Discovery of novel SARS-CoV-2 inhibitors targeting the main protease Mpro by virtual screenings and hit optimization

Mercorelli, Beatrice; Desantis, Jenny; Celegato, Marta; Bazzacco, Alessandro; Siragusa, Lydia; Benedetti, Paolo; Eleuteri, Michela; Croci, Federico; Cruciani, Gabriele; Goracci, Laura; Loregian, Arianna

doi:10.1016/j.antiviral.2022.105350

Cited by 14 publications

(10 citation statements)

References 37 publications

(50 reference statements)

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“…As sterols interact with the active site, they can be promising candidates, particularly oxygenous tetrahydroxy sterol, which has a high tendency to form hydrogen bonds. Schiff base ligands have been shown to inhibit M pro in previous studies [ 54 ] as well as caffeine [ 54 , 55 ], nethylxanthines [ 56 ], natural product isolates [ 57 ], glycyrrhizin [ 58 ], ML188 [ 59 ], pyrimidonic and pyridonic pharmaceuticals [ 60 , 61 ], kaempferol [ 62 ], fungal natural products [ 63 ], marine natural compounds [ 64 ], Ceftazidime [ 65 ], hepatitis C virus protease drugs [ 66 ], and other inhibitors [ 67 , 68 , 69 , 70 , 71 , 72 ]. In our molecular docking study, these natural compounds were identified as potential M pro inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Inhibitory Activity of Saussurea costus Extract against Bacteria, Candida, Herpes, and SARS-CoV-2

Idriss

Siddig

González-Maldonado

et al. 2023

Plants

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Medicinal herbs have long been utilized to treat various diseases or to relieve the symptoms of some ailments for extended periods. The present investigation demonstrates the phytochemical profile, molecular docking, anti-Candida activity, and anti-viral activity of the Saussurea costus acetic acid extract. GC-MS analysis of the extract revealed the presence of 69 chemical compounds. The chemical compounds were alkaloids (4%), terpenoids (79%), phenolic compounds (4%), hydrocarbons (7%), and sterols (6%). Molecular docking was used to study the inhibitory activity of 69 identified compounds against SARS-CoV-2. In total, 12 out of 69 compounds were found to have active properties exhibiting SARS-CoV-2 inhibition. The binding scores of these molecules were significantly low, ranging from −7.8 to −5.6 kcal/mol. The interaction of oxatricyclo [20.8.0.0(7,16)] triaconta-1(22),7(16),9,13,23,29-hexaene with the active site is more efficient. Furthermore, the extract exhibited significant antimicrobial activity (in vitro) against Candida albicans, which was the most susceptible microorganism, followed by Bacillus cereus, Salmonella enterica, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, respectively. On the other hand, its antiviral activity was evaluated against HSV-1 and SARS-CoV-2, and the results showed a significant positive influence against HSV-1 (EC50 = 82.6 g/mL; CC50 = 162.9 g/mL; selectivity index = 1.9). In spite of this, no impact could be observed in terms of inhibiting the entry of SARS-CoV-2 in vitro.

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Section: Resultsmentioning

confidence: 99%

Inhibitory Activity of Saussurea costus Extract against Bacteria, Candida, Herpes, and SARS-CoV-2

Idriss

Siddig

González-Maldonado

et al. 2023

Plants

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“…For example, a ligand-based virtual screen of 790,000 compounds followed by structure-based screens for M pro led to the testing of 30 compounds, of which 8 had high 10's μM IC 50 and antiviral activity. 27 A docking and molecular dynamics approach was used to develop a covalent inhibitor of M pro from a fragment hit, although the antiviral activity or selectivity was not assessed. 28 An in silico approach to screening over a billion compounds led to over 400 being synthesized, of which only 5 were active and ultimately resulted in a non-covalent inhibitor with a M pro IC 50 = 1 μM.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Extensive effort has been applied toward developing M pro inhibitors using a range of experimental approaches. For example, a ligand-based virtual screen of 790,000 compounds followed by structure-based screens for M pro led to the testing of 30 compounds, of which 8 had high 10’s μM IC 50 and antiviral activity . A docking and molecular dynamics approach was used to develop a covalent inhibitor of M pro from a fragment hit, although the antiviral activity or selectivity was not assessed .…”

