Inhibition of cysteine proteases by a natural biflavone: behavioral evaluation of fukugetin as papain and cruzain inhibitor

Assis, Diego M.; Gontijo, Vanessa Silva; Pereira, Ivan de Oliveira; Santos, Jorge A.N.; Camps, Ihosvany; Nagem, Tânus Jorge; Ellena, Javier; Izidoro, Mario Augusto; Tersariol, Ivarne L.S.; Barros, Nilana M.T.; Santos, Marcelo Henrique dos; Juliano, María A.

doi:10.3109/14756366.2012.668539

Cited by 27 publications

(19 citation statements)

References 39 publications

(38 reference statements)

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“…Papain and trypsin were selected because they are commercially available in large quantities, and their structures are known. The hydrophobic interactions and hydrogen bonds for compound 3 in papain, trypsin and cruzain were related previously (Martins et al, 2007(Martins et al, , 2009Assis et al, 2012;Sasaki et al, 1986Sasaki et al, , 1990.…”

Section: Resultsmentioning

confidence: 75%

“…On the other hand, the cysteine protease irreversible inhibitor E64 is 4614-fold and 78970-fold more effective in the inhibition of papain and cruzain, respectively. All three tested enzymes are known as trypsin-like hydrolases due to S 1 specificity for both Arg and Lys basic residues, cleaving the C-N bond of substrate Z-FR-MCA between the Arg amino acid and MCA group (Assis et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

“…The amino acid sequences of papain and cruzain are 38% homologous, and their active sites are nearly identical (Assis et al, 2012;Melo et al, 2001;PDB ID, 1996). Papain and trypsin were selected because they are commercially available in large quantities, and their structures are known.…”

Section: Resultsmentioning

confidence: 99%

“…In the docking studies, the 1.8 Å resolution structure files for trypsin, papain and cruzain were downloaded from the Brookhaven Protein Data Bank (PDB code 2RA3, 1PE6 and 1F2C, respectively) (Assis et al, 2012). This structure was prepared using the Protein Preparation Wizard protocol implemented in the Schrödinger Suite (2009a).…”

Section: Computational Dockingmentioning

confidence: 99%

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Morelloflavone and its semisynthetic derivatives as potential novel inhibitors of cysteine and serine proteases

Gontijo¹,

Januário²,

Júdice³

et al. 2015

J. Med. Plants Res.

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This article reports the three biflavonoids isolated from the fruit pericarp of Garcinia brasiliensis Mart. (Clusiaceae): Morelloflavone-4```-glycoside (compound 1), (±)-Fukugiside (compound 2), and Morelloflavone (compound 3). Structural modifications by acylation and alkylation reactions were performed on the natural biflavonoid (±) morelloflavone to obtain three semisynthetic compounds: Morelloflavone-7,4`,7``,3```,4```-penta-O-acetyl (compound 4), Morelloflavone-7,4`,7``,3```,4```-penta-Omethyl (compound 5), and Morelloflavone-7,4`,7``,3```,4```-penta-O-butanoyl (compound 6). The inhibitory effects of these naturally isolated biflavonoid-type compounds and three semisynthetic derivatives on the activity of the cysteine proteases papain and cruzain, and on the serine protease trypsin were investigated. The potential inhibitory IC 50 of natural bioflavonoids compounds 1, 2, and 3 were 11.0 ± 3.0, 23.0 ± 4.0, and 10.5 ± 0.3 µM, respectively, for papain; 0.86 ± 0.12, 106 ± 7, and 3.8 ± 0.1, 50 ± 2, 119.5 ± 5, and 9.6 ± 1.0 µM, respectively, for cruzain. On the other hand, the semisynthetic biflavonoids compounds 4, 5, and 6 were more efficient in the inhibition of enzyme activity with IC 50 values 0.60 ± 0.02 µM (papain) for biflavonoids compound 4, 1.64 ± 0.11 µM (trypsin) for biflavonoids compound 5, and 8.1 ± 0.6 µM (cruzain) for biflavonoids compound 6. Compound 4 is more active owing to the carbonyl group in the structure; perhaps, this modification could favor a higher nucleophilic attack by serine and cysteine proteases. However, the semisynthetic compound 5 (IC 50 = 15.4 ± 0.7 µM for papain), which has no carbonyl group in structure, was less active in the inhibition. Interestingly, structure-activity relationships (SARs) were confirmed by flexible docking simulations. Likewise, the potential usefulness of natural compound 1 as an antioxidant compound was strengthened by our results concerning the antiproteolytic activity.

