Discovery of diminazene as a dual inhibitor of SARS-CoV-2 human host proteases TMPRSS2 and furin using cell-based assays

Xu, Ya-Ming; Inácio, Marielle Cascaes; Liu, Manping X.; Gunatilaka, A. A. Leslie

doi:10.1016/j.crchbi.2022.100023

Cited by 8 publications

(6 citation statements)

References 63 publications

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“…The study used the consensus docking approach via the structure-based virtual screening of human furin protease to effectively identify seven potential novel anti-COVID-19 compounds consisting of quercitrin, teucrol, malvinidin-3-arabinoside, N-E-caffeoyl tyramine, ZINC000085967772, pinobanksin_3-(E)-caffeate, and abyssinone IV. This is in a bid to support ongoing efforts to identify effective therapeutics against the SARS-CoV-2 by targeting the furin protease [ 29 , 30 ]. Furin protease is a plausible COVID-19 target due to its cleavage site on the spike protein and its role in facilitating the entry of SARS-CoV-2 into host cells.…”

Section: Discussionmentioning

confidence: 99%

“…Diminazene, an antiparasitic drug was identified to be a potent furin inhibitor via structure-based virtual screening and in vitro enzyme-based assay with an IC 50 of 5.42 ± 0.11 μM [ 29 ]. Another study reported an IC 50 of 13.2 μM for diaminazene against the furin protease [ 30 ]. It has also been reported that furin inhibitors, decanoyl-RVKR-chloromethylketone (CMK), and naphthofluorescein showed antiviral activity against the SARS-CoV-2 virus in VeroE6 cells by blocking viral entry and suppressing viral RNA transcription [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Consensus docking and MM-PBSA computations identify putative furin protease inhibitors for developing potential therapeutics against COVID-19

et al. 2022

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The coronavirus disease 2019 (COVID-19) is a pandemic that has severely posed substantial health challenges and claimed millions of lives. Though vaccines have been produced to stem the spread of this disease, the death rate remains high since drugs used for treatment have therapeutic challenges. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the disease, has a slew of potential therapeutic targets. Among them is the furin protease, which has a cleavage site on the virus’s spike protein. The cleavage site facilitates the entry of the virus into human cells via cell–cell fusion. This critical involvement of furin in the disease pathogenicity has made it a viable therapeutic strategy against the virus. This study employs the consensus docking approach using HYBRID and AutoDock Vina to virtually screen a pre-filtered library of 3942 natural product compounds of African origin against the human furin protease (PDB: 4RYD). Twenty of these compounds were selected as hits after meeting molecular docking cut-off of − 7 kcal.mol −1 , pose alignment inspection, and having favorable furin-ligand interactions. An area under the curve (AUC) value of 0.72 was computed from the receiver operator characteristic (ROC) curve, and Boltzmann-enhanced discrimination of the ROC curve (BEDROC) value of 0.65 showed that AutoDock Vina was a reasonable tool for selecting actives for this target. Seven of these hits were proposed as potential leads having had bonding interactions with catalytic triad residues Ser368, His194, and Asp153, and other essential residues in the active site with plausible binding free energies between − 189 and − 95 kJ/mol from the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations as well as favorable ADME/Tox properties. The molecules were also predicted as antiviral, anti-inflammatory, membrane permeability inhibitors, RNA synthesis inhibitors, cytoprotective, and hepatoprotective with probable activity (Pa) above 0.5 and probable inactivity values below 0.1. Some of them also have anti-influenza activity. Influenza virus has many similarities with SARS-CoV-2 in their mode of entry into human cells as both are facilitated by the furin protease. Pinobanksin 3-(E)-caffeate, one of the potential leads is a propolis compound. Propolis compounds have shown inhibitory effects against ACE2, TMPRSS2, and PAK1 signaling pathways of SARS-CoV-2 in previous studies. Likewise, quercitrin is structurally similar to isoquercetin, which is currently in clinical trials as possible medication for COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s11224-022-02056-1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Consensus docking and MM-PBSA computations identify putative furin protease inhibitors for developing potential therapeutics against COVID-19

et al. 2022

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“…Furthermore, the IC50 value obtained (20.62 μM) is similar to those found in the literature evaluating the antiviral effect against SARS-CoV-2 of lopinavir with 26 μM [ 84 ]. Recently it was demonstrated that DIZE was able to inhibit proteases, furin and TMPRSS2, in cell cultures, with IC50 of 1.35 and 13.2 μM, respectively [ 85 ]. Still, when the concentrations of our compound are increased, its effect on inhibition becomes greater; thus, we suggest that DIZE may have promising effects on the interaction between spike-ACE2 and other proteases, reducing SARS-CoV-2 infection and may generate encouraging clinical effects.…”

Section: Discussionmentioning

confidence: 99%

Antiviral potential of diminazene aceturate against SARS-CoV-2 proteases using computational and in vitro approaches

Santos

Silva²,

Sousa

et al. 2022

Chemico-Biological Interactions

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“…The docking results show that DIZE exerts dual inhibitory effects by binding to the catalytic triplet of TMPRSS2 (S441−H296− D345) and the catalytic binding site of Furin (N192, L227, S253, D258, D306, T367, and S368). 87 However, the role of DIZE as an ACE2 receptor activator in SARS-CoV-2 is controversial. Some studies posit that this activity of DIZE has a positive effect on the treatment of SARS-CoV-2, citing two main reasons: (i) DIZE can protect the heart by activating ACE2 receptors, alleviating various cardiovascular complications in the late stage of COVID-19 and reducing the mortality rate of patients.…”

Section: S/d4 Dual Inhibitorsmentioning

confidence: 99%

New Strategies for Responding to SARS-CoV-2: The Present and Future of Dual-Target Drugs

Zhang,

Xiao,

et al. 2024

J. Med. Chem.

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The 2019 coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of deaths, posing a serious threat to public health and safety. Rapid mutations of SARS-CoV-2 and complex interactions among multiple targets during infection pose a risk of expiry for small molecule inhibitors. This suggests that the traditional concept of "one bug, one drug" could be ineffective in dealing with the coronavirus. The dual-target drug strategy is expected to be the key to ending coronavirus infections. However, the lack of design method and improper combination of dual-targets poses obstacle to the discovery of new dual-target drugs. In this Perspective, we summarized the profiles concerning drug design methods, structure−activity relationships, and pharmacological parameters of dual-target drugs for the treatment of COVID-19. Importantly, we underscored how target combination and rational drug design illuminate the development of dualtarget drugs for SARS-CoV-2. ■ SIGNIFICANCE• This is the first Perspective on dual-target drugs for treating coronavirus. • Dual-target drugs, acting on multiple pathways, offer enhanced efficacy and can delay resistance compared to single-target treatments. • Drug repurposing for dual-target design can significantly shorten the timeline for clinical trials, addressing urgent medication needs during the early COVID-19 outbreak. • The introduction of covalent warheads can compensate for active site similarity issues, aiding in the development of high-affinity dual-target inhibitors.

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Discovery of diminazene as a dual inhibitor of SARS-CoV-2 human host proteases TMPRSS2 and furin using cell-based assays

Cited by 8 publications

References 63 publications

Consensus docking and MM-PBSA computations identify putative furin protease inhibitors for developing potential therapeutics against COVID-19

Consensus docking and MM-PBSA computations identify putative furin protease inhibitors for developing potential therapeutics against COVID-19

Antiviral potential of diminazene aceturate against SARS-CoV-2 proteases using computational and in vitro approaches

New Strategies for Responding to SARS-CoV-2: The Present and Future of Dual-Target Drugs

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