Section: Discussionmentioning

confidence: 99%

Discovery of PL^pro and M^pro Inhibitors for SARS-CoV-2

et al. 2023

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There are very few small-molecule antivirals for SARS-CoV-2 that are either currently approved (or emergency authorized) in the US or globally, including remdesivir, molnupiravir, and paxlovid. The increasing number of SARS-CoV-2 variants that have appeared since the outbreak began over three years ago raises the need for continual development of updated vaccines and orally available antivirals in order to fully protect or treat the population. The viral main protease (Mpro) and the papain-like protease (PLpro) are key for viral replication; therefore, they represent valuable targets for antiviral therapy. We herein describe an in vitro screen performed using the 2560 compounds from the Microsource Spectrum library against Mpro and PLpro in an attempt to identify additional small-molecule hits that could be repurposed for SARS-CoV-2. We subsequently identified 2 hits for Mpro and 8 hits for PLpro. One of these hits was the quaternary ammonium compound cetylpyridinium chloride with dual activity (IC50 = 2.72 ± 0.09 μM for PLpro and IC50 = 7.25 ± 0.15 μM for Mpro). A second inhibitor of PLpro was the selective estrogen receptor modulator raloxifene (IC50 = 3.28 ± 0.29 μM for PLpro and IC50 = 42.8 ± 6.7 μM for Mpro). We additionally tested several kinase inhibitors and identified olmutinib (IC50 = 0.54 ± 0.04 μM), bosutinib (IC50 = 4.23 ± 0.28 μM), crizotinib (IC50 = 3.81 ± 0.04 μM), and dacominitinib (IC50 = IC50 3.33 ± 0.06 μM) as PLpro inhibitors for the first time. In some cases, these molecules have also been tested by others for antiviral activity for this virus, or we have used Calu-3 cells infected with SARS-CoV-2. The results suggest that approved drugs can be identified with promising activity against these proteases, and in several cases we or others have validated their antiviral activity. The additional identification of known kinase inhibitors as molecules targeting PLpro may provide new repurposing opportunities or starting points for chemical optimization.

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“…Several intracellular targets involved in different stages of the viral life cycle have been identified as potential targets for nanobodies to inhibit SARS-CoV-2 replication and packaging, such as Mpro, RdRp, and viral N protein. , Although nanobodies’ small size enables us to effectively target intracellular proteins and other targets involved in various cellular pathways, delivering nanobodies into the cytoplasm of target cells is a significant challenge due to the presence of cellular membranes that prevent their entry. There are several approaches to deliver nanobodies into the cytoplasm, including chemical conjugation, cell-penetrating peptides, − and nanoparticle-based delivery systems. , These methods have been used successfully for the delivery of other therapeutic molecules.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Emerging Landscape of Nanobodies and Their Neutralizing Applications against SARS-CoV-2 Virus

Feng

Wang

2023

ACS Pharmacol. Transl. Sci.

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The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the coronavirus disease 2019 (COVID-19) has significantly altered people's way of life. Despite widespread knowledge of vaccination, mask use, and avoidance of close contact, COVID-19 is still spreading around the world. Numerous research teams are examining the SARS-CoV-2 infection process to discover strategies to identify, prevent, and treat COVID-19 to limit the spread of this chronic coronavirus illness and restore lives to normalcy. Nanobodies have advantages over polyclonal and monoclonal antibodies (Ab) and Ab fragments, including reduced size, high stability, simplicity in manufacture, compatibility with genetic engineering methods, and lack of solubility and aggregation issues. Recent studies have shown that nanobodies that target the SARS-CoV-2 receptor-binding domain and disrupt ACE2 interactions are helpful in the prevention and treatment of SARS-CoV-2-infected animal models, despite the lack of evidence in human patients. The creation and evaluation of nanobodies, as well as their diagnostic and therapeutic applications against COVID-19, are discussed in this paper.

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Discovery of novel SARS-CoV-2 inhibitors targeting the main protease Mpro by virtual screenings and hit optimization

Cited by 14 publications

References 37 publications

Inhibitory Activity of Saussurea costus Extract against Bacteria, Candida, Herpes, and SARS-CoV-2

Inhibitory Activity of Saussurea costus Extract against Bacteria, Candida, Herpes, and SARS-CoV-2

Discovery of PL^pro and M^pro Inhibitors for SARS-CoV-2

Emerging Landscape of Nanobodies and Their Neutralizing Applications against SARS-CoV-2 Virus

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Discovery of novel SARS-CoV-2 inhibitors targeting the main protease Mpro by virtual screenings and hit optimization

Cited by 14 publications

References 37 publications

Inhibitory Activity of Saussurea costus Extract against Bacteria, Candida, Herpes, and SARS-CoV-2

Inhibitory Activity of Saussurea costus Extract against Bacteria, Candida, Herpes, and SARS-CoV-2

Discovery of PLpro and Mpro Inhibitors for SARS-CoV-2

Emerging Landscape of Nanobodies and Their Neutralizing Applications against SARS-CoV-2 Virus

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Product

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Discovery of PL^pro and M^pro Inhibitors for SARS-CoV-2