Evaluation of flavonols and derivatives as human cathepsin B inhibitor

Ramalho, Suelem D.; Sousa, Lorena Ramos Freitas de; Burger, Marcela C M; Lima, Matheus P.; Silva, Maria Fátima das Graças Fernandes da; Fernandes, João B.; Vieira, Paulo C.

doi:10.1080/14786419.2014.1002404

Cited by 18 publications

(13 citation statements)

References 10 publications

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“…Notably, the inhibition with the VSV system was similar to the inhibition found with wild-type Ebola virus (4-to 5-log reduction), suggesting that the VSV system recapitulates the effect of Q3G on wild-type virus and is a useful model for studying its effect on viral entry. The entry mechanisms used by Ebola virus include, for example, viral attachment; internalization into endosomes by macropinocytosis; processing of the glycoprotein by endosomal host cathepsins (14,26), which is accelerated by fusion with acidic lysosomes; and interaction of the glycoprotein with the endosomal transporter Niemann-Pick C1 (NPC1) (27,28). Although we did not test the effect of Q3G on NPC1, all of the other known processes of Ebola virus entry were not inhibited by Q3G.…”

Section: Discussionmentioning

confidence: 93%

“…The mechanisms behind flavonoid-derived effects on disease include the inhibition of numerous cellular pathways such as mitogen-activated protein kinase (MAPK) (9) and NF-B (10,11) as well as the inhibition of Src, phosphatidylinositol 3-kinase (PI3K), PDK1, and Akt (10). Cellular processes that are inhibited or modulated by flavonoids include oxidative stress (reviewed in reference 12), cathepsin activity (13,14), and autophagy induction (reviewed in reference 15).…”

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confidence: 99%

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Prophylactic Efficacy of Quercetin 3-β- O - d -Glucoside against Ebola Virus Infection

Qiu

Kroeker

et al. 2016

Antimicrob Agents Chemother

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Ebola outbreaks occur on a frequent basis, with the 2014-2015 outbreak in West Africa being the largest one ever recorded. This outbreak has resulted in over 11,000 deaths in four African countries and has received international attention and intervention. Although there are currently no approved therapies or vaccines, many promising candidates are undergoing clinical trials, and several have had success in promoting recovery from Ebola. However, these prophylactics and therapeutics have been designed and tested only against the same species of Ebola virus as the one causing the current outbreak. Future outbreaks involving other species would require reformulation and possibly redevelopment. Therefore, a broad-spectrum alternative is highly desirable. We have found that a flavonoid derivative called quercetin 3-␤-O-D-glucoside (Q3G) has the ability to protect mice from Ebola even when given as little as 30 min prior to infection. Furthermore, we have demonstrated that this compound targets the early steps of viral entry. Most promisingly, antiviral activity against two distinct species of Ebola virus was seen. This study serves as a proof of principle that Q3G has potential as a prophylactic against Ebola virus infection.

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Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

Prophylactic Efficacy of Quercetin 3-β- O - d -Glucoside against Ebola Virus Infection

Qiu

Kroeker

et al. 2016

Antimicrob Agents Chemother

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“…There are three additional groups of naturally occurring cathepsin B inhibitors: the aziridinyl peptides, peptide epoxysuccinyls, and peptide aldehydes [25,26] . Known synthetic cathepsin B inhibitors can be divided into groups of compounds, which contain either flavonoids, cyclic sulfates, or nitriles [27,28] . Cathepsins B and K are inhibited with reasonable potency by gold(I)-based compounds such as auranofin (Ridaura), which is clinically used as an anti-rheumatic agent, and its analogs [29] .…”

Section: Introductionmentioning

confidence: 99%

In silico design of novel gold-phosphate containing compounds as selective inhibitors of cathepsin B in neuroinflammation

Raevsky¹,

Sharifi²,

Pinchuk³

et al. 2018

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Aim: Alzheimer's disease is characterized by pathological protein aggregates and microglia-driven chronic neuroinflammation. Cathepsin B has been proposed as the potential target for inhibiting adverse activation of microglia and slowing down this neurodegenerative disease. Currently available inhibitors of cathepsin B enzymatic activity are non-selective; therefore, the design and synthesis of novel specific inhibitors could facilitate the development of a new class of anti-Alzheimer medications targeting the neuroinflammatory component of this disease. Methods: We describe molecular design strategies, which were used to create specific cathepsin B inhibitors based on the structure of the gold-containing drug auranofin (Ridaura), and its covalent binding to the cysteine residue of the active site of cathepsins. Results: This in silico study investigated the structure-activity relationship of a series of newly designed derivatives of auranofin with regard to their cathepsin B inhibitory activity. An exhaustive molecular screening model was designed and validated by using a set of known cathepsin B inhibitors. Its validity was further tested during the preliminary stage of the biological screening of newly designed inhibitors. Based on the structure-function relationships discovered by recording the empirical score values generated for the screening model, a series of subsequent in silico predictions of compound inhibitory activity were generated, which led to new structures with increased inhibitory activity and selectivity towards cathepsin B. Conclusion: The described molecular modeling strategy could be employed to design novel inhibitors of cathepsin B enzymatic activity, which could be used to slow down neuroinflammation in neurodegenerative disorders including Alzheimer's disease.

