Potential inhibitors for blocking the interaction of the coronavirus SARS-CoV-2 spike protein and its host cell receptor ACE2

Li, Changzhi; Zhou, Honggeng; Guo, Lingling; Xie, Donglai; He, Huiping; Zhang, Hong; Liu, Yixiu; Peng, Li‐Xia; Zheng, Lixin; Lu, Wenhua; Mei, Yan; Liu, Zhijie; Huang, Jie; Wang, Ming‐Dian; Shu, Ditian; Ding, Liuyan; Lang, Yan-Hong; Luo, Feifei; Wang, Jing; Huang, Bi‐Jun; Huang, Peng; Gao, Song; Chen, Jindong; Qian, Chao‐Nan

doi:10.1186/s12967-022-03501-9

Cited by 10 publications

(10 citation statements)

References 30 publications

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“…Prior to the experiments, we bought a commercial library of 2526 natural products (catalog number L6000, TargetMol, September 2020) from Shanghai Topscience Biochemical Technology Co., Ltd. for the inhibitor screening ( Supplementary Table S1 ); it had been reported for compound screening of S protein [ 26 , 27 ], but not for M pro . Baicalein, a natural product known to have an inhibitory effect on SARS CoV-2 M pro in vitro [ 25 ], was used as a positive control for the first round of screening of 2526 compounds at a single dose of 80 μΜ.…”

Section: Resultsmentioning

confidence: 99%

Natural Product-Based Screening for Lead Compounds Targeting SARS CoV-2 Mpro

et al. 2023

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Drugs that cure COVID-19 have been marketed; however, this disease continues to ravage the world without becoming extinct, and thus, drug discoveries are still relevant. Since Mpro has known advantages as a drug target, such as the conserved nature of the active site and the absence of homologous proteins in the body, it receives the attention of many researchers. Meanwhile, the role of traditional Chinese medicine (TCM) in the control of epidemics in China has also led to a focus on natural products, with the hope of finding some promising lead molecules through screening. In this study, we selected a commercial library of 2526 natural products from plants, animals and microorganisms with known biological activity for drug discovery, which had previously been reported for compound screening of the SARS CoV-2 S protein, but had not been tested on Mpro. This library contains compounds from a variety of Chinese herbs, including Lonicerae Japonicae Flos, Forsythiae Fructus and Scutellariae Radix, which are derived from traditional Chinese medicine prescriptions that have been shown to be effective against COVID-19. We used the conventional FRET method for the initial screening. After two rounds of selection, the remaining 86 compounds were divided into flavonoids, lipids, phenylpropanoids, phenols, quinones, alkaloids, terpenoids and steroids according to the skeleton structures, with inhibition rates greater than 70%. The top compounds in each group were selected to test the effective concentration ranges; the IC50 values were as follows: (−)–gallocatechin gallate (1.522 ± 0.126 μM), ginkgolic acid C15:1 (9.352 ± 0.531 μM), hematoxylin (1.025 ± 0.042 μM), fraxetin (2.486 ± 0.178 μM), wedelolactone (1.003 ± 0.238 μM), hydroxytyrosol acetate (3.850 ± 0.576 μM), vanitiolide (2.837 ± 0.225 μM), β,β–dimethylacrylalkannin (2.731 ± 0.308 μM), melanin (7.373 ± 0.368 μM) and cholesteryl sodium sulfate (2.741 ± 0.234μM). In the next step, we employed two biophysical techniques, SPR and nanoDSF, to obtain KD/Kobs values: hematoxylin (0.7 μM), (−)–gallocatechin gallate (126 μM), ginkgolic acid C15:1 (227 μM), wedelolactone (0.9770 μM), β,β–dimethylacrylalkannin (1.9004 μM,), cholesteryl sodium sulfate (7.5950 μM) and melanin (11.5667 μM), which allowed better assessments of the binding levels. Here, seven compounds were the winners. Then, molecular docking experiments were specially performed by AutoDock Vina to analyze the mode of interactions within Mpro and ligands. We finally formulated the present in silico study to predict pharmacokinetic parameters as well as drug-like properties, which is presumably the step that tells humans whether the compounds are drug-like or not. Moreover, hematoxylin, melanin, wedelolactone, β,β–dimethylacrylalkannin and cholesteryl sodium sulfate are in full compliance with the “Lipinski” principle and possess reasonable ADME/T properties, they have a greater potential of being lead compounds. The proposed five compounds are also the first to be found to have potential inhibitory effects on SARS CoV-2 Mpro. We hope that the results in this manuscript may serve as benchmarks for the above potentials.

