Recent advance on PTP1B inhibitors and their biomedical applications

Sharma, Bigyan; Xie, Liuxing; Yang, Fen; Wang, Wei; Zhou, Quanming; Xiang, Meng; Zhou, Shizhe; Lv, Wanting; Jia, Yan; Pokhrel, Laxman; Shen, Jun; Xiao, Qicai; Gao, Liqian; Deng, Wenbin

doi:10.1016/j.ejmech.2020.112376

Cited by 85 publications

(41 citation statements)

References 171 publications

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“…To investigate a possible interaction between compound 10 and PTP1B, a molecular docking was performed using Gold software [ 76 ]. As shown in Figure 10 , a docking result revealed that the carbonyl group of the pyran-2-one core could form hydrogen bonds with the –NH of Gly220 and –SH of Cys215, which is essential for catalysis [ 77 , 78 ], while the hydroxyl group could form a hydrogen bond with the c arbonyl oxygen atom of the Gln262 amide side chain, another important residue in the second catalytic step [ 79 ]. The hydrophobic side of the molecule also makes van der Waals contacts with the side chains of Tyr46, Val49, Ala217 and Ile219.…”

Section: Resultsmentioning

confidence: 99%

Untargeted Metabolomics Approach for the Discovery of Environment-Related Pyran-2-Ones Chemodiversity in a Marine-Sourced Penicillium restrictum

Bertrand

Pont

et al. 2021

Marine Drugs

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Very little is known about chemical interactions between fungi and their mollusc host within marine environments. Here, we investigated the metabolome of a Penicillium restrictum MMS417 strain isolated from the blue mussel Mytilus edulis collected on the Loire estuary, France. Following the OSMAC approach with the use of 14 culture media, the effect of salinity and of a mussel-derived medium on the metabolic expression were analysed using HPLC-UV/DAD-HRMS/MS. An untargeted metabolomics study was performed using principal component analysis (PCA), orthogonal projection to latent structure discriminant analysis (O-PLSDA) and molecular networking (MN). It highlighted some compounds belonging to sterols, macrolides and pyran-2-ones, which were specifically induced in marine conditions. In particular, a high chemical diversity of pyran-2-ones was found to be related to the presence of mussel extract in the culture medium. Mass spectrometry (MS)- and UV-guided purification resulted in the isolation of five new natural fungal pyran-2-one derivatives—5,6-dihydro-6S-hydroxymethyl-4-methoxy-2H-pyran-2-one (1), (6S, 1’R, 2’S)-LL-P880β (3), 5,6-dihydro-4-methoxy-6S-(1’S, 2’S-dihydroxy pent-3’(E)-enyl)-2H-pyran-2-one (4), 4-methoxy-6-(1’R, 2’S-dihydroxy pent-3’(E)-enyl)-2H-pyran-2-one (6) and 4-methoxy-2H-pyran-2-one (7)—together with the known (6S, 1’S, 2’S)-LL-P880β (2), (1’R, 2’S)-LL-P880γ (5), 5,6-dihydro-4-methoxy-2H-pyran-2-one (8), (6S, 1’S, 2’R)-LL-P880β (9), (6S, 1’S)-pestalotin (10), 1’R-dehydropestalotin (11) and 6-pentyl-4-methoxy-2H-pyran-2-one (12) from the mussel-derived culture medium extract. The structures of 1-12 were determined by 1D- and 2D-MMR experiments as well as high-resolution tandem MS, ECD and DP4 calculations. Some of these compounds were evaluated for their cytotoxic, antibacterial, antileishmanial and in-silico PTP1B inhibitory activities. These results illustrate the utility in using host-derived media for the discovery of new natural products.

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Section: Resultsmentioning

confidence: 99%

Untargeted Metabolomics Approach for the Discovery of Environment-Related Pyran-2-Ones Chemodiversity in a Marine-Sourced Penicillium restrictum

Bertrand

Pont

et al. 2021

Marine Drugs

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“…There are several critical amino acid residues (Arg221, Ala217, Asp 48, Asp181, Gly183, Gly220, Lys116, Phe182 and Tyr46) of PTP1B were found to directly interact with potential inhibitors isolated from natural products (Jung et al, 2017;Sharma et al, 2020;Hu et al, 2021). Notably, Arg221 exerts an important function in optimizing salt bridge interactions with the phosphate bound to the catalytic site and stabilizing the phosphoryl-enzyme intermediator (Niu et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Ferulic Acid Ameliorates Hepatic Inflammation and Fibrotic Liver Injury by Inhibiting PTP1B Activity and Subsequent Promoting AMPK Phosphorylation

Xue

Fan

et al. 2021

Front. Pharmacol.

