Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses

Napolitano, Valeria; Dąbrowska, Agnieszka; Schorpp, Kenji; Mourão, André; Barreto-Durán, Emilia; Benedyk, Małgorzata; Botwina, Paweł; Brandner, S; Bostock, Mark J.; Chykunova, Yuliya; Czarna, Anna; Dubin, Grzegorz; Fröhlich, Tony; Hölscher, Michael; Jedrysik, Malwina; Matsuda, Alex; Owczarek, Katarzyna; Pachota, Magdalena; Plettenburg, Oliver; Potempa, Jan; Rothenaigner, Ina; Schlauderer, Florian; Słysz, Klaudia; Szczepański, Artur; Mohn, Kristin Greve-Isdahl; Blomberg, Björn; Sattler, Michael; Hadian, Kamyar; Popowicz, Grzegorz M.; Pyrć, Krzysztof

doi:10.1016/j.chembiol.2021.11.006

Cited by 44 publications

(55 citation statements)

References 61 publications

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“…Acriflavine was recently reported to inhibit papain-like protease (PL pro ) from SARS-CoV-2, which contributed to drug-dependent suppression of viral replication. 7 Here, we explored another putative mechanism of the antiviral activity of acriflavine, i.e ., the inhibition of the interaction between the viral RBD domain of Spike protein and ACE2, the host receptor driving viral cell entry. Interaction between RBD and ACE2 in the presence of a vehicle (DMSO) was set to 100%.…”

Section: Resultsmentioning

confidence: 99%

Zirconium-Based Metal–Organic Frameworks as Acriflavine Cargos in the Battle against Coronaviruses─A Theoretical and Experimental Approach

Jodłowski

Dymek

Kurowski

et al. 2022

ACS Appl. Mater. Interfaces

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In this study, we present a complementary approach for obtaining an effective drug, based on acriflavine (ACF) and zirconium-based metal–organic frameworks (MOFs), against SARS-CoV-2. The experimental results showed that acriflavine inhibits the interaction between viral receptor-binding domain (RBD) of spike protein and angiotensin converting enzyme-2 (ACE2) host receptor driving viral cell entry. The prepared ACF@MOF composites exhibited low (MOF-808 and UiO-66) and high (UiO-67 and NU-1000) ACF loadings. The drug release profiles from prepared composites showed different release kinetics depending on the local pore environment. The long-term ACF release with the effective antiviral ACF concentration was observed for all studied ACF@MOF composites. The density functional theory (DFT) calculations allowed us to determine that π–π stacking together with electrostatic interaction plays an important role in acriflavine adsorption and release from ACF@MOF composites. The molecular docking results have shown that acriflavine interacts with several possible binding sites within the RBD and binding site at the RBD/ACE2 interface. The cytotoxicity and ecotoxicity results have confirmed that the prepared ACF@MOF composites may be considered potentially safe for living organisms. The complementary experimental and theoretical results presented in this study have confirmed that the ACF@MOF composites may be considered a potential candidate for the COVID-19 treatment, which makes them good candidates for clinical trials.

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Section: Resultsmentioning

confidence: 99%

Zirconium-Based Metal–Organic Frameworks as Acriflavine Cargos in the Battle against Coronaviruses─A Theoretical and Experimental Approach

Jodłowski

Dymek

Kurowski

et al. 2022

ACS Appl. Mater. Interfaces

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“…A drug repurposing screening by Napolitano et al identified acriflavine ( 23 ) as a potent inhibitor of SARS-CoV-2 PL pro with in vivo antiviral efficacy. 82 Acriflavine ( 23 ) is a mixture of trypaflavine ( 24 ) and proflavine ( 25 ). 82 Acriflavine ( 23 ) inhibited PL pro with IC 50 values of 1.66 and 1.46 μM when RLRGG-AMC and ISG15-AMC were used as substrates, respectively ( Table 1 ).…”

