Sequence and structure conservation analysis of the key coronavirus proteins supports the feasibility of discovering broad-spectrum antiviral medications.

Abstract

Coronaviruses are a class of single-stranded, positive-sense RNA viruses that have caused three notable outbreaks over the past two decades: Middle East respiratory syndrome–related coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). All outbreaks have been associated with significant morbidity and mortality. In this study, we hypothesized that conserved binding sites in the key coronavirus proteins can be explored for the development of broad-spectrum direct acting anti-coronaviral compounds, identified such conserved binding site residues across coronaviruses, and validated our hypotheses with existing experimental data. We have identified four coronaviral proteins with highly conserved binding site sequence and 3D structure similarity: PLpro, Mpro, nsp10-nsp16 complex(methyltransferase), and nsp15 endoribonuclease. We have compiled all available experimental data for known antiviral medications inhibiting these targets and identified compounds active against multiple coronaviruses. The identified compounds representing potential broad-spectrum antivirals include: GC376, which is active against six viral Mpro (out of six tested, as described in research literature); mycophenolic acid, which is active against four viral PLpro (out of four); and emetine, which is active against four viral RdRp (out of four). The approach described in this study for coronaviruses, which combines the assessment of sequence and structure conservation across a viral family with the analysis of accessible chemical structure – antiviral activity data, can be explored for the development of broad-spectrum drugs for multiple viral families.

Enhancing Protein Function Prediction Performance by Utilizing AlphaFold-Predicted Protein Structures

“…As biological macromolecules, protein is an indispensable component of all cells and tissues, accounting for ∼15.1% of the body weight . Enzyme catalysis, hormone regulation, antibody immunity, and other processes are inseparable from the participation of proteins, and which proteins are involved in these different processes depends on the structure of the proteins . For example, globulin with an approximately spherical shape can specifically identify the depression or fissure site of other compounds, whereas keratin, which consists of polypeptide chains in α-helix or β-folded conformations, plays a protective role in epithelial cells.…”