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COVID-2019: The role of the nsp2 and nsp3 in its pathogenesis

Silvia Angeletti1, Domenico Benvenuto2, Martina Bianchi3

  • 1Unit of Clinical Laboratory Science, University Campus Bio-Medico of Rome, Rome, Italy.

Journal of Medical Virology
|February 22, 2020
PubMed

Insights

Analysis of the novel Coronavirus (COVID-2019) Open Reading Frame 1ab (ORF1ab) revealed mutations under selective pressure. These genetic changes in nsp2 and nsp3 proteins may explain COVID-2019

Area of Science:

  • Virology
  • Molecular Biology
  • Genomics

Background:

  • The novel Coronavirus (COVID-2019) emerged in Wuhan, China, in December 2019, causing severe pneumonia with limited understanding of its pathogenesis.
  • The Open Reading Frame 1ab (ORF1ab) is crucial for viral replication and represents a potential target for therapeutic interventions.

Purpose of the Study:

  • To analyze the selective pressure on the COVID-2019 ORF1ab to identify mutations potentially influencing viral pathogenesis and transmissibility.
  • To investigate the structural and functional implications of identified mutations in non-structural proteins (nsp2 and nsp3).

Main Methods:

  • Selective pressure analysis using fast-unconstrained Bayesian approximation (FUBAR).
  • Homology modeling performed with SwissModel and HHPred servers.
  • Transmembrane helical segment prediction using TMHMM, MEMSAT, and MEMPACK tools; 3D structure visualization with PyMOL.

Main Results:

  • FUBAR analysis identified potential sites under positive selective pressure (P < .05), including specific amino acid substitutions (e.g., Serine at position 723, Proline at 1010).
  • Significant pervasive negative selection was found in 55% of sites (2416 sites, P < .05).
  • A stabilizing mutation in nsp2's endosome-associated-protein-like domain may enhance COVID-2019's contagiousness, while a destabilizing mutation in nsp3 could differentiate it from SARS.

Conclusions:

  • Identified mutations under selective pressure provide insights into COVID-2019's unique clinical features and high transmissibility.
  • Structural analysis of nsp2 and nsp3 mutations offers potential therapeutic targets and vaccine strategies for combating the ongoing epidemic.

Keywords:
epidemiologyinfectionpandemicspathogenesisprotein-protein interaction analysisresearch and analysis methods

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