Discovery of A Chimeric Polyketide Family as Cancer Immunogenic Chemotherapeutic Leads DOI Open Access
Dan Xue, Mingming Xu, Michael R. Madden

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 6, 2024

Abstract Discovery of cancer immunogenic chemotherapeutics represents an emerging, highly promising direction for treatment that uses a chemical drug to achieve the efficacy both chemotherapy and immunotherapy. Herein we report high-throughput screening platform subsequent discovery new class chemotherapeutic leads. Our integrates informatics-based activity metabolomics rapid identification microbial natural products with novel structures potent activities. Additionally, demonstrate use microcrystal electron diffraction (MicroED) direct structure elucidation lead compounds from partially purified mixtures. Using this strategy screen geographically phylogenetically diverse metabolites against pseudomyxoma peritonei, rare severe cancer, discovered leads, aspercyclicins. The aspercyclicins feature unprecedented tightly packed polycyclic polyketide scaffold comprises continuous fused, bridged, spiro rings. biogenesis involves two distinct biosynthetic pathways, leading formation chimeric cannot be predicted by bottom-up approaches mining genes. With comparable potency some clinically used anticancer drugs, are active multiple cell types inducing death (ICD), including release damage-associated molecular patterns phagocytosis cells. broad-spectrum ICD-inducing aspercyclicins, combined their low toxicity normal cells, potential particularly first peritonei treatment.

Language: Английский

Degrading the key component of the inflammasome: Development of an NLRP3 PROTAC DOI

Tim Keuler,

Dominic Ferber,

Jonas Engelhardt

et al.

Chemical Communications, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

The bifunctional compound V2 induced a VHL-dependent NLRP3 degradation. postulated ternary complex formation involves the molecular interaction of (cyan) to binding sites VHL (magenta) and (orange).

Language: Английский

Citations

1
Sorbicitrinols A and B, Two Sorbicillinoids with Unprecedented Skeletons Uncovered from Sponge-Derived Fungus Penicillium sp. S4I4-3 by a Molecular Networking Strategy DOI

Z P Chen,

Hui-Xian Liang,

Wan‐Ying Guo

et al.

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

Sorbicitrinol A (1) and its biosynthetic precursor sorbicitrinol B (2), two novel sorbicillinoids with unprecedented skeletons, were isolated from the sponge-derived fungus Penicillium sp. by molecular networking. Their structures identified spectroscopic analyses quantum chemistry. Both of them exhibited an innovative fusion pattern sorbicillinol a citrinin derivative. Compound 1 was first example sorbicillinoid featuring unique cage-like 2,5-dioxa-pentacyclo[10.4.03,11.04,8.04,15]tetradecane scaffold. Plausible biogenetic pathways proposed, their antitumor antifungal activities also evaluated.

Language: Английский

Citations

0
Scaffold Hopping-Based Structural Modification of Tranilast Led to the Identification of HNW005 as a Promising NLRP3 Inflammasome and URAT1 Dual Inhibitor for the Treatment of Gouty Arthritis DOI
Ming Sun,

Fengwei Lin,

Chenglei Yue

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 292, P. 117644 - 117644

Published: April 17, 2025

Language: Английский

Citations

0
MFS Transporter as the Molecular Switch Unlocking the Production of Cage-Like Acresorbicillinol C DOI

Chengbao Duan,

Shiyuan Wang, Yongpeng Yao

et al.

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: 72(34), P. 19061 - 19070

Published: Aug. 16, 2024

Sorbicillinoids are a class of fungal polyketides with diverse structures and distinguished bioactivities. Although remarkable progress has been achieved in their chemistry biosynthesis, the efflux sorbicillinoids is poorly understood. Here, we found MFS transporter AcsorT was responsible for biosynthesis Acremonium chrysogenum. Combinatorial knockout subcellular location demonstrated that plasma membrane-associated transportation sorbicillinol subsequent formation oxosorbicillinol acresorbicillinol C via berberine bridge enzyme-like oxidase AcsorD periplasm. Homology modeling site-directed mutation revealed Tyr303 Arg436 were key residues AcsorT, which further explained by molecular dynamics simulation. Based on our study, it suggested modulates sorbicillinoid production coordinating its export, transport model proposed A.

Language: Английский

Citations

3
Deep-Sea-Derived Isobisvertinol Targets TLR4 to Exhibit Neuroprotective Activity via Anti-Inflammatory and Ferroptosis-Inhibitory Effects DOI Creative Commons
Zihan Xu,

Ming‐Min Xie,

Chun‐Lan Xie

et al.

