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Polyphenolic compounds isolated from marine algae; potent inhibitors in SARS-CoV-2 proteases and cell entry

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Abstract
The recent pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has raised global health concern. The identified coronavirus expressed significant differences from the other respiratory pathogens such as severe acute respiratory coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), influenza, adenovirus, and avian influenza. The actual infection mechanism of SARS-CoV-2 is still unrevealed 100% such as why the virus has selected humans as a principal host and how to escape the innate immune system. However, the viral entry mechanism has been identified and it invades the human body through the respiratory system using respiratory droplets via sneeze and cough.
SARS-CoV-2 consists of protein capsid covered by glycoprotein with anchored spike proteins. These spike proteins initiate the viral entry into target cells. Entry of SARS-CoV-2 into the host cell is an important factor to determine the infectivity and pathogenesis. SARS-CoV-2 spike protein initially binds to the cell surface receptor called angiotensin-converting enzyme 2 (ACE-2) and this is known as viral attachment, subsequently, enter to endosome and finally viral membrane fuse with lysosomal membrane. Thus, if some particular compound has a potential to interfere with the interaction of ACE-2: RBD of spike protein of SARS-CoV-2, it has a potential for using against SARS-CoV-2 cell entry mechanism.
Among the excellent drug targets of SARS-CoV-2 are its proteases (NSP 3 and NSP 5) that play vital role in polyprotein processing giving rise to functional non-structural proteins, essential for viral replication and survival. Nsp5 (also known as 3CLpro) hydrolyses replicase polyprotein (1ab) at eleven different sites. The resulted products are important for survival and replication of virus in host cell. The papain-like protease (PLpro) cleaves the viral polyprotein, and reverses inflammatory ubiquitin and anti-viral ubiquitin-like ISG15 protein modifications. Therefore, Drugs that target SARS-CoV-2 PLpro may hence be effective as treatments or prophylaxis for covid-19, reducing viral load and reinstating innate immune responses.
The SARS-CoV-2 infection and replication is a complex mechanism and this aspect suggests that a COVID-19 therapy by a multi-targeting approach is the right way. Bioactive components from marine algae have provided new insight to the natural product research. The present study aims to inhibit SARS-CoV-2 through 3CLpro, PLpro, and SARS-CoV-2 cell entry mechanism by natural products isolated from marine algae. Molecular docking was utilized for the initial screening of selected natural products based on the 3CLpro, PLpro, and ACE-2 protein structures. Moreover, the resulted compounds were isolated and used for biological assays for further confirmation of the inhibition activity. To the best of our knowledge, this is the first report concerning the assessment of marine natural products on 3CLpro, PLpro, and ACE-2 of SARS-CoV-2.
Author(s)
D.P. Nagahawatta
Issued Date
2021
Awarded Date
2021. 2
Type
Dissertation
URI
https://oak.jejunu.ac.kr/handle/2020.oak/23501
Affiliation
제주대학교 대학원
Department
대학원 해양생명과학과
Advisor
Jeon, You Jin
Table Of Contents
Summary iii
List of figures v
List of Tables viii
Polyphenolic compounds isolated from marine algae; potent inhibitors in SARS-CoV-2 proteases and cell entry 1
1. Introduction 2
2. Methods and Materials 8
2.1 Chemicals and reagents 8
2.2 Preparation of Receptors 8
2.3. Preparation of ligands 9
2.4 Molecular docking 11
2.5 Sample collection and extraction 11
2.6 Isolation of Ishophloroglucin A 12
2.7 Isolation of Dieckol 14
2.8 Isolation of Eckmaxol 15
2.9 3CLpro in-vitro cleavage inhibition assay 17
2.10 PLpro in-vitro cleavage inhibition assay 17
2.11 Inhibition assay in binding of ACE-2 receptor and SARS-CoV-2 spike protein 18
2.12 Statistical analysis 19
3. Results 20
3.1 Receptor and ligand preparation 20
3.1.1. Structure of ACE-2 receptor protein preparation 20
3.1.2. Structure of 3CLpro receptor protein preparation 22
3.1.3 Structure of PLpro receptor protein preparation 24
3.1.4 Ligand preparation 26
3.2 Molecular docking 28
3.2.1. ACE-2 enzyme 32
3.2.2. 3CLpro enzyme 34
3.2.3. PLpro enzyme 37
3.3 In-vitro inhibition of marine algal compounds 40
4. Discussion 43
5. Conclusions 46
Acknowledgment 47
References 48
Degree
Master
Publisher
제주대학교 대학원
Citation
D.P. Nagahawatta. (2021). Polyphenolic compounds isolated from marine algae; potent inhibitors in SARS-CoV-2 proteases and cell entry
Appears in Collections:
General Graduate School > Marine Life Sciences
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