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All Studies   Meta Analysis    Recent:   

An Integrated In Silico and In Vitro Approach for the Identification of Natural Products Active against SARS-CoV-2

Pennisi et al., Biomolecules, doi:10.3390/biom14010043
Dec 2023  
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In Vitro and In Silico study showing SARS-CoV-2 inhibition with folic acid and luteolin-7-O-glucuronide. Enzymatic assays showed that both compounds have micromolar range inhibition of SARS-CoV-2 proteases 3CLpro and PLpro. However, pseudovirus entry assays demonstrated much stronger antiviral effects, with both compounds significantly reducing infection of cells by alpha and omicron SARS-CoV-2 pseudoviruses. Molecular modeling revealed binding sites within the spike protein receptor binding domain of both variants, suggesting they may interfere with viral entry.
13 preclinical studies support the efficacy of vitamin B9 for COVID-19:
Vitamin B9 has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function11-13. Vitamin B9 inhibits SARS-CoV-2 In Silico2-10, reduces spike protein binding ability10, binds with the spike protein receptor binding domain for alpha and omicron variants1, inhibits the SARS-CoV-2 nucleocapsid protein2, inhibits 3CLpro and PLpro in enzymatic assays1, significantly reduces infection for alpha and omicron SARS-CoV-2 pseudoviruses1, and inhibits ACE2 expression and SARS-CoV-2 infection in a mouse model10.
Pennisi et al., 28 Dec 2023, Italy, peer-reviewed, 7 authors. Contact: rpennisi@unime.it (corresponding author), paola.trischitta@studenti.unime.it, anna.piperno@unime.it, mtsciortino@unime.it, arescifina@unict.it, edoardo.napoli@icb.cnr.it, davide.gentile@polimi.it.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperVitamin B9All
An Integrated In Silico and In Vitro Approach for the Identification of Natural Products Active against SARS-CoV-2
Rosamaria Pennisi, Davide Gentile, Antonio Rescifina, Edoardo Napoli, Paola Trischitta, Anna Piperno, Maria Teresa Sciortino
Biomolecules, doi:10.3390/biom14010043
Coronavirus disease 2019 (COVID-19) , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has provoked a global health crisis due to the absence of a specific therapeutic agent. 3CL pro (also known as the main protease or M pro ) and PL pro are chymotrypsin-like proteases encoded by the SARS-CoV-2 genome, and play essential roles during the virus lifecycle. Therefore, they are recognized as a prospective therapeutic target in drug discovery against SARS-CoV-2 infection. Thus, this work aims to collectively present potential natural 3CL pro and PL pro inhibitors by in silico simulations and in vitro entry pseudotype-entry models. We screened luteolin-7-O-glucuronide (L7OG), cynarin (CY), folic acid (FA), and rosmarinic acid (RA) molecules against PL pro and 3CL pro through a luminogenic substrate assay. We only reported moderate inhibitory activity on the recombinant 3CL pro and PL pro by L7OG and FA. Afterward, the entry inhibitory activity of L7OG and FA was tested in cell lines transduced with the two different SARS-CoV-2 pseudotypes harboring alpha (α) and omicron (o) spike (S) protein. The results showed that both compounds have a consistent inhibitory activity on the entry for both variants. However, L7OG showed a greater degree of entry inhibition against α-SARS-CoV-2. Molecular modeling studies were used to determine the inhibitory mechanism of the candidate molecules by focusing on their interactions with residues recognized by the protease active site and receptor-binding domain (RBD) of spike SARS-CoV-2. This work allowed us to identify the binding sites of FA and L7OG within the RBD domain in the alpha and omicron variants, demonstrating how FA is active in both variants. We have confidence that future in vivo studies testing the safety and effectiveness of these natural compounds are warranted, given that they are effective against a variant of concerns.
Conflicts of Interest: The authors declare no conflict of interest.
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Therefore, they are recognized as a prospective therapeutic target in ' 'drug discovery against SARS-CoV-2 infection. Thus, this work aims to collectively present ' 'potential natural 3CLpro and PLpro inhibitors by in silico simulations and in vitro entry ' 'pseudotype-entry models. We screened luteolin-7-O-glucuronide (L7OG), cynarin (CY), folic ' 'acid (FA), and rosmarinic acid (RA) molecules against PLpro and 3CLpro through a luminogenic ' 'substrate assay. We only reported moderate inhibitory activity on the recombinant 3CLpro and ' 'PLpro by L7OG and FA. Afterward, the entry inhibitory activity of L7OG and FA was tested in ' 'cell lines transduced with the two different SARS-CoV-2 pseudotypes harboring alpha (α) and ' 'omicron (o) spike (S) protein. The results showed that both compounds have a consistent ' 'inhibitory activity on the entry for both variants. However, L7OG showed a greater degree of ' 'entry inhibition against α-SARS-CoV-2. Molecular modeling studies were used to determine the ' 'inhibitory mechanism of the candidate molecules by focusing on their interactions with ' 'residues recognized by the protease active site and receptor-binding domain (RBD) of spike ' 'SARS-CoV-2. This work allowed us to identify the binding sites of FA and L7OG within the RBD ' 'domain in the alpha and omicron variants, demonstrating how FA is active in both variants. 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Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as ' 'Electrophilic Warhead with Activity against Coronaviruses. Int. J. Mol. ' 'Sci., 22.', 'DOI': '10.3390/ijms22031398'}, { 'key': 'ref_5', 'doi-asserted-by': 'crossref', 'unstructured': 'Citarella, A., Dimasi, A., Moi, D., Passarella, D., Scala, A., Piperno, ' 'A., and Micale, N. (2023). Recent Advances in SARS-CoV-2 Main Protease ' 'Inhibitors: From Nirmatrelvir to Future Perspectives. Biomolecules, 13.', 'DOI': '10.20944/preprints202308.0055.v1'}, { 'key': 'ref_6', 'doi-asserted-by': 'crossref', 'first-page': '393', 'DOI': '10.4155/fmc-2021-0269', 'article-title': 'Design of SARS-CoV-2 Mpro, PLpro Dual-Target Inhibitors Based on Deep ' 'Reinforcement Learning and Virtual Screening', 'volume': '14', 'author': 'Zhang', 'year': '2022', 'journal-title': 'Future Med. 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