Section: Sars-cov-2 Pl Pro Inhibitorsmentioning

confidence: 99%

“… 82 Acriflavine ( 23 ) is a mixture of trypaflavine ( 24 ) and proflavine ( 25 ). 82 Acriflavine ( 23 ) inhibited PL pro with IC 50 values of 1.66 and 1.46 μM when RLRGG-AMC and ISG15-AMC were used as substrates, respectively ( Table 1 ). Acriflavine ( 23 ) also inhibited the deubiquitylating activity of PL pro in gel-based assay, thus ruling out the potential fluorescence interference effect of acriflavine ( 23 ).…”

Section: Sars-cov-2 Pl Pro Inhibitorsmentioning

confidence: 99%

Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

Tan

Jadhav

et al. 2022

J. Med. Chem.

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SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral polymerase inhibitors remdesivir and molnupiravir and the viral main protease inhibitor nirmatrelvir/ritonavir have been approved by the U.S. FDA. However, the emergence of variants of concern/interest calls for additional antivirals with novel mechanisms of action. The SARS-CoV-2 papain-like protease (PL pro ) mediates the cleavage of viral polyprotein and modulates the host’s innate immune response upon viral infection, rendering it a promising antiviral drug target. This Perspective highlights major achievements in structure-based design and high-throughput screening of SARS-CoV-2 PL pro inhibitors since the beginning of the pandemic. Encouraging progress includes the design of non-covalent PL pro inhibitors with favorable pharmacokinetic properties and the first-in-class covalent PL pro inhibitors. In addition, we offer our opinion on the knowledge gaps that need to be filled to advance PL pro inhibitors to the clinic.

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“…Acriflavine (ACF), published as a low µM (IC 50 ) PLpro inhibitor, was another drug identified with potential for repurposing. ACF showed promising antiviral activity in a number of different cell lines though it was unable to rival Remdesivir in blocking viral replication in the lungs of K18-ACE2 mice ( Napolitano et al, 2022 ). The published structure of PLpro in complex with a component of ACF, Proflavine (PDB 7NT4), indicates Proflavine is the active component inhibiting PLpro.…”

Section: Critical Assessment Of Examples Of Drug Repurposing “Hits”mentioning

confidence: 99%

Inhibitors of SARS-CoV-2 PLpro

2022

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The emergence of SARS-CoV-2 causing the COVID-19 pandemic, has highlighted how a combination of urgency, collaboration and building on existing research can enable rapid vaccine development to fight disease outbreaks. However, even countries with high vaccination rates still see surges in case numbers and high numbers of hospitalized patients. The development of antiviral treatments hence remains a top priority in preventing hospitalization and death of COVID-19 patients, and eventually bringing an end to the SARS-CoV-2 pandemic. The SARS-CoV-2 proteome contains several essential enzymatic activities embedded within its non-structural proteins (nsps). We here focus on nsp3, that harbours an essential papain-like protease (PLpro) domain responsible for cleaving the viral polyprotein as part of viral processing. Moreover, nsp3/PLpro also cleaves ubiquitin and ISG15 modifications within the host cell, derailing innate immune responses. Small molecule inhibition of the PLpro protease domain significantly reduces viral loads in SARS-CoV-2 infection models, suggesting that PLpro is an excellent drug target for next generation antivirals. In this review we discuss the conserved structure and function of PLpro and the ongoing efforts to design small molecule PLpro inhibitors that exploit this knowledge. We first discuss the many drug repurposing attempts, concluding that it is unlikely that PLpro-targeting drugs already exist. We next discuss the wealth of structural information on SARS-CoV-2 PLpro inhibition, for which there are now ∼30 distinct crystal structures with small molecule inhibitors bound in a surprising number of distinct crystallographic settings. We focus on optimisation of an existing compound class, based on SARS-CoV PLpro inhibitor GRL-0617, and recapitulate how new GRL-0617 derivatives exploit different features of PLpro, to overcome some compound liabilities.

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Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses

Cited by 44 publications

References 61 publications

Zirconium-Based Metal–Organic Frameworks as Acriflavine Cargos in the Battle against Coronaviruses─A Theoretical and Experimental Approach

Zirconium-Based Metal–Organic Frameworks as Acriflavine Cargos in the Battle against Coronaviruses─A Theoretical and Experimental Approach

Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

Inhibitors of SARS-CoV-2 PLpro

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