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Structural Basis for the Understanding of Entry Inhibitors against SARS Viruses

Author(s):

Prem Kumar Kushwaha, Neha Kumari, Sneha Nayak, Keshav Kishor and Ashoke Sharon*   Pages 1 - 16 ( 16 )

Abstract:


Outbreaks due to Severe Acute Respiratory Syndrome-Corona virus 2 (SARSCoV- 2) initiated in Wuhan city, China, in December 2019 and continued to spread Internationally, posing a pandemic threat as declared by WHO and as of March 10, 2021, confirmed cases reached 118 million along with 2.6 million deaths worldwide. In the absence of specific antiviral medication, symptomatic treatment and physical isolation remain the options to control the disease and contagion. The recent clinical trials on antiviral drugs highlighted some promising compounds such as umifenovir (haemagglutininand has only 70% similarity to SAmediated fusion inhibitor), remdesivir (RdRp nucleoside inhibitor), and favipiravir (RdRp Inhibitor). WHO launched a multinational clinical trial on several promising analogs as a potential treatment to combat SARS infection. This situation urges a holistic approach to invent safe and specific drugs as a prophylactic and therapeutic cure for SARS-related viral diseases, including COVID-19. It is significant to note that researchers worldwide have been doing their best to handle the crisis and have produced an extensive and promising literature body. It opens a scope and allows understanding the viral entry at the molecular level. A structure-based approach can reveal the molecular-level understanding of viral entry interaction. The ligand profiling and non-covalent interactions among participating amino-acid residues are critical information to delineate a structural interpretation. The structural investigation of SARS virus entry into host cells will reveal the possible strategy for designing drugs like entry inhibitors. The structure-based approach demonstrates details at the 3D molecular level. It shows specificity about SARS-CoV-2 spike interaction, which uses human angiotensin-converting enzyme 2 (ACE2) as a receptor for entry, and the human protease completes the process of viral fusion and infection. The 3D structural studies reveal the existence of two units, namely S1 and S2. S1 is called a receptor-binding domain (RBD) and responsible for interacting with the host (ACE2), and the S2 unit participates in the fusion of viral and cellular membranes. TMPRSS2 mediates the cleavage at the S1/S2 subunit interface in the S-protein of SARS CoV-2, leading to viral fusion. Conformational difference associated with S1 binding alters ACE2 interaction and inhibits viral fusion. Overall, the detailed 3D structural studies help understand the 3D structural basis of interaction between viruses with host factors and open scope for the new drug discovery process targeting SARS-related virus entry into the host cell.

Keywords:

Severe acute respiratory syndrome (SARS), SARS-CoV2, COVID-19, receptor-binding domain (RBD), protein-protein interface, entry inhibitors.

Affiliation:

Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhand



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