Broad-Spectrum Antiviral Therapeutics: From Conserved Vulnerabilities to Mechanism-Guided Drug Discovery

The continuous emergence and re-emergence of viral pathogens pose persistent threats to global health. Although direct-acting antivirals (DAAs) have transformed the treatment of multiple viral infections, their spectrum is often constrained by viral diversity and the rapid emergence of drug resistance. Host-targeted antivirals (HTAs) provide a complementary strategy by targeting cellular processes exploited by diverse viruses, but their development is limited by host toxicity and context-dependent viral dependence. Here, we propose that antiviral breadth is not an intrinsic property of a drug or target but an emergent phenotype governed by four interconnected determinants: conservation of biological vulnerability, viral dependency, chemical tractability, and therapeutic selectivity. We examine how these determinants shape the antiviral spectrum of both virus- and host-directed strategies and discuss key translational barriers, including metabolic compensation, viral adaptation, and the gap between in vitro activity and in vivo efficacy. We further propose a mechanism-guided framework that integrates viral evolution, host dependency, pharmacological tractability, intracellular exposure, and rational combination strategies to enable more predictive broad-spectrum antiviral discovery. Rather than seeking a universal antiviral, this framework supports the development of modular therapeutic strategies tailored to viral dependency, tissue context, and pharmacological constraints.