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

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.