Natural Product Libraries to Accelerate the High-Throughput Discovery of Therapeutic Leads

Johnson, Tyler A.; Sohn, Jungwoo; Inman, Wayne D.; Estee, Samarkand A.; Loveridge, Steven T.; Vervoort, Hélène C.; Tenney, Karen; Liu, Junke; Ang, Kenny Kean‐Hooi; Ratnam, Joseline; Bray, Walter M.; Gassner, N.C.; Shen, Yongchun; Lokey, R. Scott; McKerrow, James H.; Boundy‐Mills, Kyria; Nurkanto, Arif; Kanti, Atit; Julistiono, Heddy; Kardono, Leonardus B.S.; Bjeldanes, Leonard F.; Crews, Phillip

doi:10.1021/np200673b

Cited by 60 publications

(63 citation statements)

References 54 publications

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“…15,16 The success of HTS is inherently dependent on chemical diversity and a lack of chemical redundancy. 3,17 Historically, natural product extract sources were chosen either randomly or on the basis of their ecology and/or taxonomy.…”

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confidence: 99%

Microbial Strain Prioritization Using Metabolomics Tools for the Discovery of Natural Products

et al. 2012

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Natural products profoundly impact many research areas, including medicine, organic chemistry, and cell biology. However, discovery of new natural products suffers from a lack of high throughput analytical techniques capable of identifying structural novelty in the face of a high degree of chemical redundancy. Methods to select bacterial strains for drug discovery have historically been based on phenotypic qualities or genetic differences and have not been based on laboratory production of secondary metabolites. Therefore, untargeted LC/MS-based secondary metabolomics was evaluated to rapidly and efficiently analyze marine-derived bacterial natural products using LC/MS-principal component analysis (PCA). A major goal of this work was to demonstrate that LC/MS-PCA was effective for strain prioritization in a drug discovery program. As proof of concept, we evaluated LC/MS-PCA for strain selection to support drug discovery, for the discovery of unique natural products, and for rapid assessment of regulation of natural product production.

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confidence: 99%

Microbial Strain Prioritization Using Metabolomics Tools for the Discovery of Natural Products

et al. 2012

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“…46 Our HTS utilized HEK293T cells stably expressing the human μ -OR and δ- OR. 51 Our approach, shown in Scheme 1, generated purified libraries of marine natural products compatible with cell and target based HTS programs.…”

Section: Resultsmentioning

confidence: 99%

“…45 This has since been addressed by industry and academic research groups that have shown that using purified natural product libraries can streamline lead compound discovery using HTS methods. 46–50 …”

Section: Introductionmentioning

confidence: 99%

Identification of the First Marine-Derived Opioid Receptor “Balanced” Agonist with a Signaling Profile That Resembles the Endorphins

Johnson

Milan‐Lobo

Che

et al. 2016

ACS Chem. Neurosci.

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Opioid therapeutics are excellent analgesics, whose utility is compromised by dependence. Morphine (1) and its clinically relevant derivatives such as OxyContin (2), Vicodin (3), and Dilaudid (4) are “biased” agonists at the μ opioid receptor (OR), wherein they engage G protein signaling but poorly engage β-arrestin and the endocytic machinery. In contrast, endorphins, the endogenous peptide agonists for ORs, are potent analgesics, show reduced liability for tolerance and dependence, and engage both G protein and β-arrestin pathways as “balanced” agonists. We set out to determine if marine-derived alkaloids could serve as novel OR agonist chemotypes with a signaling profile distinct from morphine and more similar to the endorphins. Screening of 96 sponge-derived extracts followed by LC-MS-based purification to pinpoint the active compounds and subsequent evaluation of a mini library of related alkaloids identified two structural classes that modulate the ORs. These included the following: aaptamine (10), 9-demethyl aaptamine (11), demethyl (oxy)–aaptamine (12) with activity at the δ-OR (EC50: 5.1, 4.1, 2.3 μM, respectively) and fascaplysin (17), and 10-bromo fascaplysin (18) with activity at the μ-OR (EC50: 6.3, 4.2 μM respectively). An in vivo evaluation of 10 using δ-KO mice indicated its previously reported antidepressant-like effects are dependent on the δ-OR. Importantly, 17 functioned as a balanced agonist promoting both G protein signaling and β-arrestin recruitment along with receptor endocytosis similar to the endorphins. Collectively these results demonstrate the burgeoning potential for marine natural products to serve as novel lead compounds for therapeutic targets in neuroscience research.

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“…62,63 One of the most effective approaches increasingly taken to address natural product-specific liquid handling issues is partial purification (or “prefractionation”) of crude extracts for removal and/or sequestration of problem constituents as well as increasing consistency of samples. 64,63,65 …”

Section: 0 Challenges Of Natural Product Samples For Htsmentioning

confidence: 99%

Matching the power of high throughput screening to the chemical diversity of natural products

2013

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Natural Product Libraries to Accelerate the High-Throughput Discovery of Therapeutic Leads

Cited by 60 publications

References 54 publications

Microbial Strain Prioritization Using Metabolomics Tools for the Discovery of Natural Products

Microbial Strain Prioritization Using Metabolomics Tools for the Discovery of Natural Products

Identification of the First Marine-Derived Opioid Receptor “Balanced” Agonist with a Signaling Profile That Resembles the Endorphins

Matching the power of high throughput screening to the chemical diversity of natural products

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