scholarly journals High-Throughput Functional Annotation of Natural Products by Integrated Activity Profiling

2019 ◽  
Author(s):  
Suzie K. Hight ◽  
Kenji L. Kurita ◽  
Elizabeth A. McMillan ◽  
Walter Bray ◽  
Trevor N. Clark ◽  
...  
Keyword(s):  
Natural Products ◽  
Untargeted Metabolomics ◽  
Bioactive Metabolites ◽  
Integrative Approach ◽  
Expression Platform ◽  
Gene Expression Platform ◽  
Powerful Approach ◽  
Natural Products Discovery ◽  
Cytological Profiling ◽  
Screening Approaches

AbstractDetermining mechanism of action (MOA) is one of the biggest challenges in natural products discovery. Here, we report a comprehensive platform that uses Similarity Network Fusion (SNF) to improve MOA predictions by integrating data from the cytological profiling high-content imaging platform and the gene expression platform FUSION. The predictive value of the integrative approach was assessed using a library of target-annotated small molecules as benchmarks. Using KS-tests to compare in-class to out-of-class similarity, we found that SNF resulted in improved power to correctly assign MOA over either dataset alone. Furthermore, we integrated untargeted metabolomics of complex natural product fractions to map biological signatures to specific metabolites. Three examples are presented where SNF coupled with metabolomics was used to directly functionally characterize natural products and accelerate identification of bioactive metabolites. Our results support SNF integration of multiple phenotypic screening approaches along with untargeted metabolomics as powerful approach for advancing natural products drug discovery.

scholarly journals Integration of high-content screening and untargeted metabolomics for comprehensive functional annotation of natural product libraries

2015 ◽  
Vol 112 (39) ◽  
pp. 11999-12004 ◽  
Author(s):  
Kenji L. Kurita ◽  
Emerson Glassey ◽  
Roger G. Linington
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Chemical Properties ◽  
Untargeted Metabolomics ◽  
Bioactive Metabolites ◽  
Discovery Process ◽  
Bioactive Constituents ◽  
Modes Of Action ◽  
New Family ◽  
Natural Products Discovery

Traditional natural products discovery using a combination of live/dead screening followed by iterative bioassay-guided fractionation affords no information about compound structure or mode of action until late in the discovery process. This leads to high rates of rediscovery and low probabilities of finding compounds with unique biological and/or chemical properties. By integrating image-based phenotypic screening in HeLa cells with high-resolution untargeted metabolomics analysis, we have developed a new platform, termed Compound Activity Mapping, that is capable of directly predicting the identities and modes of action of bioactive constituents for any complex natural product extract library. This new tool can be used to rapidly identify novel bioactive constituents and provide predictions of compound modes of action directly from primary screening data. This approach inverts the natural products discovery process from the existing ‟grind and find” model to a targeted, hypothesis-driven discovery model where the chemical features and biological function of bioactive metabolites are known early in the screening workflow, and lead compounds can be rationally selected based on biological and/or chemical novelty. We demonstrate the utility of the Compound Activity Mapping platform by combining 10,977 mass spectral features and 58,032 biological measurements from a library of 234 natural products extracts and integrating these two datasets to identify 13 clusters of fractions containing 11 known compound families and four new compounds. Using Compound Activity Mapping we discovered the quinocinnolinomycins, a new family of natural products with a unique carbon skeleton that cause endoplasmic reticulum stress.

Image-Based Screening Approaches to Natural Products Discovery

2014 ◽  
pp. 371-395
Author(s):  
Christopher J. Schulze ◽  
Roger G. Linington
Keyword(s):  
Natural Products ◽  
Natural Products Discovery ◽  
Screening Approaches

scholarly journals Phenotype-Guided Natural Products Discovery Using Cytological Profiling

2015 ◽  
Vol 78 (9) ◽  
pp. 2242-2248 ◽  
Author(s):  
Jessica L. Ochoa ◽  
Walter M. Bray ◽  
R. Scott Lokey ◽  
Roger G. Linington
Keyword(s):  
Natural Products ◽  
Natural Products Discovery ◽  
Cytological Profiling

Fungal biodiversity and natural products discovery: perspectives and prospects

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
JB Gloer
Keyword(s):  
Natural Products ◽  
Fungal Biodiversity ◽  
Natural Products Discovery

scholarly journals Selectable Markers and Reporter Genes for Engineering the Chloroplast of Chlamydomonas reinhardtii

Biology ◽  
2018 ◽  
Vol 7 (4) ◽  
pp. 46 ◽  
Author(s):  
Lola Esland ◽  
Marco Larrea-Alvarez ◽  
Saul Purton
Keyword(s):  
Chlamydomonas Reinhardtii ◽  
Higher Plants ◽  
Reporter Genes ◽  
Bioactive Metabolites ◽  
Cell Protein ◽  
Cell Factory ◽  
Expression Platform ◽  
Foreign Genes ◽  
Valuable Compounds ◽  
High Level

Chlamydomonas reinhardtii is a model alga of increasing interest as a cell factory for the production of valuable compounds, including therapeutic proteins and bioactive metabolites. Expression of foreign genes in the chloroplast is particularly advantageous as: (i) accumulation of product in this sub-cellular compartment minimises potential toxicity to the rest of the cell; (ii) genes can integrate at specific loci of the chloroplast genome (plastome) by homologous recombination; (iii) the high ploidy of the plastome and the high-level expression of chloroplast genes can be exploited to achieve levels of recombinant protein as high as 5% total cell protein; (iv) the lack of any gene silencing mechanisms in the chloroplast ensures stable expression of transgenes. However, the generation of C. reinhardtii chloroplast transformants requires efficient methods of selection, and ideally methods for subsequent marker removal. Additionally, the use of reporter genes is critical to achieving a comprehensive understanding of gene expression, thereby informing experimental design for recombinant applications. This review discusses currently available selection and reporter systems for chloroplast engineering in C. reinhardtii, as well as those used for chloroplast engineering in higher plants and other microalgae, and looks to the future in terms of possible new markers and reporters that will further advance the C. reinhardtii chloroplast as an expression platform.

scholarly journals CMNPD: a comprehensive marine natural products database towards facilitating drug discovery from the ocean

2020 ◽  
Vol 49 (D1) ◽  
pp. D509-D515
Author(s):  
Chuanyu Lyu ◽  
Tong Chen ◽  
Bo Qiang ◽  
Ningfeng Liu ◽  
Heyu Wang ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Marine Natural Products ◽  
Terrestrial Plants ◽  
Activity Data ◽  
Related Data ◽  
Free Data ◽  
Pharmacokinetic Properties ◽  
Natural Products Discovery ◽  
User Friendly

Abstract Marine organisms are expected to be an important source of inspiration for drug discovery after terrestrial plants and microorganisms. Despite the remarkable progress in the field of marine natural products (MNPs) chemistry, there are only a few open access databases dedicated to MNPs research. To meet the growing demand for mining and sharing for MNPs-related data resources, we developed CMNPD, a comprehensive marine natural products database based on manually curated data. CMNPD currently contains more than 31 000 chemical entities with various physicochemical and pharmacokinetic properties, standardized biological activity data, systematic taxonomy and geographical distribution of source organisms, and detailed literature citations. It is an integrated platform for structure dereplication (assessment of novelty) of (marine) natural products, discovery of lead compounds, data mining of structure-activity relationships and investigation of chemical ecology. Access is available through a user-friendly web interface at https://www.cmnpd.org. We are committed to providing a free data sharing platform for not only professional MNPs researchers but also the broader scientific community to facilitate drug discovery from the ocean.

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