Marine Drugs, Journal Year: 2025, Volume and Issue: 23(1), P. 49 - 49

Published: Jan. 20, 2025

Neuroinflammation and neuronal cell death are leading causes of in the elderly underlie various neurodegenerative diseases. These diseases involve complex pathophysiological mechanisms, including inflammatory responses, oxidative stress, ferroptosis. Compounds derived from deep-sea fungi exhibit low toxicity potent neuroprotective effects, offering a promising source for drug development. In this study, we isolated 44 natural products deep-sea-derived identified isobisvertinol (17) as compound with anti-inflammatory ferroptosis-inhibiting effects. Using LPS-induced microglial inflammation RSL3-induced ferroptosis models, found that 17 targets TLR4 to provide neuroprotection. Molecular docking studies revealed inhibits activation by occupying hydrophobic pocket at TLR4-MD2 binding site. Additionally, suppresses TLR4, reducing p38 MAPK phosphorylation, decreasing lipid peroxidation modulating mitochondrial membrane potential. Metabolomic analysis showed rescues alterations multiple metabolic pathways induced RSL3 increases levels antioxidant metabolites, glutamine, glutamate, glutathione. summary, our results indicate neural cells reduce inhibit while regulating pathways, mainly GSH synthesis, effects prevent neurons.

Language: Английский

Citations

0
Bioinformatics assisted construction of the link between biosynthetic gene clusters and secondary metabolites in fungi DOI
Huawei Lv,

Jia-Gui Tang,

Bin Wei

et al.

Biotechnology Advances, Journal Year: 2025, Volume and Issue: unknown, P. 108547 - 108547

Published: Feb. 1, 2025

Language: Английский

Citations

0
Polyketide Derivatives from the Mangrove-Derived Fungus Penicillium sp. HDN15-312 DOI Creative Commons
Fuhao Liu, Wenxue Wang, Feifei Wang

et al.

Marine Drugs, Journal Year: 2024, Volume and Issue: 22(8), P. 360 - 360

Published: Aug. 8, 2024

Four new polyketides, namely furantides A–B (1–2), talamin E (3) and arugosinacid A (4), two known polyketides were obtained from the mangrove-derived fungus Penicillium sp. HDN15-312 using One Strain Many Compounds (OSMAC) strategy. Their chemical structures, including configurations, elucidated by detailed analysis of extensive NMR spectra, HRESIMS ECD. The DPPH radicals scavenging activity 3, with an IC50 value 6.79 µM, was better than vitamin C.

Language: Английский

Citations

2
Enzymatic Ring Contraction for the Biosynthesis of Sulfur-Containing Cyclopentachromone DOI

Qiuyue Nie,

Chunxiao Sun, Shuai Liu

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Cyclopentachromone, distinguished by its 6/6/5 heterotricyclic ring structure, is a key building block in many bioactive natural products, yet enzymatic origin remains unclear. We identified new class of cyclopentachromone-containing compounds, termed isochromosulfines, characterized unique C-S bonds. A distinct FAD-dependent monooxygenase, IscL, was to catalyze the formation cyclopentadiene intermediate, 2

Language: Английский

Citations

2
Discovery of a Chimeric Polyketide Family as Cancer Immunogenic Chemotherapeutic Leads DOI
Dan Xue, Mingming Xu, Michael R. Madden

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 28, 2024

Discovery of cancer immunogenic chemotherapeutics represents an emerging, highly promising direction for treatment that uses a chemical drug to achieve the efficacy both chemotherapy and immunotherapy. Herein, we report high-throughput screening platform subsequent discovery new class chemotherapeutic leads. Our integrates informatics-based activity metabolomics rapid identification microbial natural products with novel structures potent activities. Additionally, demonstrate use microcrystal electron diffraction (MicroED) direct structure elucidation lead compounds from partially purified mixtures. Using this strategy screen geographically phylogenetically diverse metabolites against pseudomyxoma peritonei, rare severe cancer, discovered leads, aspercyclicins. The aspercyclicins feature unprecedented tightly packed polycyclic polyketide scaffold comprises continuous fused, bridged, spiro rings. biogenesis involves two distinct biosynthetic pathways, leading formation chimeric cannot be predicted by bottom-up approaches mining product genes. With comparable potency some clinically used anticancer drugs, are active multiple cell types inducing death (ICD), including release damage-associated molecular patterns phagocytosis cells. broad-spectrum ICD-inducing aspercyclicins, combined their low toxicity normal cells, potential and, particularly, first peritonei treatment.

Language: Английский

Citations

1
Hot off the Press DOI
Robert A. Hill, Andrew Sutherland

Natural Product Reports, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

A personal selection of 32 recent papers is presented covering various aspects current developments in bioorganic chemistry and novel natural products such as asperochone from

Language: Английский

Citations

0