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“…Note that the positive modulation of CatB by E64d was less pronounced than the enhancing effect produced by PADK (increase of 76% vs. 549%; p<0.001). Other weak cysteine protease inhibitors were also found to up-regulate active CatB to varying degrees, including i ) SD1002, a non-peptidyl PADK analogue previously found to promote Aβ 42 clearance (Viswanathan et al, 2012), ii ) the polyphenol quercetin that, like PADK and E64d, exhibits very weak CatB inhibitory action (Ramalho et al, 2015), and iii ) Cathepsin Inhibitor 1 (CATI-1, also known as Z-Phe-Gly-NHO-Bz), a broad inhibitor of papain and several cathepsins (Table 2). The potent CatB inhibitors CA074, CA074me, and E64 did not exhibit positive modulation of CatB-30.…”

Section: Resultsmentioning

confidence: 99%

“…3. Other IC 50 values for inhibiting CatB and calpain were obtained from the following references: a Butler et al, 2011; b Jeon et al, 2016; c Huang et al, 1992; d Viswanathan et al, 2012; e Ramalho et al, 2015; f Je Ma et al, 2009; g Weiss et al, 2009 and Coers et al, 2004 J Biol Chem 279:36397-404 h Montagne et al, 2017; i Inubushi et al, 1994; j Trinchese et al, 2008. CATI-1, Cathepsin Inhibitor 1; n.d., not determined.…”

Section: Figurementioning

confidence: 99%

Potential Alzheimer’s Disease Therapeutics Among Weak Cysteine Protease Inhibitors Exhibit Mechanistic Differences Regarding Extent of Cathepsin B Up-Regulation and Ability to Block Calpain

Romine

Rentschler

Smith

et al. 2017

ESJ

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Cysteine protease inhibitors have long been part of drug discovery programs for Alzheimer’s disease (AD), traumatic brain injury (TBI), and other disorders. Select inhibitors reduce accumulating proteins and AD pathology in mouse models. One such compound, Z-Phe-Aladiazomethylketone (PADK), exhibits a very weak IC50 (9–11 μM) towards cathepsin B (CatB), but curiously PADK causes marked up-regulation of the Aβ-degrading CatB and improves spatial memory. Potential therapeutic and weak inhibitor E64d (14 μM IC50) also up-regulates CatB. PADK and E64d were compared regarding the blockage of calcium-induced cytoskeletal deterioration in brain samples, monitoring the 150-kDa spectrin breakdown product (SBDP) known to be produced by calpain. PADK had little to no effect on SBDP production at 10–100 μM. In contrast, E64d caused a dose-dependent decline in SBDP levels with an IC50 of 3–6 μM, closely matching its reported potency for inhibiting μ-calpain. Calpain also cleaves the cytoskeletal organizing protein gephyrin, producing 49-kDa (GnBDP49) and 18-kDa (GnBDP18) breakdown products. PADK had no apparent effect on calcium-induced gephyrin fragments whereas E64d blocked their production. E64d also protected the parent gephyrin in correspondence with reduced BDP levels. The findings of this study indicate that PADK’s positive and selective effects on CatB are consistent with human studies showing exercise elevates CatB and such elevation correlates with improved memory. On the other hand, E64d exhibits both marginal CatB enhancement and potent calpain inhibition. This dual effect may be beneficial for treating AD. Alternatively, the potent action on calpain-related pathology may explain E64d’s protection in AD and TBI models.

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Evaluation of flavonols and derivatives as human cathepsin B inhibitor

Cited by 18 publications

References 10 publications

Prophylactic Efficacy of Quercetin 3-β- O - d -Glucoside against Ebola Virus Infection

Prophylactic Efficacy of Quercetin 3-β- O - d -Glucoside against Ebola Virus Infection

In silico design of novel gold-phosphate containing compounds as selective inhibitors of cathepsin B in neuroinflammation

Potential Alzheimer’s Disease Therapeutics Among Weak Cysteine Protease Inhibitors Exhibit Mechanistic Differences Regarding Extent of Cathepsin B Up-Regulation and Ability to Block Calpain

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