Discovery and characterization of natural products as novel indoleamine 2,3-dioxygenase 1 inhibitors through high-throughput screening

Guo, Wei; Yao, Sheng; Sun, Pu; Yang, Tianjun; Tang, Chunping; Zheng, Mingyue; Yang, Yong; Meng, Linghua

doi:10.1038/s41401-019-0246-4

Cited by 9 publications

(3 citation statements)

References 44 publications

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“…Traditional drug discovery typically involves identification of a promising, druggable target and then screening tens of thousands to millions of compounds to identify those that bind with the highest affinity [9][10][11]. Although this method can be effective, it is beset by several shortcomings.…”

Section: Introductionmentioning

confidence: 99%

Novel Immune Modulators EnhanceCaenorhabditis elegansResistance to Multiple Pathogens

Hummell

Revtovich

Kirienko

2020

Preprint

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Traditionally, treatments for bacterial infection have focused on killing the microbe or preventing its growth. As antimicrobial resistance becomes more ubiquitous, attention has begun to shift toward disrupting the host-pathogen interaction by improving the host defense. Using a high-throughput, fragment-based screen to identify compounds that alleviate Pseudomonas aeruginosa-mediated killing of Caenorhabditis elegans, we identified over 20 compounds that stimulated host defense gene expression. Five of these molecules were selected for further characterization. Four compounds showed little toxicity against mammalian cells or worms, consistent with their identification in a phenotypic, high-content screen. Each of the compounds activated several host defense pathways, but the pathways were generally dispensable for compound-mediated rescue in Liquid Killing, suggesting redundancy or that the activation of one or more unknown pathways may be driving compound effects. A genetic mechanism was identified for LK56, which required the Mediator subunit MDT-15/MED15 and NHR-49/HNF4 for its function. Interestingly, LK32, LK34, LK38, and LK56 also rescue C. elegans from P. aeruginosa in an agar-based assay, which uses different virulence factors and defense mechanisms. Rescue in an agar-based assay for LK38 entirely depended upon the PMK-1/p38 MAPK pathway. Three compounds, LK32, LK34, and LK56 also conferred resistance to Enterococcus faecalis, and the two lattermost, LK34 and LK56, also reduced pathogenesis from Staphylococcus aureus. This study supports a growing role for MDT-15 and NHR-49 in immune response and identifies 5 molecules that with significant potential for use as tools in the investigation of innate immunity.

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Section: Introductionmentioning

confidence: 99%

Novel Immune Modulators EnhanceCaenorhabditis elegansResistance to Multiple Pathogens

Hummell

Revtovich

Kirienko

2020

Preprint

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“…For example, Exiguamine A, isolated from the marine sponge Neopetrosia exigua, has a Ki of 210 nM for inhibition of IDO1 in vitro ( Brastianos et al, 2006 ). Moreover, the inhibitory activities of tanshinone derivatives and naphthoquinone on IDO1 have also been reported ( Pan et al, 2018 ; Guo et al, 2020 ). Therefore, it is preferable to discover dual inhibitors of IDO1/TDO2 from natural products or derivatives.…”

Section: Introductionmentioning

confidence: 93%

Sodium Tanshinone IIA Sulfonate as a Potent IDO1/TDO2 Dual Inhibitor Enhances Anti-PD1 Therapy for Colorectal Cancer in Mice

et al. 2022

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Although the antitumor efficacy of immune checkpoint blockade (ICB) has been proved in colorectal cancer (CRC), the results are unsatisfactory, presumably owing to the presence of tryptophan metabolism enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2). However, only a few dual inhibitors for IDO1 and TDO2 have been reported. Here, we discovered that sodium tanshinone IIA sulfonate (STS), a sulfonate derived from tanshinone IIA (TSN), reduced the enzymatic activities of IDO1 and TDO2 with a half inhibitory concentration (IC50) of less than 10 μM using enzymatic assays for natural product screening. In IDO1- or TDO2- overexpressing cell lines, STS decreased kynurenine (kyn) synthesis. STS also reduced the percentage of forkhead box P3 (FOXP3) T cells in lymphocytes from the mouse spleen cocultured with CT26. In vivo, STS suppressed tumor growth and enhanced the antitumor effect of the programmed cell death 1 (PD1) antibody. Compared with anti-PD1 (α-PD1) monotherapy, combined with STS had lower level of plasma kynurenine. Immunofluorescence assay suggested that STS decreased the number of FOXP3+ T cells and increased the number of CD8+ T cells in tumors. Flow cytometry analysis of immune cells in tumor tissues demonstrated an increase in the percentage of tumor-infiltrating CD8+ T cells. According to our findings, STS acts as an immunotherapy agent in CRC by inhibiting both IDO1 and TDO2.