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Section: Resultsmentioning

confidence: 99%

Natural Product-Based Screening for Lead Compounds Targeting SARS CoV-2 Mpro

et al. 2023

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“…Furthermore, the three antiviral drugs did not increase the incidence of adverse events. Recently, the interaction between the S protein of coronavirus and the human cell ACE2 receptor was found to be inhibited by three compounds, TS-1276 (anthraquinone), tannic acid, and TS-984 (9-methoxycanthin-6-one), as mentioned in the study of Li et al [ 58 ].…”

Section: Collected Data and Discussionmentioning

confidence: 99%

Problems Associated with Co-Infection by Multidrug-Resistant Klebsiella pneumoniae in COVID-19 Patients: A Review

Yahya

2022

Healthcare

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To date, coronavirus disease 2019 (COVID-19) and its variants have been reported as a novel public health concern threatening us worldwide. The presence of Klebsiella pneumoniae in COVID-19-infected patients is a major problem due to its resistance to multiple antibiotics, and it can possibly make the management of COVID-19 in patients more problematic. The impact of co-infection by K. pneumoniae on COVID-19 patients was explored in the current review. The spread of K. pneumoniae as a co-infection among critically ill COVID-19 patients, particularly throughout hospitalization, was identified and recorded via numerous reports. Alarmingly, the extensive application of antibiotics in the initial diagnosis of COVID-19 infection may reduce bacterial co-infection, but it increases the antibiotic resistance of bacteria such as the strains of K. pneumoniae. The correct detection of multidrug-resistant K. pneumoniae can offer a supportive reference for the diagnosis and therapeutic management of COVID-19 patients. Furthermore, the prevention and control of K. pneumoniae are required to minimize the risk of COVID-19. The aim of the present review is, therefore, to report on the virulence factors of the K. pneumonia genotypes, the drug resistance of K. pneumonia, and the impact of K. pneumoniae co-infection with COVID-19 on patients through a study of the published scientific papers, reports, and case studies.

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“…Previous studies have also reported on small compounds that inhibit SARS-CoV-2 entry. After screening a natural and FDA-approved compound libraries using homogeneous time resolved fluorescence, Li et al found that TS-984 (9-methoxycanthin-6-one) suppresses the spike:ACE2 interaction via pseudovirus neutralization assay on ACE2-overexpressing 293T cells, suggesting that it may have potential as an anti-COVID-19 drug [ 27 ]. Wang et al also confirmed the binding affinity of H69C2, which was virtually screened from a natural product database, to the RBD domain of SARS-CoV-2 spike protein using native mass spectrometry and surface plasmon resonance for binding: K D value of 0.0947 µM.…”

Section: Discussionmentioning

confidence: 99%

Mulberrofuran G, a Mulberry Component, Prevents SARS-CoV-2 Infection by Blocking the Interaction between SARS-CoV-2 Spike Protein S1 Receptor-Binding Domain and Human Angiotensin-Converting Enzyme 2 Receptor

Kim

Kwon

et al. 2022

Nutrients

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Despite the recent development of RNA replication-targeted COVID-19 drugs by global pharmaceutical companies, their prescription in clinical practice is limited by certain factors, including drug interaction, reproductive toxicity, and drug resistance. COVID-19 drugs with multiple targets for the SARS-CoV-2 life cycle may lead to a successful reduction in drug resistance as well as enhanced therapeutic efficacy, and natural products are a potential source of molecules with therapeutic effects against COVID-19. In this study, we investigated the inhibitory efficacy of mulberrofuran G (MG), a component of Morus alba L., also known as mulberry, which has been used as food and traditional medicine, on the binding of the spike S1 receptor-binding domain (RBD) protein to the angiotensin-converting enzyme 2 (ACE2) receptor, which is the initial stage of the SARS-CoV-2 infection. In competitive enzyme-linked immunosorbent assays, MG effectively blocked the spike S1 RBD: ACE2 receptor molecular binding, and investigations using the BLItz system and in silico modeling revealed that MG has high affinity for both proteins. Finally, we confirmed that MG inhibits the entry of SARS-CoV-2 spike pseudotyped virus and a clinical isolate of SARS-CoV-2 into cells, suggesting that MG might be a promising therapeutic candidate for preventing SARS-CoV-2 binding to the cell surface during early infection.

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Potential inhibitors for blocking the interaction of the coronavirus SARS-CoV-2 spike protein and its host cell receptor ACE2

Cited by 10 publications

References 30 publications

Natural Product-Based Screening for Lead Compounds Targeting SARS CoV-2 Mpro

Natural Product-Based Screening for Lead Compounds Targeting SARS CoV-2 Mpro

Problems Associated with Co-Infection by Multidrug-Resistant Klebsiella pneumoniae in COVID-19 Patients: A Review

Mulberrofuran G, a Mulberry Component, Prevents SARS-CoV-2 Infection by Blocking the Interaction between SARS-CoV-2 Spike Protein S1 Receptor-Binding Domain and Human Angiotensin-Converting Enzyme 2 Receptor

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