Secondary Metabolites of Alternaria Alternate Appraisal of Their SARS-CoV-2 Inhibitory and Anti-inflammatory Potentials

Overview

Journal PLoS One

Date 2025 Jan 24

PMID 39854441

Authors

Fatma A Moharram

Reham R Ibrahim

Shahenda Mahgoub

Mohamed S Abdel-Aziz

Ahmed M Said

Hui-Chi Huang

Lo-Yun Chen

Kuei-Hung Lai

Nashwa Hashad

Mohamed S Mady

Affiliations

Soon will be listed here.

Abstract

This study identifies the secondary metabolites from Alternaria alternate and evaluates their ACE-2: Spike RBD (SARS-CoV-2) inhibitory activity confirmed via immunoblotting in human lung microvascular endothelial cells. In addition, their in vitro anti-inflammatory potential was assessed using a cell-based assay in LPS-treated RAW 264.7 macrophage cells. Two novel compounds, altenuline (1), phthalic acid bis (7'/7'' pentyloxy) isohexyl ester (2), along with 1-deoxyrubralactone (3) alternariol-5-O-methyl ether (4) and alternariol (5) were identified. Molecular docking and in vitro studies showed that compounds 2 and 4 were promising to counteract SARS-CoV-2 attachment to human ACE-2. Thus, they are considered promising natural anti-viral agents. SwissADME in silico analysis was conducted to predict the drug-like potential. Immunoblotting analysis confirmed that the tested compounds (1-4) demonstrated downregulation of ACE-2 expression in the endothelial cells from the lungs with variable degrees. Furthermore, the tested compounds (1-4) showed promising anti-inflammatory activities through TNF-α: TNFR2 inhibitory activity and their inhibitory effect on the proinflammatory cytokines (TNF-α and IL-6) in LPS-stimulated monocytes. In conclusion, our study, for the first time, provides beneficial experimental confirmation for the efficiency of the A. alternate secondary metabolites for the treatment of COVID-19 as they hinder SARS-CoV-2 infection and lower inflammatory responses initiated by SARS-CoV-2. A. alternate and its metabolites are considered in developing preventative and therapeutic tactics for COVID-19.

References

Noor A, Almasri D, Bagalagel A, Abdallah H, Mohamed S, Mohamed G . Naturally Occurring Isocoumarins Derivatives from Endophytic Fungi: Sources, Isolation, Structural Characterization, Biosynthesis, and Biological Activities. Molecules. 2020; 25(2). PMC: 7024277. DOI: 10.3390/molecules25020395. View

Mahgoub S, Hashad N, Ali S, Ibrahim R, Said A, Moharram F . Polyphenolic Profile of Aerial Parts: Antioxidant, Anticancer and In Silico 5-LOX Inhibitory Evaluations. Molecules. 2021; 26(9). PMC: 8123052. DOI: 10.3390/molecules26092481. View

Correia R, Fernandes B, Alves P, Carrondo M, Roldao A . Improving Influenza HA-Vlps Production in Insect High Five Cells via Adaptive Laboratory Evolution. Vaccines (Basel). 2020; 8(4). PMC: 7711658. DOI: 10.3390/vaccines8040589. View

Salesi M, Shojaie B, Farajzadegan Z, Salesi N, Mohammadi E . TNF-α Blockers Showed Prophylactic Effects in Preventing COVID-19 in Patients with Rheumatoid Arthritis and Seronegative Spondyloarthropathies: A Case-Control Study. Rheumatol Ther. 2021; 8(3):1355-1370. PMC: 8299175. DOI: 10.1007/s40744-021-00342-8. View

Muniandy K, Gothai S, Badran K, Suresh Kumar S, Mohd Esa N, Arulselvan P . Suppression of Proinflammatory Cytokines and Mediators in LPS-Induced RAW 264.7 Macrophages by Stem Extract of via the Inhibition of the NF-B Pathway. J Immunol Res. 2018; 2018:3430684. PMC: 6093060. DOI: 10.1155/2018/3430684. View

Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H . Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020; 130(5):2620-2629. PMC: 7190990. DOI: 10.1172/JCI137244. View

