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Identification of Leads against Chronic Obstructive Pulmonary Disease from natural and synthetic sources

IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata


Field	Value

Title	Identification of Leads against Chronic Obstructive Pulmonary Disease from natural and synthetic sources

Creator	Sengupta, Sayantan

Subject	Cell Biology & Physiology

Description	Asthma and chronic obstructive pulmonary disease (COPD) are significant and growing global health issues. About 80–90% of all COPD cases worldwide are caused by smoking. Emphysema is predominantly brought on by neutrophil elastase in COPD, which results in the loss of lung tissue and the closure of tiny airways. When it comes to the advancement of the disease in COPD patients, neutrophil elastase has become a crucial target for therapeutic development. The Indian Sundarban regions are home to a variety of mangrove plants, including Sonneratia apetala Buch.-Ham. Fruit and leaf extracts have been demonstrated to alleviate the symptoms of cough and asthma, despite the fact that the plant's fruits also include antibacterial, antifungal, antioxidant, and astringent properties. This study aims to determine if fruit extracts of Sonneretia apetala inhibit neutrophil elastase and so stop the advancement of lung emphysema caused by neutrophil elastase. The IC50 of the hydroalcoholic extract of the fresh fruits of Sonneratia apetala Buch.-Ham. (SAM) was calculated using the neutrophil elastase enzyme kinetic test. The extract was standardised using gallic acid and ellagic acid as standards using the new HPLC technique. The extract underwent additional LC-MS2 profiling to determine the main phytochemicals and ten such compounds were identified. According to the HPLC calibration, Sonneretia apetala crude extract (SAM) contains 53 g/mg of gallic acid and 95 g/mg of ellagic acid. Human epithelial cells' in vitro morphological change caused by elastase was likewise reversed by SAM, and the vitality was determined by an MTT experiment which showed no toxicity of the herbal extracts. Furthermore, in the mice model, neutrophil elastase-induced alveolar collapse was lessened by 10mg/kg SAM. Thus, we discovered for the first time in this work that Sonneretia apetala fruit extract (SAM) has the ability to both in vitro and in vivo block human neutrophil elastase. In a quest for novel synthetic neutrophil elastase inhibitors, we synthesised and tested seven brand-new benzoxazinone derivatives. By using an enzyme substrate kinetic assay and discovered that they were inhibitors of human neutrophil elastase. One of these substances, PD05, became the most effective inhibitor with a lower IC50 compared to the sivelestat control substance. ONO 6818 and AZD9668 are two well-known elastase inhibitors. However, PD05 demonstrated a high binding affinity for human neutrophil elastase (Kd=1.63nM) and a faster association and dissociation rate, and its interaction with human neutrophil elastase was totally reversible. In vitro preclinical pharmacokinetic investigations revealed a protein binding efficiency of 72%, a rapid recovery rate, an aqueous solubility of 194.7μM, a low permeability, and a favourable hERG. The chemical successfully inhibited elastase-induced rounding and retracted cell morphology and cell cytotoxicity, per the experiments with human lung epithelial cell lines. In a mouse model, neutrophil elastase-induced alveolar collapse can be decreased by PD05. In conclusion, we show that the newly synthesised benzoxazinone derivative PD05 has anti-elastase capability in situ, in vitro, and in vivo, making it a suitable option for additional research as a COPD treatment.

Date	2022

Type	Thesis NonPeerReviewed

Format	application/pdf

Identifier	http://www.eprints.iicb.res.in/2865/1/Thesis_Sayantan_Sengupta_ID_No_8354%2D_Dr_Arun_Bandyopadhyay.pdf Sengupta, Sayantan (2022) Identification of Leads against Chronic Obstructive Pulmonary Disease from natural and synthetic sources. PhD thesis, JADAVPUR UNIVERSITY.

Relation	http://www.eprints.iicb.res.in/2865/