Green tea polyphenols in drug discovery: a success or failure?

Smith, Thomas J.

doi:10.1517/17460441.2011.570750

Cited by 38 publications

(23 citation statements)

References 38 publications

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“…We are now exploring these possible mechanisms. EGCG, like other green tea polyphenols, is relatively unstable, poorly absorbed, and undergoes metabolic alterations (69). The serum concentration obtained after oral ingestion of pure EGCG (2 mg/kg in 100 ml of water, which is approximately the equivalent of two cups of green tea) was 0.17 M (70), below the antiviral EC 50 .…”

Section: Discussionmentioning

confidence: 96%

A Small Molecule Inhibits Virion Attachment to Heparan Sulfate- or Sialic Acid-Containing Glycans

Colpitts

Schang

2014

J Virol

127

111

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Primary attachment to cellular glycans is a critical entry step for most human viruses. Some viruses, such as herpes simplex virus type 1 (HSV-1) and hepatitis C virus (HCV), bind to heparan sulfate, whereas others, such as influenza A virus (IAV), bind to sialic acid. Receptor mimetics that interfere with these interactions are active against viruses that bind to either heparan sulfate or to sialic acid. However, no molecule that inhibits the attachment of viruses in both groups has yet been identified. Epigallocatechin gallate (EGCG), a green tea catechin, is active against many unrelated viruses, including several that bind to heparan sulfate or to sialic acid. We sought to identify the basis for the broad-spectrum activity of EGCG. Here, we show that EGCG inhibits the infectivity of a diverse group of enveloped and nonenveloped human viruses. IMPORTANCEThis study shows that it is possible to develop a small molecule antiviral or microbicide active against the two largest groups of human viruses: those that bind to glycosaminoglycans and those that bind to sialoglycans. This group includes the vast majority of human viruses, including herpes simplex viruses, cytomegalovirus, influenza virus, poxvirus, hepatitis C virus, HIV, and many others.

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Section: Discussionmentioning

confidence: 96%

A Small Molecule Inhibits Virion Attachment to Heparan Sulfate- or Sialic Acid-Containing Glycans

Colpitts

Schang

2014

J Virol

127

111

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“…Although EGCG is a natural product with extremely low toxicity issues, it has several problems if it is to be used as a therapeutic agent (49). It is poorly absorbed in the intestinal tract, it is rapidly modified by enzymes such as catechol-O-methyltransferease, and its anti-oxidant activity makes it relatively unstable in solution.…”

Section: Discussionmentioning

confidence: 99%

Green Tea Polyphenols Control Dysregulated Glutamate Dehydrogenase in Transgenic Mice by Hijacking the ADP Activation Site

Chen

et al. 2011

Journal of Biological Chemistry

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Glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of L-glutamate and, in animals, is extensively regulated by a number of metabolites. Gain of function mutations in GDH that abrogate GTP inhibition cause the hyperinsulinism/hyperammonemia syndrome (HHS), resulting in increased pancreatic ␤-cell responsiveness to leucine and susceptibility to hypoglycemia following high protein meals. We have previously shown that two of the polyphenols from green tea (epigallocatechin gallate (EGCG) and epicatechin gallate (ECG)) inhibit GDH in vitro and that EGCG blocks GDH-mediated insulin secretion in wild type rat islets. Using structural and site-directed mutagenesis studies, we demonstrate that ECG binds to the same site as the allosteric regulator, ADP. Perifusion assays using pancreatic islets from transgenic mice expressing a human HHS form of GDH demonstrate that the hyperresponse to glutamine caused by dysregulated GDH is blocked by the addition of EGCG. As observed in HHS patients, these transgenic mice are hypersensitive to amino acid feeding, and this is abrogated by oral administration of EGCG prior to challenge. Finally, the low basal blood glucose level in the HHS mouse model is improved upon chronic administration of EGCG. These results suggest that this common natural product or some derivative thereof may prove useful in controlling this genetic disorder. Of broader clinical implication is that other groups have shown that restriction of glutamine catabolism via these GDH inhibitors can be useful in treating various tumors. This HHS transgenic mouse model offers a highly useful means to test these agents in vivo.

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“…Further, another study [19] has also mentioned that OSU-03012 treatment reduced GRP78 expression in GBM cells and that there is likelihood that OSU-03012 destabilizes GRP78 by binding to it. Like EGCG [20], OSU-03012 readily crosses the blood-brain barrier [19].…”

Section: Inhibitors Against Grp78mentioning

confidence: 99%

Molecular docking and molecular dynamics studies reveal structural basis of inhibition and selectivity of inhibitors EGCG and OSU-03012 toward glucose regulated protein-78 (GRP78) overexpressed in glioblastoma

2015

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Glioblastoma (GBM), a malignant form of brain tumor, has a high mortality rate. GRP78, one of the HSP70 protein family members, is overexpressed in GBM. GRP78 is the key chaperone protein involved in the unfolded protein response. Upregulated GRP78 expression in cancer cells inhibits apoptosis and promotes chemoresistance. GRP78 has an ATPase domain, a substrate-binding domain, and a linker region. ATP-competitive inhibitors such as EGCG and OSU-03012 inhibit GRP78 activity and reduce its expression in GBM. However, there is a lack of structural data on the binding modes of these inhibitors to GRP78 ATPase domain. Further, the mode of selectivity of these inhibitors toward GRP78 also is unknown. Toward this end, molecular docking was performed with AutoDock Vina and confirmation obtained by docking using ROSIE. The stability and MM-PBSA binding energy of GRP78-inhibitor complexes as well as energetic contribution of individual residues was analyzed by 50 ns molecular dynamics run with GROMACS. MSA by ClustalW2 identified unique amino acid residues in the ATPase domain of GRP78 which were different from the residues present in other HSP70 proteins. Important and unique amino acid residues of GRP78 such as Ile61, Glu293, Arg297, and Arg367 played a major role in the intermolecular interactions with these inhibitors. The interactions with unique residues of GRP78 as compared with those of HSP70-1A provided the basis for selectivity. It was found that the binding affinity and specificity/selectivity of EGCG toward GRP78 was higher than that toward HSP70-1A, and selectivity was even better than OSU-03012. OSU-03012 was predicted to bind to GRP78. Analyses from MD runs showed tight binding and stability of complexes, and the highest number of hydrogen bonds during the trajectory runs were comparable to those found in the docking studies. Energetic contribution of individual inhibitor-interacting residues showed that energy values of Ile61 and Glu293 were among the most negative. These studies are, to the best of our knowledge, the first studies characterizing EGCG and OSU-03012 interactions with GRP78 on a structural basis and provide a significant insight into their binding modes, selectivity, and structural stability.

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Green tea polyphenols in drug discovery: a success or failure?

Cited by 38 publications

References 38 publications

A Small Molecule Inhibits Virion Attachment to Heparan Sulfate- or Sialic Acid-Containing Glycans

A Small Molecule Inhibits Virion Attachment to Heparan Sulfate- or Sialic Acid-Containing Glycans

Green Tea Polyphenols Control Dysregulated Glutamate Dehydrogenase in Transgenic Mice by Hijacking the ADP Activation Site

Molecular docking and molecular dynamics studies reveal structural basis of inhibition and selectivity of inhibitors EGCG and OSU-03012 toward glucose regulated protein-78 (GRP78) overexpressed in glioblastoma

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