Frontiers of high-throughput metabolomics

Zampieri, Mattia; Sekar, Karthik; Zamboni, Nicola; Sauer, Uwe

doi:10.1016/j.cbpa.2016.12.006

Cited by 139 publications

(90 citation statements)

References 87 publications

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“…They were developed during the last 10-15 years in plant natural products. Using highly sensitive and reproducible analytical methods, they allow the correlation between chemical profile (qualitative or quantitative) and bioactivity data (Zampieri et al, 2017;Parrot et al, 2018;Wolfender et al, 2019) with recent progress in the field of data analysis and integration at the extract level (Wolfender et al, 2019). Finally, the group of direct phytochemical isolation approaches focuses on the comprehensive chemical characterization of the plant extract and the isolation of novel scaffolds without immediately evaluating their bioactivity.…”

Section: Strategies For Identification Of Bioactive Compounds From Crmentioning

confidence: 99%

Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes

Lautie

Russo

Ducrot³

2020

Front. Pharmacol.

141

114

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The screening and testing of extracts against a variety of pharmacological targets in order to benefit from the immense natural chemical diversity is a concern in many laboratories worldwide. And several successes have been recorded in finding new actives in natural products, some of which have become new drugs or new sources of inspiration for drugs. But in view of the vast amount of research on the subject, it is surprising that not more drug candidates were found. In our view, it is fundamental to reflect upon the approaches of such drug discovery programs and the technical processes that are used, along with their inherent difficulties and biases. Based on an extensive survey of recent publications, we discuss the origin and the variety of natural chemical diversity as well as the strategies to having the potential to embrace this diversity. It seemed to us that some of the difficulties of the area could be related with the technical approaches that are used, so the present review begins with synthetizing some of the more used discovery strategies, exemplifying some key points, in order to address some of their limitations. It appears that one of the challenges of natural product-based drug discovery programs should be an easier access to renewable sources of plant-derived products. Maximizing the use of the data together with the exploration of chemical diversity while working on reasonable supply of natural product-based entities could be a way to answer this challenge. We suggested alternative ways to access and explore part of this chemical diversity with in vitro cultures. We also reinforced how important it was organizing and making available this worldwide knowledge in an "inventory" of natural products and their sources. And finally, we focused on strategies based on synthetic biology and syntheses that allow reaching industrial scale supply. Approaches based on the opportunities lying in untapped natural plant chemical diversity are also considered.

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Section: Strategies For Identification Of Bioactive Compounds From Crmentioning

confidence: 99%

Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes

Lautie

Russo

Ducrot³

2020

Front. Pharmacol.

141

114

View full text Add to dashboard Cite

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“…Metabolomics-based approaches have a notable advantage over existing functional genomics platforms in that they enable an unparalleled throughput 20,21 . However, despite significant advancements in high-resolution mass-spectrometry (MS) profiling of cellular samples 21–23 , efficient experimental and computational workflows for large-scale dynamic metabolome profiling in mammalian cells in vitro are lagging behind.…”

Section: Introductionmentioning

confidence: 99%

“…However, despite significant advancements in high-resolution mass-spectrometry (MS) profiling of cellular samples 21–23 , efficient experimental and computational workflows for large-scale dynamic metabolome profiling in mammalian cells in vitro are lagging behind. Metabolome screenings that adopt classical metabolomics techniques 24,25 are often hampered by a limited throughput, laborious sample preparation and the lack of rigorous, yet simple, data analysis pipelines to interpret dynamic metabolome profiles.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, we provide a proof of principle that our approach can generate testable predictions to elucidate the origin of drug response variability and drug modes of action. Such a platform may complement and improve the translational value of classical in vitro phenotype-based drug screenings 21,27 , and provide insights into the mechanisms of action of small molecules facilitating early stages of drug discovery 28–30 .…”

