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Reframing quercetin as a promiscuous inhibitor against SARS-CoV-2 main protease

Yan et al., Proceedings of the National Academy of Sciences, doi:10.1073/pnas.2309289120
Sep 2023  
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In Vitro study Yan and associated response from the original authors Xu, collectively showing that quercetin and echinatin had weak SARS-CoV-2 protease inhibition in SDS-PAGE assays Xu, despite false positive FRET results from MCA-AVLQ quenching Xu, Yan. Authors note that the compounds may act via other targets to achieve reported anti-COVID-19 effects Xu, and underscore the importance of meticulous validation with multiple assays when identifying SARS-CoV-2 protease inhibitors Xu, Yan.
Yan et al., 5 Sep 2023, peer-reviewed, 5 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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Abstract: LETTER Reframing quercetin as a promiscuous inhibitor against SARS-­CoV-­2 main protease Haohao Yana,1, Rui Zhanga,1, Xiaoping Liua, Yanchang Wangb,2 , and Yunyu Chena,2 Fig. 1. Inhibitory effect of quercetin on SARS-­CoV-­2 Mpro in vitro. (A) The chemical structure of quercetin. (B) Inhibition of Mpro by quercetin using FRET assay. (C) The fluorescence quenching effect of quercetin on MCA-­AVLQ fragment in the FRET assay. MCA: 7-­methoxycoumarin-­4-­acetic acid. (D) The comparison between Mpro inhibition and fluorescence quenching effect of quercetin in the FRET assay. (E) Inhibition of Mpro by quercetin using FP assay. The FRET and FP assays were carried out as previously described (4, 5, 7). The IC50 value of quercetin was shown. Nirmatrelvir (PF-­332, 1 μM) and DMSO served as the positive and negative controls, respectively. (F and G) Inhibition of Mpro by quercetin using ddRFP assay. The time course trajectories of ddRFP biosensor in the presence of quercetin at the indicated concentrations were recorded every minute for 30 min by a microplate reader (BioTek). A fluorescent ddRFP biosensor produces a high RFU value in the presence of Mpro inhibitors, whereas the cleavage by Mpro generates two separate RFP fragments with a low RFU signal. In the gel-­based assay, the ddRFP biosensor (55 kDa) can be cleaved by Mpro (34 kDa) to generate RFP-­A1 (top band, 29 kDa) and RFP-­B1 fragments (bottom band, 26 kDa). The testing concentration of quercetin was 50, 100, or 200 μM. Nirmatrelvir (PF-­332, 10 μM) and DMSO were used as the positive and negative controls, respectively. The ddRFP assay was performed based on our previous publications (6, 7). Traditional Chinese medicine has made contributions to the treatment of coronavirus disease 2019 (COVID-­19) because of its favorable efficacy, such as Huashi Baidu decoction (Q-­14) (1, 2). Recently, quercetin, a main component of Q-­14, has been identified as a potent inhibitor against severe acute respiratory syndrome coronavirus 2 (SARS-­CoV-­2) main protease (Mpro) using an integrative pharmacological strategy, and its inhibitory effect on Mpro is examined by the fluorescence resonance energy transfer (FRET) assay with the half-­ maximal inhibitory concentration (IC50) value of 22.47 μM (3). Considering the potential of quercetin in COVID-­19 treatment, a rigorous validation for its Mpro inhibition is necessary. We have developed a systematic high-­throughput screening (HTS) platform for the discovery and assessment of Mpro inhibitors, including FRET, fluorescence polarization (FP), and dimerization-­dependent red fluorescent protein (ddRFP) assays (4–7). With these assays, we previously demonstrated that baicalein is a nonspecific Mpro inhibitor (7). Herein, we rigorously evaluated the inhibition of Mpro by quercetin in vitro using these HTS assays (Fig. 1A). To ensure the PNAS 2023 Vol. 120 No. 37 e2309289120 reliability of these assays, nirmatrelvir (PF-­07321332, PF-­332) served as a positive control in the presence of dithiothreitol (DTT) (7). Using FRET assay, our results showed that quercetin exhibits apparent inhibition against Mpro (IC50 = 42.81 μM) (Fig. 1B). However, the presence of quercetin at the testing concentrations was able to quench the fluorescence signal of MCA-­AVLQ fragment, which is generated by the cleaved FRET substrate (Fig. 1C). Importantly, this quenching effect Author affiliations: aInstitute for Drug Screening and Evaluation, Wannan Medical..
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