Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen

Kuzikov, Maria; Costanzi, Elisa; Reinshagen, Jeanette; Esposito, Francesca; Vangeel, Laura; Wolf, Markus; Ellinger, Bernhard; Claussen, Carsten; Geißlinger, Gerd; Corona, Angela; Iaconis, Daniela; Talarico, Carmine; Manelfi, Candida; Cannalire, Rolando; Rossetti, Giulia; Goßen, Jonas; Albani, Simone; Musiani, Francesco; Herzog, Katja; Yang, Ye; Giabbai, Barbara; Demitri, Nicola; Jochmans, Dirk; Jonghe, Steven De; Rymenants, Jasper; Summa, Vincenzo; Tramontano, Enzo; Beccari, Andrea R.; Leyssen, Pieter; Storici, Paola; Neyts, Johan; Gribbon, Philip; Zaliani, Andrea

doi:10.1021/acsptsci.0c00216

Cited by 106 publications

(107 citation statements)

References 63 publications

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“…Luteolin and apigenin, two flavones detected in the PGL extract, were found to be active on both HIV-1 enzymes, showing IC 50 values of 3.7 µM and 16.1 µM for RNase H activity and 6.5 µM and 22 µM for HIV-1 IN LEDGF-dependent activity, respectively, in agreement with our previous studies [38] although we found a lower degree of inhibition compared with ellagic acid and the control. Flavonoids are a class of natural compounds endowed with a broad spectrum of biological activities, including anti-SARS-CoV-2 activity [52] and promising anti-HIV-1 properties [53,54]. Interestingly, luteolin was found to be capable of inhibiting HIV-1 infection in Jurkat cells, showing better inhibition when added after HIV-1 infection, indicating that it exerts antiviral activity in the later stages of the HIV-1 lifecycle [55].…”

Section: Anti-hiv-1 Activity Of Pure Compounds Detected In Pgb Pgl and Pgpmentioning

confidence: 99%

In Vitro Anti-HIV-1 Reverse Transcriptase and Integrase Properties of Punica granatum L. Leaves, Bark, and Peel Extracts and Their Main Compounds

Sanna

Marengo

Acquadro

et al. 2021

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In a search for natural compounds with anti-HIV-1 activity, we studied the effect of the ethanolic extract obtained from leaves, bark, and peels of Punica granatum L. for the inhibition of the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) and integrase (IN) LEDGF-dependent activities. The chemical analyses led to the detection of compounds belonging mainly to the phenolic and flavonoid chemical classes. Ellagic acid, flavones, and triterpenoid molecules were identified in leaves. The bark and peels were characterized by the presence of hydrolyzable tannins, such as punicalins and punicalagins, together with ellagic acid. Among the isolated compounds, the hydrolyzable tannins and ellagic acid showed a very high inhibition (IC50 values ranging from 0.12 to 1.4 µM and 0.065 to 0.09 µM of the RNase H and IN activities, respectively). Of the flavonoids, luteolin and apigenin were found to be able to inhibit RNase H and IN functions (IC50 values in the 3.7–22 μM range), whereas luteolin 7-O-glucoside showed selective activity for HIV-1 IN. In contrast, betulinic acid, ursolic acid, and oleanolic acid were selective for the HIV-1 RNase H activity. Our results strongly support the potential of non-edible P. granatum organs as a valuable source of anti-HIV-1 compounds.

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Section: Anti-hiv-1 Activity Of Pure Compounds Detected In Pgb Pgl and Pgpmentioning

confidence: 99%

In Vitro Anti-HIV-1 Reverse Transcriptase and Integrase Properties of Punica granatum L. Leaves, Bark, and Peel Extracts and Their Main Compounds

Sanna

Marengo

Acquadro

et al. 2021

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“…In order to find drug candidates against SARS-CoV-2, we performed a large-scale x-ray crystallographic screen of M pro against two repurposing libraries containing 5953 compounds from the Fraunhofer IME Repurposing Collection and the Safe-in-man library from Dompé Farmaceutici S.p.A. ( 5 ).…”

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confidence: 99%

X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

Günther

Reinke

Yaiza

et al. 2021

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The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.

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“…To ensure a high level of data integrity, only compounds with explicitly defined IC 50 values were selected, using a cut-off of 5 μM as minimum potency to define compounds as "actives". A third dataset consisted of a recently added repository generated within the "EXaSCale smArt pLatform Against paThogEns for Corona-Virus, Exscalate4CoV or E4C" project (CHEMBL4495564), containing activity data for ~ 8000 compounds from the primary screening against SARS-CoV-2 Main protease (Mpro) [30]. In this case, compounds were considered as actives if enzyme inhibition was at least 40%.…”

Section: Chembl Datasetsmentioning

confidence: 99%

“Molecular Anatomy”: a new multi-dimensional hierarchical scaffold analysis tool

et al. 2021

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The scaffold representation is widely employed to classify bioactive compounds on the basis of common core structures or correlate compound classes with specific biological activities. In this paper, we present a novel approach called “Molecular Anatomy” as a flexible and unbiased molecular scaffold-based metrics to cluster large set of compounds. We introduce a set of nine molecular representations at different abstraction levels, combined with fragmentation rules, to define a multi-dimensional network of hierarchically interconnected molecular frameworks. We demonstrate that the introduction of a flexible scaffold definition and multiple pruning rules is an effective method to identify relevant chemical moieties. This approach allows to cluster together active molecules belonging to different molecular classes, capturing most of the structure activity information, in particular when libraries containing a huge number of singletons are analyzed. We also propose a procedure to derive a network visualization that allows a full graphical representation of compounds dataset, permitting an efficient navigation in the scaffold’s space and significantly contributing to perform high quality SAR analysis. The protocol is freely available as a web interface at https://ma.exscalate.eu.

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Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen

Cited by 106 publications

References 63 publications

In Vitro Anti-HIV-1 Reverse Transcriptase and Integrase Properties of Punica granatum L. Leaves, Bark, and Peel Extracts and Their Main Compounds

In Vitro Anti-HIV-1 Reverse Transcriptase and Integrase Properties of Punica granatum L. Leaves, Bark, and Peel Extracts and Their Main Compounds

X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

“Molecular Anatomy”: a new multi-dimensional hierarchical scaffold analysis tool

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