Untargeted Metabolomics and Bioactivities Assessment of Xylaria ellisii, an Endophytic Fungus Isolated from the Leaf of the Plant Acorus calamus Linn.

Article

Author: Garg, Neha ; Rai, Sachchida Nand ; Singh, Santosh Kumar ; Rajak, Naina ; Singh, Anurag Kumar ; Prajapati, Chandrabhan

Introduction:Fungal endophytes have mutualistic associations with the plant's host, communicating through genetic and metabolic processes. As a result, they gain the ability to generate therapeutically effective metabolites and their derivatives.Methods:The current study aims to assess antioxidant potential along with the identification of robust metabolites within the crude extract of a potent endophytic fungus Xylaria ellisii isolated from leaf tissues of the Acorus calamus Linn. plant. Four endophytic fungi were obtained from leaf tissues of Acorus calamus Linn., and identified morphologically and molecularly as distinct species. Each ethyl acetate extract of the isolated fungi exhibited a unique chemical profile in the HPTLC fingerprint at various wavelengths. The ethyl acetate (EA) extract from the fungal strain ACL-4 (Xylaria ellisii) demonstrated the strongest antioxidant activity among the four fungal endophytes examined, with an EC50 value of 292.64 ± 3.558 μg/mL. Remarkably, fungal endophyte ACL-4 extract exhibited superior antimicrobial activity at the less concentrations compared to ACL-ME extract of leaf crude.Results:The extract of ACL-ME-treated HEK 293T cells exhibited significant toxicity, with an IC50 value of 1481.74 ± 23.772 μg/mL, compared to fungal strain ACL-4-treated HEK 293T cells, which had an IC50 value greater than 2000 μg/mL. Consequently, the crude extract of ACL-4 and ACL-ME along with the standard drug methotrexate exhibited cytotoxic activity against cancer cell line MDA-MB-231 with IC50 concentrations of 146.65 ± 0.394 μg/mL, 528.46 ± 10.912 μg/mL, and 134.11 ± 3.446 μg/mL, respectively. A total of 2,255 compounds were detected through LC-HRMS-based metabolomics in the crude metabolites of Xylaria ellisii, with certain compounds identified in multiple instances. Among this repertoire, 62 robust bioactive compounds were identified through meticulous screening, guided by existing literature. Comparative HPTLC fingerprint analysis, along with antioxidant efficacy assays of ethyl acetate extracts of Xylaria ellisii derived from Acorus calamus leaves and Cassia fistula twigs revealed the host-specific production of bioactive chemicals.Conclusion:The top-scoring Keap1 inhibitors derived from Xylaria ellisii, including Pregabalin (-6.083 Kcal/mol), Ferulic acid (-5.434 Kcal/mol), (R)-Piperidine-2-carboxylic acid (-5.31 Kcal/mol), Genipin (-5.197 Kcal/mol), and Brivaracetam (-5.17 Kcal/mol), respectively were considered as Keap 1 inhibitors, potentially mitigate oxidative stress.

03 Apr 2025·Expert Opinion on Therapeutic Patents

Patenting perspective on Keap1 inhibitors (2019–2024)

Review

Author: Lu, Mengchen ; Zhang, Yuan ; Li, Xiangyang ; Yang, Ziyu ; Luo, Yongfu ; Zhu, Jingyu ; Jiang, Shutong ; You, Qidong

INTRODUCTIONKelch-like ECH-associated protein 1 (Keap1), an E3 ligase negatively regulating the nuclear factor erythroid 2-related factor 2 (Nrf2), has emerged as an auspicious drug target for treating ailments associated with oxidative stress and inflammation. Discovery of Keap1 inhibitors have attracted significant interest.AREAS COVEREDThis review covers patents on Keap1 inhibitors from 2019 to 2024, providing a comprehensive analysis of their structural characteristics, optimization strategies, pharmacological properties and clinical progress.EXPERT OPINIONExtensive efforts have been devoted to enhance potency and drug-like properties of Keap1 inhibitors. Strategies such as ROS-cleavable prodrug design, bivalent inhibition and PROTACs are emerging. As the range of drug types and applications expands, Keap1 inhibitors are becoming a sagacious option for disease treating.

01 Jan 2025·Toxicology and Applied Pharmacology

Synthesis and evaluation of novel ethyl ferulate derivatives as potent Keap1 inhibitors to activate the Nrf2/ARE pathway in Parkinson's disease

Article

Author: Chakkittukandiyil, Amritha ; Sugumar, Deepa ; Ramachandran, Vadivelan ; Selvaraj, Divakar ; Mathew, Jinu ; Rymbai, Emdormi ; Arumugam, Suresh ; Sajini, Deepak Vasudevan

The Kelch-like ECH-associated protein 1/Nuclear factor erythroid 2 related factor 2/Antioxidant Response Elements (Keap1/Nrf2/ARE) pathway is essential for neuronal resilience against the complex pathogenesis of Parkinson's disease (PD). Activating this pathway by covalently modifying Keap1 cysteine residues is a promising strategy for regulating neuroprotective gene expression. Our study aimed to identify phytochemicals that could irreversibly inhibit Keap1. A preliminary docking analysis revealed that ethyl ferulate could covalently bind with Cys151 of Keap1 by Michael's addition reaction. Further, we designed several ethyl ferulate derivatives with improved lipophilicity and assessed their binding affinity with Keap1. The molecules with good binding scores were synthesized and structures were confirmed through ¹H NMR, ¹³C NMR, FT-IR, and mass spectroscopy. Neuroprotection screening was conducted in all-trans retinoic acid differentiated SH-SY5Y cells using rotenone as a disease-inducing agent. Pre-treatment with compounds C2 and C4 significantly mitigated rotenone toxicity. Additionally, C2 and C4 decreased rotenone-induced ROS production and mitochondrial membrane potential loss. C2 and C4 also induced Nrf2 nuclear translocation in SH-SY5Y cells and increased mRNA expression of heme oxygenase-1, an Nrf2-regulated antioxidant response element. In vivo, pretreatment with C2 (50, 100 mg/kg, p.o.) and C4 (50, 100 mg/kg, p.o.) protected against neurodegenerative phenotypes associated with rotenone (1.5 mg/kg, s.c.) induction in Wistar rats. Results indicate, C2 and C4 dose-dependently improved muscle rigidity, catalepsy, and cognitive deficits in rotenone-induced Wistar rats, and mitigated dopaminergic neurodegeneration in the substantia nigra. These findings highlight the potential of ethyl ferulate derivatives in modulating oxidative stress and neurodegeneration in PD via activation of Nrf2.

100 Deals associated with VVD-702

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammatory Bowel Diseases	Preclinical	United States	Vividion Therapeutics, Inc.	01 Nov 2024
Colitis	Preclinical	United States	Vividion Therapeutics, Inc.	25 Jun 2021

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