Discovery of Manassantin A Protein Targets Using Large-Scale Protein Folding and Stability Measurements

Wallace, M. Ariel Geer; Kwon, Deok-Ho; Weitzel, Douglas H.; Lee, Chen-Ting; Stephenson, Tesia N.; Chi, Jen‐Tsan; Mook, Robert A.; Dewhirst, Mark W.; Hong, Jiyong; Fitzgerald, Michael C.

doi:10.1021/acs.jproteome.6b00237

Cited by 31 publications

(32 citation statements)

References 29 publications

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“…For example, The PP and SPROX techniques were both used to assay over 1,000 proteins in a MDA-MB-231 cell lysate grown under hypoxic conditions for interactions with manassantin A, a natural product which has been shown to have anti-cancer activity in cell-based assays but has a currently unknown mode-of-action. 67 This work identified a total of 28 protein hits with manassantin A-induced thermodynamic stability changes. Of particular note, was that two hits (filamin A and elongation factor 1-alpha) were identified with manassantin A-induced stability changes using both experimental approaches.…”

Section: New Application Areasmentioning

confidence: 99%

“… 1 Pseudomonas Aeruginosa cells from reference 112 . 2 Escherichia coli cells from reference 38 . 3 Mouse heart tissue from reference 110 . 4 Vero cells from reference 42. 5 U87-MG cells (human glioblastoma) from reference 44. 6 Yeast cells from reference 13. 7 Escherichia coli cells from reference 18. 8 MDA-MB-231 cells from reference 67 . 9 K562 cells from reference 51. …”

Section: Figurementioning

confidence: 99%

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Proteome-Wide Structural Biology: An Emerging Field for the Structural Analysis of Proteins on the Proteomic Scale

Kaur

Lui

et al. 2018

J. Proteome Res.

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Over the past decade, a suite of new mass-spectrometry-based proteomics methods has been developed that now enables the conformational properties of proteins and protein-ligand complexes to be studied in complex biological mixtures, from cell lysates to intact cells. Highlighted here are seven of the techniques in this new toolbox. These techniques include chemical cross-linking (XL-MS), hydroxyl radical footprinting (HRF), Drug Affinity Responsive Target Stability (DARTS), Limited Proteolysis (LiP), Pulse Proteolysis (PP), Stability of Proteins from Rates of Oxidation (SPROX), and Thermal Proteome Profiling (TPP). The above techniques all rely on conventional bottom-up proteomics strategies for peptide sequencing and protein identification. However, they have required the development of unconventional proteomic data analysis strategies. Discussed here are the current technical challenges associated with these different data analysis strategies as well as the relative analytical capabilities of the different techniques. The new biophysical capabilities that the above techniques bring to bear on proteomic research are also highlighted in the context of several different application areas in which these techniques have been used, including the study of protein ligand binding interactions (e.g., protein target discovery studies and protein interaction network analyses) and the characterization of biological states.

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Section: New Application Areasmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Proteome-Wide Structural Biology: An Emerging Field for the Structural Analysis of Proteins on the Proteomic Scale

Kaur

Lui

et al. 2018

J. Proteome Res.

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“…Analog 47 regulated HIF‐1α but not HIF‐1β, and reduced Cdk6, VEGF, and mRNA levels markedly . Mechanistically, the hit protein of manassantin A related to HIF‐1 activity is filamin A, but more work is needed to understand the exact mechanism …”

Section: Manassantin a And Analogsmentioning

confidence: 99%

“…50 Mechanistically, the hit protein of manassantin A related to HIF-1 activity is filamin A, but more work is needed to understand the exact mechanism. 51 Furthermore, more derivatives of manassantin A were reported with improved biological potency and simplified structural complexity. 52 53 The less complex analog 51 exhibited good HIF-1 inhibitory activity in different cancer cell lines with better potency than manassantin A.…”

Section: Manassantin a And Analogsmentioning

confidence: 99%

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

Bhattarai

Lee

2017

Medicinal Research Reviews

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Tumor hypoxia is a common feature in most solid tumors and is associated with overexpression of the hypoxia response pathway. Overexpression of the hypoxia-inducible factor (HIF-1) protein leads to angiogenesis, metastasis, apoptosis resistance, and many other pro-tumorigenic responses in cancer development. HIF-1 is a promising target in cancer drug development to increase the patient's response to chemotherapy and radiotherapy as well as the survival rate of cancer patients. Since up to 1% of genes are hypoxia-sensitive, a target-specific HIF-1 inhibitor may be a better clinical candidate in cancer drug discovery. Though no HIF-1 inhibitor is clinically available to date, a lot of effort has been applied during the last decade in search of potent HIF-1 inhibitors. In this review, we will summarize the structure-activity relationship of ten different chemotypes reported to be HIF-1 inhibitors in the last decade (2007-2016), their mechanisms of action for HIF-1 inhibition, progress in the way of target-specific inhibitors, and problems associated with current inhibitors. It is anticipated that the results of these research on the medicinal chemistry of HIF-1 inhibitors will provide decent information in the design and development of future inhibitors.

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“…Moreover, it remains unknown how these effectors contribute to the broad spectrum of medical benefits of manassantin seen in humans. Systematic screening via large-scale protein folding and stability measurements identified a number of hits that did not significantly overlap with those found from random cell-based analyses (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

The lignan manassantin is a potent and specific inhibitor of mitochondrial complex I and bioenergetic activity in mammals

Min

Oh³

et al. 2017

Journal of Biological Chemistry

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Dineolignans manassantin A and B from the plant are used in traditional medicine to manage a wide range of ailments such as edema, jaundice, and gonorrhea. Cell-based studies have identified several molecular target candidates of manassantin including NF-κB, MAPK, STAT3, and hypoxia-inducible factor 1α (HIF-1α). It is unclear whether or how these structurally diverse proteins or pathways mediate any of the medical benefits of manassantin Moreover, it has recently been reported that manassantin causes developmental arrest in zebrafish by inhibiting the mitochondrial complex I, but it is unknown whether manassantin inhibits mitochondrial respiration in intact mammalian cells and live animals. Here, we present direct evidence that manassantin potently and specifically inhibits the mitochondrial complex I and bioenergetic activity in mammalian systems. Manassantin had no effect on complex II- or complex IV-mediated respiration. Of note, it decreased NADH-ubiquinone reductase activity but not the activity of NADH-ferricyanide reductase. Treatment with manassantin reduced cellular ATP levels and concomitantly stimulated AMP-activated protein kinase and As an adaptive response to manassantin-induced bioenergetic deficiency, mammalian cells up-regulated aerobic glycolysis, a process mediated by AMP-activated protein kinase (AMPK) independently of HIF-1α. Together these results demonstrate a biologically important activity of manassantin in the control of complex I-mediated respiration and its profound effects on oxygen utilization, energy homeostasis, and glucose metabolism in mammalian cells.

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Discovery of Manassantin A Protein Targets Using Large-Scale Protein Folding and Stability Measurements

Cited by 31 publications

References 29 publications

Proteome-Wide Structural Biology: An Emerging Field for the Structural Analysis of Proteins on the Proteomic Scale

Proteome-Wide Structural Biology: An Emerging Field for the Structural Analysis of Proteins on the Proteomic Scale

Hypoxia‐inducible factor‐1 (HIF‐1) inhibitors from the last decade (2007 to 2016): A “structure–activity relationship” perspective

The lignan manassantin is a potent and specific inhibitor of mitochondrial complex I and bioenergetic activity in mammals

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