Structural Insight into the Binding of Cyanovirin-N with the Spike Glycoprotein, Mpro and PLpro of SARS-CoV-2: Protein-Protein Interactions, Dynamics Simulations and Free Energy Calculations.

Ayan Roy,Pallab Kar,Taurai Mutanda,Joseph Bwapwa,Devashan Naidoo,Arnab Sen,Akash Anandraj

doi:10.3390/molecules26175114

Abstract

The emergence of COVID-19 continues to pose severe threats to global public health. The pandemic has infected over 171 million people and claimed more than 3.5 million lives to date. We investigated the binding potential of antiviral cyanobacterial proteins including cyanovirin-N, scytovirin and phycocyanin with fundamental proteins involved in attachment and replication of SARS-CoV-2. Cyanovirin-N displayed the highest binding energy scores (−16.8 ± 0.02 kcal/mol, −12.3 ± 0.03 kcal/mol and −13.4 ± 0.02 kcal/mol, respectively) with the spike protein, the main protease (Mpro) and the papainlike protease (PLpro) of SARS-CoV-2. Cyanovirin-N was observed to interact with the crucial residues involved in the attachment of the human ACE2 receptor. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson–Boltzmann surface area (MM-PBSA) approach revealed that all forms of energy, except the polar solvation energy, favourably contributed to the interactions of cyanovirin-N with the viral proteins. With particular emphasis on cyanovirin-N, the current work presents evidence for the potential inhibition of SARS-CoV-2 by cyanobacterial proteins, and offers the opportunity for in vitro and in vivo experiments to deploy the cyanobacterial proteins as valuable therapeutics against COVID-19.

Highlights

The genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), associated with the COVID-19 pandemic, encodes several structural and non-structural proteins that play pivotal roles in host attachment, infection and replication [1,2]
We recently reported on the potential of small molecules from cyanobacteria as promising therapeutic candidates against the main protease (Mpro) and the papainlike protease (PLpro) of SARS-CoV-2 [21]
We investigated the potential for the inhibition of the SARS-CoV-2 spike protein, Mpro and PLpro [27,28] by antiviral cyanobacterial proteins; cyanovirin-N [29], scytovirin [30] and phycocyanin [31] employing molecular docking approach

Summary

Introduction

The genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), associated with the COVID-19 pandemic, encodes several structural and non-structural proteins that play pivotal roles in host attachment, infection and replication [1,2]. SARS-CoV-2 enters and infects the human host through interactions of the viral spike glycoprotein with the host receptor angiotensin-converting enzyme II (ACE2) and the process is mediated by the S1 subunit of the spike protein [3]. The virus enters endosomes and the subsequent cleavage of the spike by TMPRSS2 results in the fusion of viral and lysosomal membranes [7,8]. SARS-CoV-2 infection causes damage to the alveolar wall leading to increased thrombus burden in pulmonary capillaries leading to acute respiratory distress syndrome [10,11]. Chemokines and cytokines are released in response to an influx of infectious viral particles to establish normal immune responses [12]

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Conclusion