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Section: Resultsmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Computational Dockingmentioning

confidence: 99%

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Morelloflavone and its semisynthetic derivatives as potential novel inhibitors of cysteine and serine proteases

Gontijo¹,

Januário²,

Júdice³

et al. 2015

J. Med. Plants Res.

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“…From the database searches, 830 (“malaria and flavonoids”: 540; “Chagas disease and flavonoids”: 60; “leishmaniasis and flavonoids”: 124; “dengue and flavonoids”: 106) potentially relevant records were identified, from which 737 were excluded after screening the titles or abstracts. The full reports of 93 articles were acquired: 83 studies related to natural flavonoids (Adinehbeigi, Razi Jalali, Shahriari, & Bahrami, ; Allard et al, ; Anusuya & Gromiha, ; Anusuya & Gromiha, ; Assis et al, ; Azebaze et al, ; Beer et al, ; Cabanillas et al, ; Castro, Barrios, Chinchilla, & Guerrero, ; Cheema et al, ; Cornelio et al, ; Coulerie et al, ; Cunha‐Rodrigues et al, ; Da Rocha et al, ; Da Silva, Maquiaveli, & Magalhães, ; De Monbrison et al, ; De Sousa et al, ; De Sousa et al, ; Dos Reis, Manjolin, Maquiaveli, Santos‐Filho, & da Silva, ; Ezenyi et al, ; Fonseca‐Silva, Inacio, Canto‐Cavalheiro, & Almeida‐Amaral, ; Fonseca‐Silva, Inacio, Canto‐Cavalheiro, Menna‐Barreto, & Almeida‐Amaral, ; Frabasile et al, ; Freitas et al, ; Ganesh et al, ; Gontijo et al, ; Grael, Albuquerque, & Lopes, ; Grecco et al, ; Güida et al, ; Heh et al, ; Houël et al, ; Ichino et al, ; Ijaz, Ahmad, Ahmad, ul Haq, & Wang, ; Inacio, Gervazoni, Canto‐Cavalheiro, & Almeida‐Amaral, ; Ismail & Jusoh, ; Jasmeen et al, ; Jin et al, ; Kapingu et al, ; Kiat et al, ; Kimmel et al, ; Konziase, ; Kraft et al, ; Kraft et al, ; Lage et al, ; Lage et al, ; Lehane & Saliba, ; Leite et al, ; Lu et al, ; Manjolin, dos Reis, Maquiaveli, Santos‐Filho, & da Silva, ; Marín et al, ; Marín et al, ; Mittra et al, ; Moghaddam et al, ; Montenegro, Gonzalez, Ortega‐Barria, & Luis Cubi...…”

Section: Methodsmentioning

confidence: 99%

Flavonoids as efficient scaffolds: Recent trends for malaria, leishmaniasis, Chagas disease, and dengue

Boniface

Ferreira

2019

Phytotherapy Research

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Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually with over 500,000 deaths. Among the NTDs, some of the most severe consist of leishmaniasis, Chagas disease, and dengue. The impact of the combined NTDs closely rivals that of malaria. According to the World Health Organization, 216 million cases of malaria were reported in 2016 with 445,000 deaths. Current treatment options are associated with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Flavonoids are a class of compounds that has been the subject of considerable scientific interest. New developments of flavonoids have made promising advances for the potential treatment of malaria, leishmaniasis, Chagas disease, and dengue, with less toxicity, high efficacy, and improved bioavailability. This review summarizes the current standings of the use of flavonoids to treat malaria and neglected diseases such as leishmaniasis, Chagas disease, and dengue. Natural and synthetic flavonoids are leading compounds that can be used for developing antiprotozoal and antiviral agents. However, detailed studies on toxicity, pharmacokinetics, and mechanisms of action of these compounds are required to confirm the in vitro pharmacological claims of flavonoids for pharmaceutical applications. Highlights In the current review, we have tried to compile recent discoveries on natural and synthetic flavonoids as well as their implication in the treatment of malaria, leishmaniasis, Chagas disease, and dengue. A total of 373 (220 natural and 153 synthetic) flavonoids have been evaluated for antimalarial, antileishmanial, antichagasic, and antidengue activities. Most of these flavonoids showed promising results against the above diseases. Reports on molecular modeling of flavonoid compounds to the disease target indicated encouraging results. Flavonoids can be prospected as potential leads for drug development; however, more rigorously designed studies on toxicity and pharmacokinetics, as well as the quantitative structure–activity relationship studies of these compounds, need to be addressed.

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Proteolytic activity in soil: A review

Vranová

Rejšek

Formánek

2013

Applied Soil Ecology

133

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Inhibition of cysteine proteases by a natural biflavone: behavioral evaluation of fukugetin as papain and cruzain inhibitor

Cited by 27 publications

References 39 publications

Morelloflavone and its semisynthetic derivatives as potential novel inhibitors of cysteine and serine proteases

Morelloflavone and its semisynthetic derivatives as potential novel inhibitors of cysteine and serine proteases

Flavonoids as efficient scaffolds: Recent trends for malaria, leishmaniasis, Chagas disease, and dengue

Proteolytic activity in soil: A review

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