Dual inhibition of SARS-CoV-2 and human rhinovirus with protease inhibitors in clinical development

Liu, Cheng; Boland, Sandro; Scholle, Michael D.; Bardiot, Dorothée; Marchand, Arnaud; Chaltin, Patrick; Blatt, Lawrence M.; Beigelman, Leonid; Symons, Julian; Raboisson, Pierre; Gurard-Levin, Zachary A.; Vandyck, Koen; Deval, Jérôme

doi:10.1016/j.antiviral.2021.105020

Cited by 45 publications

(38 citation statements)

References 28 publications

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“…The SAMDI-MS technology has recently proven to be a powerful approach for measuring SARS-CoV-2 3CLpro activity, 32 including simultaneously reporting on SARS-CoV-2 3CLpro and rhinovirus HRV3C protease activities. 33 In addition to the SARS-CoV-2 target, the SAMDI-MS technology has been reported to characterize dozens of biochemical activities, including posttranslational modifying enzymes, 24,34–37 RNA-modifying proteins, 30 and arginase, 29 highlighting its flexibility and broad drug discovery solutions. SAMDI-MS offers several solutions over other MS approaches, including traditional MALDI.…”

Section: Discussionmentioning

confidence: 99%

Label-Free Screening of SARS-CoV-2 NSP14 Exonuclease Activity Using SAMDI Mass Spectrometry

Scholle¹,

Liu²,

Deval³

et al. 2021

SLAS Discovery

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the global COVID-19 pandemic. Nonstructural protein 14 (NSP14), which features exonuclease (ExoN) and guanine N7 methyltransferase activity, is a critical player in SARS-CoV-2 replication and fidelity and represents an attractive antiviral target. Initiating drug discovery efforts for nucleases such as NSP14 remains a challenge due to a lack of suitable high-throughput assay methodologies. This report describes the combination of self-assembled monolayers and matrix-assisted laser desorption ionization mass spectrometry to enable the first label-free and high-throughput assay for NSP14 ExoN activity. The assay was used to measure NSP14 activity and gain insight into substrate specificity and the reaction mechanism. Next, the assay was optimized for kinetically balanced conditions and miniaturized, while achieving a robust assay (Z factor > 0.8) and a significant assay window (signal-to-background ratio > 200). Screening 10,240 small molecules from a diverse library revealed candidate inhibitors, which were counterscreened for NSP14 selectivity and RNA intercalation. The assay methodology described here will enable, for the first time, a label-free and high-throughput assay for NSP14 ExoN activity to accelerate drug discovery efforts and, due to the assay flexibility, can be more broadly applicable for measuring other enzyme activities from other viruses or implicated in various pathologies.

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Section: Discussionmentioning

confidence: 99%

Label-Free Screening of SARS-CoV-2 NSP14 Exonuclease Activity Using SAMDI Mass Spectrometry

Scholle¹,

Liu²,

Deval³

et al. 2021

SLAS Discovery

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“…The fi rst group of compounds with a signifi cant antiviral effect is peptidomimetics 1-23 [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] (Figs. 1, 2).…”

Section: Doi: 101134/s107042802105002xmentioning

confidence: 99%

“…Among the representatives of this type of coronavirus reproduction inhibitors, there are both drugs already used in clinical practice, such as boceprevir 21 [36,42] and lopinavir 23 [48], and new compounds. Compounds of this group can be conditionally divided into aryl(hetaryl)aminoacetic acid derivatives 1 [30], 3 [32], 6 [33], and 10 [36] and benzotriazolylacetic acid derivatives 2 [31], 4 [32], and 5 [32], serine and isoserine derivatives 7-9 [34,35] (Fig. 1), as well as compounds 11-23 [36][37][38][39][40][41][42][43][44][45][46][47][48] (Fig.…”

Section: Doi: 101134/s107042802105002xmentioning

confidence: 99%

“…Compounds of this group can be conditionally divided into aryl(hetaryl)aminoacetic acid derivatives 1 [30], 3 [32], 6 [33], and 10 [36] and benzotriazolylacetic acid derivatives 2 [31], 4 [32], and 5 [32], serine and isoserine derivatives 7-9 [34,35] (Fig. 1), as well as compounds 11-23 [36][37][38][39][40][41][42][43][44][45][46][47][48] (Fig. 2), which contain several amino acid units, often leucine units 11 [36,37,38], 12 [39], 14 [41], 15 [36,42], 19 [45], 20 [42], and 22 [47].…”

Section: Doi: 101134/s107042802105002xmentioning

confidence: 99%

“…1), as well as compounds 11-23 [36][37][38][39][40][41][42][43][44][45][46][47][48] (Fig. 2), which contain several amino acid units, often leucine units 11 [36,37,38], 12 [39], 14 [41], 15 [36,42], 19 [45], 20 [42], and 22 [47]. A common feature of peptidomimetics is that they contain lipophilic substituents (most frequently tert-alkyl, aromatic, or heteroaromatic), which suggests the importance of binding to hydrophobic sites of the target.…”

Section: Doi: 101134/s107042802105002xmentioning

confidence: 99%

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Main Chemotypes of SARS-CoV-2 Reproduction Inhibitors

Shiryaev

Klimochkin

2021

Russ J Org Chem

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The COVID-19 pandemic has forced scientists all over the world to focus their effort on searching for targeted drugs for coronavirus chemotherapy. The present review is an attempt to systematize low-molecular-weight compounds, including well-known pharmaceuticals and natural substances that have exhibited high anti-coronavirus activity, not in terms of action on their targets, but in terms of their structural type.

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NMR Spectroscopy of the Main Protease of SARS‐CoV‐2 and Fragment‐Based Screening Identify Three Protein Hotspots and an Antiviral Fragment

et al. 2021

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The main protease (3CLp) of the SARS‐CoV‐2, the causative agent for the COVID‐19 pandemic, is one of the main targets for drug development. To be active, 3CLp relies on a complex interplay between dimerization, active site flexibility, and allosteric regulation. The deciphering of these mechanisms is a crucial step to enable the search for inhibitors. In this context, using NMR spectroscopy, we studied the conformation of dimeric 3CLp from the SARS‐CoV‐2 and monitored ligand binding, based on NMR signal assignments. We performed a fragment‐based screening that led to the identification of 38 fragment hits. Their binding sites showed three hotspots on 3CLp, two in the substrate binding pocket and one at the dimer interface. F01 is a non‐covalent inhibitor of the 3CLp and has antiviral activity in SARS‐CoV‐2 infected cells. This study sheds light on the complex structure‐function relationships of 3CLp and constitutes a strong basis to assist in developing potent 3CLp inhibitors.

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Dual inhibition of SARS-CoV-2 and human rhinovirus with protease inhibitors in clinical development

Cited by 45 publications

References 28 publications

Label-Free Screening of SARS-CoV-2 NSP14 Exonuclease Activity Using SAMDI Mass Spectrometry

Label-Free Screening of SARS-CoV-2 NSP14 Exonuclease Activity Using SAMDI Mass Spectrometry

Main Chemotypes of SARS-CoV-2 Reproduction Inhibitors

NMR Spectroscopy of the Main Protease of SARS‐CoV‐2 and Fragment‐Based Screening Identify Three Protein Hotspots and an Antiviral Fragment

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