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“…Traditional drug discovery typically involves identification of a promising, druggable target and then screening tens of thousands to millions of compounds to identify those that bind with the highest affinity ( 9 – 11 ). Although this method can be effective, it is beset by several shortcomings.…”

Section: Introductionmentioning

confidence: 99%

Novel Immune Modulators Enhance Caenorhabditis elegans Resistance to Multiple Pathogens

Hummell

Revtovich

Kirienko

2021

mSphere

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Traditionally, treatments for bacterial infection have focused on killing the microbe or preventing its growth. As antimicrobial resistance becomes more ubiquitous, the feasibility of this approach is beginning to wane and attention has begun to shift toward disrupting the host-pathogen interaction by improving the host defense. Using a high-throughput, fragment-based screen to identify compounds that alleviate Pseudomonas aeruginosa-mediated killing of Caenorhabditis elegans, we identified over 20 compounds that stimulated host defense gene expression. Five of these molecules were selected for further characterization. Four of five compounds showed little toxicity against mammalian cells or worms, consistent with their identification in a phenotypic, high-content screen. Each of the compounds activated several host defense pathways, but the pathways were generally dispensable for compound-mediated rescue in liquid killing, suggesting redundancy or that the activation of unknown pathway(s) may be driving compound effects. A genetic mechanism was identified for LK56, which required the Mediator subunit MDT-15/MED15 and NHR-49/HNF4 for its function. Interestingly, LK32, LK34, LK38, and LK56 also rescued C. elegans from P. aeruginosa in an agar-based assay, which uses different virulence factors and defense mechanisms. Rescue in an agar-based assay for LK38 entirely depended upon the PMK-1/p38 MAPK pathway. Three compounds—LK32, LK34, and LK56—also conferred resistance to Enterococcus faecalis, and the two lattermost, LK34 and LK56, also reduced pathogenesis from Staphylococcus aureus. This study supports a growing role for MDT-15 and NHR-49 in immune response and identifies five molecules that have significant potential for use as tools in the investigation of innate immunity. IMPORTANCE Trends moving in opposite directions (increasing antimicrobial resistance and declining novel antimicrobial development) have precipitated a looming crisis: the nearly complete inability to safely and effectively treat bacterial infections. To avert this, new approaches are needed. One idea is to stimulate host defense pathways to improve the clearance of bacterial infection. Here, we describe five small molecules that promote resistance to infectious bacteria by activating C. elegans’ innate immune pathways. Several are effective against both Gram-positive and Gram-negative pathogens. One of the compounds was mapped to the action of MDT-15/MED15 and NHR-49/HNF4, a pair of transcriptional regulators more generally associated with fatty acid metabolism, potentially highlighting a new link between these biological functions. These studies pave the way for future characterization of the anti-infective activity of the molecules in higher organisms and highlight the compounds’ potential utility for further investigation of immune modulation as a novel therapeutic approach.

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Discovery and characterization of natural products as novel indoleamine 2,3-dioxygenase 1 inhibitors through high-throughput screening

Cited by 9 publications

References 44 publications

Novel Immune Modulators EnhanceCaenorhabditis elegansResistance to Multiple Pathogens

Novel Immune Modulators EnhanceCaenorhabditis elegansResistance to Multiple Pathogens

Sodium Tanshinone IIA Sulfonate as a Potent IDO1/TDO2 Dual Inhibitor Enhances Anti-PD1 Therapy for Colorectal Cancer in Mice

Novel Immune Modulators Enhance Caenorhabditis elegans Resistance to Multiple Pathogens

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