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

Napolitano,; 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; Höelscher, Michael; Jedrysik, Malwina; Matsuda, Alex; Owczarek, Katarzyna; Pachota, Magdalena; Plettenburg, Oliver; Potempa, Jan; Rothenaigner, Ina; Schlauderer, Florian; Szczepański, Artur; Kg, Mohn; Blomberg, Björn; Sattler, Michael; Hadian, Kamyar; Gm, Popowicz; Pyrć, Krzysztof

doi:10.1101/2021.03.20.436259

Cited by 4 publications

(4 citation statements)

References 42 publications

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“…We focused mainly on the drugs that went successfully through the MedChemExpress HY-138687). We have also included acriflavine 7 (SigmaAldrich; A8126), which we previously shown to be a potent ex vivo and in vivo inhibitor of betacoronaviruses blocking the PL pro protease. Further, remdesivir 8 sold by Gilead Sciences as Veklury by was included in the panel (polymerase inhibitor; GS-441524; Cayman Chemical, USA) and AT-527 developed by Atea Pharmaceuticals 9 (polymerase inhibitor; bemnifosbuvir hemisulfate; MedChemExpress HY-137958).…”

Section: Textmentioning

confidence: 99%

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Efficacy of antiviral drugs against the omicron variant of SARS-CoV-2

Dąbrowska

Szczepański

Botwina

et al. 2021

Preprint

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The Omicron variant of the SARS-CoV-2 virus was first detected in South Africa in November 2021. The analysis of the sequence data in the context of earlier variants suggested that it may show very different characteristics, including immune evasion and increased transmission. These assumptions were partially confirmed, and the reduction in protection in convalescent patients and vaccinated individuals have been confirmed. Here, we have evaluated the efficacy of antivirals against SARS-CoV-2 variants, Omicron, Delta, and the early 2020 isolate.

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Section: Textmentioning

confidence: 99%

“…The infection was carried out for 72 h, and the cytopathic effect (CPE) was assessed. Culture supernatants were collected for analysis, which was carried out as previously described 7 . The experiment was performed in three biological repetitions, each in duplicate (n=6).…”

Section: Textmentioning

confidence: 99%

Efficacy of antiviral drugs against the omicron variant of SARS-CoV-2

Dąbrowska

Szczepański

Botwina

et al. 2021

Preprint

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“…CPI-169 was tested at 0.5 mM in 6% DMSO-d 6 ; GRL-0617 at 0.3 mM in 6% DMSO-d 6 . The assignment of 1 H and 13 C chemical shifts for CPI-169 and GRL-0617 was performed using 2D experiments, including 1 H-1 H TOCSY with mixing time of 0.02 s, 1 H-13 C HSQC, and 1 H-1 H tr-NOESY experiments. 1D 1 H STD experiments [27] were performed with different concentrations while the protein:compound ratio remained 1:100.…”

Section: Nmrmentioning

confidence: 99%

“…It has been shown to bind close to the catalytic site but not to occupy it [12]. The compound acriflavine was reported to be a potent nanomolar inhibitor of SARS-CoV-2 PLpro in enzymatic, cell based and in-vivo studies [13]. Using NMR and crystal structure of PLpro it was shown that two proflavine molecules occupy the substrate binding pocket.…”

Section: Introductionmentioning

confidence: 99%

Resolving the pharmacological redox-sensitivity of SARS-CoV-2 PLpro in drug repurposing screening enabled identification of the competitive GRL-0617 binding site inhibitor CPI-169

Kuzikov,

Morasso,

Reinshagen

et al. 2023

Preprint

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The SARS CoV-2 Papain-Like protease has multiple roles in the viral replication cycle, related to both its polypeptide cleavage function and its capacity to antagonize host immune response. Targeting PLpro function is recognized as a promising mechanism to modulate viral replication whilst supporting host immune responses. However, development of PLpro specific inhibitors remains challenging. Upcoming studies revealed the limitation of reported inhibitors by profiling them through a pipeline of enzymatic, binding and cellular activity assays showing unspecific activity. GRL-0617 remained the only validated molecule with demonstrated anti-viral activity in cells. In this study we refer to the pitfalls of redox-sensitivity of PLpro. Using a screening-based approach to identify inhibitors of PLpro proteolytic activity, we made extensive efforts to validate the active compounds over a range of conditions and readouts, emphasising the need for comprehensive orthogonal data when profiling putative PLpro inhibitors. The remaining active compound CPI-169, showed to compete with GRL-0617 in NMR-based experiments, suggesting to share a similar binding mode, opening novel design opportunities for further developments as antiviral agents.

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Thermodynamics and Kinetic Investigation of Reaction of Acriflavine with L-cysteine in Aqueous Medium

Nkole

Idris

2021

Chemistry Africa

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Graphic abstract The kinetic investigation of reaction of 3,6-diamino-10-methylacridin-10-ium chloride (acriflavine) with l-cysteine in aqueous acidic medium at maximum absorption = 460 nm, ionic strength (I) = 0.1 mol dm −3 and temperature (T) = 307 K has been carried out spectrophotometrically. Using a pseudo first order approach, the rate of the redox reaction resulted to first order with respect to the [acriflavine, (AF)] and [l-cysteine, (CSH)] and second order total. Stoichiometric determination confirms that a mole of the acriflavine is consumed by a mole of l-cysteine at a time for the attainment of product formation. The reaction followed a one-way acid independence path. The adjustment in ionic strength (NaCl) and solvent polarity (water/acetone mixture) of the reaction system showed no reasonable effect and there was a fairly decrease in the reaction rate, respectively. The reaction rate is also characterised by neither catalysis nor inhibition of added ions. The negative magnitude of entropy of activation, S ‡ , (− 151.39 ± 031 J mol −1 K −1 ) and positive value of enthalpy of activation, H ‡ , (+ 31.378 ± 030 kJ mol −1 ) suggest that the reaction proceeds via an associative pathway and reasonable energy are needed to lower the activation energy for a tangible products formation. Two acridine unit products polymerised afterward forming a dimer as a result of an intramolecular coupling. A determinable intermediate has been observed through a spectroscopic test and confirmed by Michaelis–Menten’s plot. Based on Taube’s inorganic electron transfer reaction, an inner-sphere mechanistic pathway is implicated with a stable intermediate complex formation as shown below;

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

Cited by 4 publications

References 42 publications

Efficacy of antiviral drugs against the omicron variant of SARS-CoV-2

Efficacy of antiviral drugs against the omicron variant of SARS-CoV-2

Resolving the pharmacological redox-sensitivity of SARS-CoV-2 PLpro in drug repurposing screening enabled identification of the competitive GRL-0617 binding site inhibitor CPI-169

Thermodynamics and Kinetic Investigation of Reaction of Acriflavine with L-cysteine in Aqueous Medium

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