# Paradoxical G-quadruplex distribution in coronavirus genomes reveals functional constraints and antiviral therapeutic opportunities

## TL;DR

This paper finds that coronavirus genomes have a unique pattern of G-quadruplex structures, which could be used to develop new antiviral drugs.

## Contribution

The study identifies conserved and stable G-quadruplex structures in critical viral proteins as potential broad-spectrum antiviral targets.

## Key findings

- Coronavirus genomes show genome-wide depletion of G4s but strong regional enrichment in Spike and Nucleocapsid proteins.
- 38 stable G4 candidates were identified, with 52.6% located in Nucleocapsid regions.
- A primary G4 target (GGCTGGCAATGGCGG) is 54.8% conserved and highly stable (ΔG = −7.35 kcal/mol).

## Abstract

•Coronavirus G4 pattern: genome-wide depletion coupled with regional enrichment•Spike (IRR=17.9) and Nucleocapsid (IRR=15.2) show strong G4 enrichment•38 stable G4 candidates (ΔG < −5 kcal/mol) identified as therapeutic targets•Primary target GGCTGGCAATGGCGG: 54.8% conservation, ΔG = −7.35 kcal/mol•Betacoronavirus G4 conservation supports broad-spectrum antiviral strategies

Coronavirus G4 pattern: genome-wide depletion coupled with regional enrichment

Spike (IRR=17.9) and Nucleocapsid (IRR=15.2) show strong G4 enrichment

38 stable G4 candidates (ΔG < −5 kcal/mol) identified as therapeutic targets

Primary target GGCTGGCAATGGCGG: 54.8% conservation, ΔG = −7.35 kcal/mol

Betacoronavirus G4 conservation supports broad-spectrum antiviral strategies

We computationally characterized G-quadruplex (G4) distributions across 31 coronavirus genomes to identify conserved structural features as potential antiviral therapeutic targets. Through an integrated approach combining consensus G4 detection, dinucleotide-preserving null models, and pooled Poisson rate ratios, we identified a paradoxical G4 distribution pattern: genome-wide depletion (mean fold change = 0.56) coupled with strong regional enrichment in Spike (S) protein (incidence rate ratio [IRR] = 17.9; 95% CI: 11.7-27.6) and Nucleocapsid (N) protein (IRR = 15.2; 95% CI: 8.7-26.6), while untranslated regions (UTRs) showed complete G4 absence. Thermodynamic stability assessment identified 38 stable G4 candidates (ΔG < -5 kcal/mol), with 52.6% concentrated in Nucleocapsid protein regions, suggesting candidates for structure-based antiviral drug development awaiting experimental confirmation.

This paradoxical distribution pattern—genome-wide depletion coupled with strong regional enrichment in functionally critical proteins (Spike and Nucleocapsid)—provides a mechanistic framework for developing betacoronavirus-targeted therapeutics based on conserved G4 structures.