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270-273. PMC: 7095418. DOI: 10.1038/s41586-020-2012-7. View

Scialo F, Daniele A, Amato F, Pastore L, Matera M, Cazzola M . ACE2: The Major Cell Entry Receptor for SARS-CoV-2. Lung. 2020; 198(6):867-877. PMC: 7653219. DOI: 10.1007/s00408-020-00408-4. View

Alam S, Rashid M, Sarker M, Emon N, Arman M, Naina Mohamed I . Antidiarrheal, antimicrobial and antioxidant potentials of methanol extract of Colocasia gigantea Hook. f. leaves: evidenced from in vivo and in vitro studies along with computer-aided approaches. BMC Complement Med Ther. 2021; 21(1):119. PMC: 8042880. DOI: 10.1186/s12906-021-03290-6. View

10.

Giovinazzo G, Gerardi C, Uberti-Foppa C, Lopalco L . Can Natural Polyphenols Help in Reducing Cytokine Storm in COVID-19 Patients?. Molecules. 2020; 25(24). PMC: 7763290. DOI: 10.3390/molecules25245888. View

11.

Santos R, Sampaio W, Alzamora A, Motta-Santos D, Alenina N, Bader M . The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7). Physiol Rev. 2018; 98(1):505-553. PMC: 7203574. DOI: 10.1152/physrev.00023.2016. View

12.

Chen R, Wang K, Yu J, Howard D, French L, Chen Z . The Spatial and Cell-Type Distribution of SARS-CoV-2 Receptor ACE2 in the Human and Mouse Brains. Front Neurol. 2021; 11:573095. PMC: 7855591. DOI: 10.3389/fneur.2020.573095. View

13.

Raihan T, Rabbee M, Roy P, Choudhury S, Baek K, Azad A . Microbial Metabolites: The Emerging Hotspot of Antiviral Compounds as Potential Candidates to Avert Viral Pandemic Alike COVID-19. Front Mol Biosci. 2021; 8:732256. PMC: 8452873. DOI: 10.3389/fmolb.2021.732256. View

14.

Islam M, Sarkar C, El-Kersh D, Jamaddar S, Uddin S, Shilpi J . Natural products and their derivatives against coronavirus: A review of the non-clinical and pre-clinical data. Phytother Res. 2020; 34(10):2471-2492. DOI: 10.1002/ptr.6700. View

15.

Quimque M, Notarte K, Adviento X, Cabunoc M, de Leon V, Delos Reyes F . Polyphenolic Natural Products Active Against SARS-CoV-2 Spike Receptor Binding Domains and Non-structural Proteins - A Review. Comb Chem High Throughput Screen. 2021; 26(3):459-488. DOI: 10.2174/1386207325666210917113207. View

16.

Chung K . Stress Response and Pathogenicity of the Necrotrophic Fungal Pathogen Alternaria alternata. Scientifica (Cairo). 2013; 2012:635431. PMC: 3820455. DOI: 10.6064/2012/635431. View

17.

Notarte K, Quimque M, Macaranas I, Khan A, Pastrana A, Villaflores O . Attenuation of Lipopolysaccharide-Induced Inflammatory Responses through Inhibition of the NF-κB Pathway and the Increased NRF2 Level by a Flavonol-Enriched -Butanol Fraction from . ACS Omega. 2023; 8(6):5377-5392. PMC: 9933231. DOI: 10.1021/acsomega.2c06451. View

18.

Wu J, Li B, Tang C, Ke C, Zhu N, Qiu S . Callistemonols A and B, Potent Antimicrobial Acylphloroglucinol Derivatives with Unusual Carbon Skeletons from . J Nat Prod. 2019; 82(7):1917-1922. DOI: 10.1021/acs.jnatprod.9b00064. View

19.

Ebrahimi K, Ansari M, Hosseyni Moghaddam M, Ebrahimi Z, Salehi Z, Shahlaei M . In silico investigation on the inhibitory effect of fungal secondary metabolites on RNA dependent RNA polymerase of SARS-CoV-II: A docking and molecular dynamic simulation study. Comput Biol Med. 2021; 135:104613. PMC: 8256662. DOI: 10.1016/j.compbiomed.2021.104613. View

20.

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View