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Chronic inflammation in response to persistent exogenous stimuli or damage results in liver fibrosis, which subsequently progresses into malignant liver diseases with high morbidity and mortality. Ferulic acid (FA) is a phenolic acid widely isolated from abundant plants and exhibits multiple biological activities including anti-oxidant, anti-inflammation and enhancement of immune responses. Adenosine monophosphate-activated protein kinase (AMPK) functions as a critical energy sensor and is regulated through the phosphorylation of liver kinases like LKB1 or dephosphorylation by protein tyrosine phosphatases (PTPs). However, the role of FA in carbon tetrachloride (CCl4)-induced chronic inflammation and liver fibrosis and AMPK activation has not been elucidated. Here we reported that FA ameliorated CCl4-induced inflammation and fibrotic liver damage in mice as indicated by reduced levels of serum liver function enzyme activities and decreased expression of genes and proteins associated with fibrogenesis. Additionally, FA inhibited hepatic oxidative stress, macrophage activation and HSC activation via AMPK phosphorylation in different liver cells. Mechanically, without the participation of LKB1, FA-induced anti-inflammatory and anti-fibrotic effects were abrogated by a specific AMPK inhibitor, compound C. Combining with the results of molecular docking, surface plasmon resonance and co-immunoprecipitation assays, we further demonstrated that FA directly bound to and inhibited PTP1B, an enzyme responsible for dephosphorylating key protein kinases, and eventually leading to the phosphorylation of AMPK. In summary, our results indicated that FA alleviated oxidative stress, hepatic inflammation and fibrotic response in livers through PTP1B-AMPK signaling pathways. Taken together, we provide novel insights into the potential of FA as a natural product-derived therapeutic agent for the treatment of fibrotic liver injury.

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“…It is a non-conserved amino acid in PTP families. 4 Both PXA and PXB interact with R24. Both compounds form hydrogen bonds with Y46 and D48, which are key amino acids in the PTP1B pTyr loop.…”

Section: Resultsmentioning

confidence: 99%

“… 3 PTP1B negatively regulates insulin and leptin signaling, which is involved in diabetes and obesity. 4 SHP1 is a widely expressed inhibitory PTP and was reported as the next checkpoint target for cancer immunotherapy. 5 Shp2 is overexpressed or hyperactivated in many human cancers and serves as a therapeutic target against human cancer.…”

Section: Introductionmentioning

confidence: 99%

Identification of Phomoxanthone A and B as Protein Tyrosine Phosphatase Inhibitors

Gao

Zhao

et al. 2020

ACS Omega

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Phomoxanthone A and B (PXA and PXB) are xanthone dimers and isolated from the endophytic fungus Phomopsis sp. By254. The results demonstrated that PXB and PXA are noncompetitive inhibitors of SHP2 and PTP1B and competitive inhibitors of SHP1. Molecular docking studies showed that PXB and PXA interact with conserved domains of protein tyrosine phosphatases such as the β5-β6 loop, WPD loop, P loop, and Q loop. PXA and PXB could significantly inhibit the cell proliferation in MCF7 cells. Our results indicated that these two compounds do not efficiently inhibit PTP1B and SHP2 activity. RNA sequencing showed that PXA and PXB may inhibit SHP1 activity in MCF7 cells leading to the upregulation of inflammatory factors. In addition to PTP inhibition, PXA and PXB are multitarget compounds to inhibit the proliferation of tumor cells. In conclusion, both compounds show inhibition of cancer cells and a certain degree of inflammatory stimulation, which make them promising for tumor immunotherapy.

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Recent advance on PTP1B inhibitors and their biomedical applications

Cited by 85 publications

References 171 publications

Untargeted Metabolomics Approach for the Discovery of Environment-Related Pyran-2-Ones Chemodiversity in a Marine-Sourced Penicillium restrictum

Untargeted Metabolomics Approach for the Discovery of Environment-Related Pyran-2-Ones Chemodiversity in a Marine-Sourced Penicillium restrictum

Ferulic Acid Ameliorates Hepatic Inflammation and Fibrotic Liver Injury by Inhibiting PTP1B Activity and Subsequent Promoting AMPK Phosphorylation

Identification of Phomoxanthone A and B as Protein Tyrosine Phosphatase Inhibitors

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