Section: Introductionmentioning

confidence: 99%

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A framework for large-scale metabolome drug profiling links coenzyme A metabolism to the toxicity of anti-cancer drug dichloroacetate

2018

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Metabolic profiling of cell line collections has become an invaluable tool to study disease etiology, drug modes of action and to select personalized treatments. However, large-scale in vitro dynamic metabolic profiling is limited by time-consuming sampling and complex measurement procedures. By adapting a mass spectrometry-based metabolomics workflow for high-throughput profiling of diverse adherent mammalian cells, we establish a framework for the rapid measurement and analysis of drug-induced dynamic changes in intracellular metabolites. This methodology is scalable to large compound libraries and is here applied to study the mechanism underlying the toxic effect of dichloroacetate in ovarian cancer cell lines. System-level analysis of the metabolic responses revealed a key and unexpected role of CoA biosynthesis in dichloroacetate toxicity and the more general importance of CoA homeostasis across diverse human cell lines. The herein-proposed strategy for high-content drug metabolic profiling is complementary to other molecular profiling techniques, opening new scientific and drug-discovery opportunities.

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“…Technological advancements in the field of MS‐based metabolomics have made it cost‐affordable for small/middle‐sized metabolomics centers to serve hundreds of investigators on a yearly basis, fostering a new era in the field of omics disciplines and their translational relevance to basic science and clinical applications. High‐throughput workflows based on flow‐injection MS or ultra‐high‐throughput liquid chromatography have made a significant portion of the metabolome amenable to detection and quantification of over 10,000 features and hundreds of named metabolites in less than 3 min. Optimization of rapid extraction protocols, automatization and, predictably, low‐cost robotization of sample extraction protocols would enable affordable processing of hundreds to a thousand samples per day in a cost‐effective manner.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the effects of storage and freezing on mixes of heavy‐labeled metabolite and amino acid standards

Culp‐Hill

Reisz

Hansen

et al. 2017

Rapid Comm Mass Spectrometry

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RATIONALE High-throughput metabolomics has now made it possible for small/medium-sized laboratories to analyze thousands of samples/year from the most diverse biological matrices including biofluids, cell and tissue extracts. In large scale metabolomics studies, stable isotope-labeled standards are increasingly used to normalize for matrix effects and control for technical reproducibility (e.g. extraction efficiency, chromatographic retention times and mass spectrometry signal stability). However, it is currently unknown how stable mixes of commercially-available standards are following repeated freeze/thaw cycles or prolonged storage of aliquots. METHODS Standard mixes for 13C, 15N or deuterated isotopologues of amino acids and key metabolites from the central carbon and nitrogen pathways (e.g. glycolysis, Krebs cycle, redox homeostasis, purines) were either repeatedly frozen/thawed for up to 10 cycles, or diluted into aliquots prior to frozen storage for up to 42 days. Samples were characterized by ultra-high pressure liquid chromatography-mass spectrometry to determine the stability of the aliquoted standards upon freezing/thawing or prolonged storage. RESULTS Metabolite standards were stable over up to 10 freeze/thaw cycles, with the exception of adenosine and glutathione, showing technical variability across aliquots in a freeze/thaw-cycle-independent fashion. Storage for up to 42 days of mixes of commercially available standards did not significantly affect the stability of amino acid or metabolite standards for the first two weeks, while progressive degradation (statistically-significant for fumarate) was observed after three weeks. CONCLUSIONS Refrigerated or frozen preservation for at least 2 weeks of aliquoted heavy-labeled standard mixes for metabolomics analysis is a feasible and time-/resource-saving strategy for standard metabolomics laboratories.

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Frontiers of high-throughput metabolomics

Cited by 139 publications

References 87 publications

Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes

Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes

A framework for large-scale metabolome drug profiling links coenzyme A metabolism to the toxicity of anti-cancer drug dichloroacetate

Investigation of the effects of storage and freezing on mixes of heavy‐labeled metabolite and amino acid standards

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