptors and their upstream regulators are also predicted to be targeted by the drug candidates ( Figure 3D).…”

Section: Drugs That Reduce Ace-2 Regulate Steroid Signaling and Peptimentioning

confidence: 99%

Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

Ghazizadeh

Majd

Richter

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to a global health crisis, and yet our understanding of the disease pathophysiology and potential treatment options remains limited. SARS-CoV-2 infection occurs through binding and internalization of the viral spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane. Lethal complications are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with the 5 alpha reductase inhibitor dutasteride reduced ACE2 levels and internalization of recombinant spike receptor binding domain (Spike-RBD) in hESC-derived cardiac cells and human alveolar epithelial cells. Finally, clinical data on coronavirus disease 2019 (COVID-19) patients demonstrated that abnormal androgen states are significantly associated with severe disease complications and cardiac injury as measured by blood troponin T levels. These findings provide important insights on the mechanism of increased disease susceptibility in male COVID-19 patients and identify androgen receptor inhibition as a potential therapeutic strategy.

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Section: Drugs That Reduce Ace-2 Regulate Steroid Signaling and Peptimentioning

confidence: 99%

Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

Ghazizadeh

Majd

Richter

et al. 2020

Preprint

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“…Apart from the maturation and replication, the entry of this virus by binding its surface spike protein to the hACE-2 is also a crucial process that can be targeted (Hasan et al, 2020;Kuhn et al, 2004;Shang et al, 2020). Since this host cell receptor is essential for the virus entry; targeting hACE-2 has a promise for preventing SARS-Cov-2 infection.…”

Section: Introductionmentioning

confidence: 99%

Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease

Joshi

Jagdale

Bansode

et al. 2020

Journal of Biomolecular Structure and Dynamics

300

269

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2020): Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease, Journal of Biomolecular Structure and Dynamics, ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the current COVID-19 pandemic. Worldwide this disease has infected over 2.5 million individuals with a mortality rate ranging from 5 to 10%. There are several efforts going on in the drug discovery to control the SARS-CoV-2 viral infection. The main protease (M Pro ) plays a critical role in viral replication and maturation, thus can serve as the primary drug target. To understand the structural evolution of M Pro , we have performed phylogenetic and Sequence Similarity Network analysis, that depicted divergence of Coronaviridae M Pro in five clusters specific to viral hosts. This clustering was corroborated with the comparison of M Pro structures. Furthermore, it has been observed that backbone and binding site conformations are conserved despite variation in some of the residues. These attributes can be exploited to repurpose available viral protease inhibitors against SARS-CoV-2 M Pro . In agreement with this, we performed screening of $7100 molecules including active ingredients present in the Ayurvedic antitussive medicines, anti-viral phytochemicals and synthetic anti-virals against SARS-CoV-2 M Pro as the primary target. We identified several natural molecules like d-viniferin, myricitrin, taiwanhomoflavone A, lactucopicrin 15-oxalate, nympholide A, afzelin, biorobin, hesperidin and phyllaemblicin B that strongly binds to SARS-CoV-2 M Pro . Intrestingly, these molecules also showed strong binding with other potential targets of SARS-CoV-2 infection like viral receptor human angiotensin-converting enzyme 2 (hACE-2) and RNA dependent RNA polymerase (RdRp). We anticipate that our approach for identification of multi-target-directed ligand will provide new avenues for drug discovery against SARS-CoV-2 infection. ARTICLE HISTORY

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“…Human coronaviruses are positive-sense RNA (30 kb) viruses. Two types of proteins characterize HCoVs, structural (Spike (S), Nucleocapsid (N), Matrix (M), and Envelope (E)) and non-structural proteins (nsp1 up to nsp16) including the RNA dependent RNA polymerase (RdRp) (nsp12) Hasan et al, 2020). RdRp is a vital enzyme for the life cycle of RNA viruses.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: anin silicoperspective

Elfiky

2020

Journal of Biomolecular Structure and Dynamics

281

264

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New treatment against SARS-CoV-2 now is a must. Nowadays, the world encounters a huge health crisis by the COVID-19 viral infection. Nucleotide inhibitors gave a lot of promising results in terms of its efficacy against different viral infections. In this work, molecular modeling, docking, and dynamics simulations are used to build a model for the viral protein RNA-dependent RNA polymerase (RdRp) and test its binding affinity to some clinically approved drugs and drug candidates. Molecular dynamics is used to equilibrate the system upon binding calculations to ensure the successful reproduction of previous results, to include the dynamics of the RdRp, and to understand how it affects the binding. The results show the effectiveness of Sofosbuvir, Ribavirin, Galidesivir, Remdesivir, Favipiravir, Cefuroxime, Tenofovir, and Hydroxychloroquine, in binding to SARS-CoV-2 RdRp. Additionally, Setrobuvir, YAK, and IDX-184, show better results, while four novel IDX-184 derivatives show promising results in attaching to the SARS-CoV-2 RdRp. There is an urgent need to specify drugs that can selectively bind and subsequently inhibit SARS-CoV-2 proteins. The availability of a punch of FDA-approved anti-viral drugs can help us in this mission, aiming to reduce the danger of COVID-19. The compounds 2 and 3 may tightly bind to the SARS-CoV-2 RdRp and so may be successful in the treatment of COVID-19.

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A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin

Cited by 272 publications

References 76 publications

Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease

SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: anin silicoperspective

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