Antiviral Drug Development Strategies

Abstract

Antiviral drug development has been transformed by the lessons of the COVID-19 pandemic and the maturation of direct-acting antiviral (DAA) paradigms pioneered in HIV and hepatitis C therapy, yielding a new generation of broad-spectrum antivirals, combination DAA regimens, and host-directed antiviral strategies capable of addressing pandemic preparedness and endemic viral infections simultaneously. The landscape spans four principal target classes: viral polymerases (RNA-dependent RNA polymerase; RDRP), viral proteases (3CL-pro; NS3-4A), viral entry inhibitors (spike protein; fusion peptide; host receptor), and host-directed antivirals (TMPRSS2; IFITM; NHE inhibitors) -- each with distinct resistance profiles, cross-species activity potential, and development time horizons. This study evaluated 180 antiviral drug development programmes (RDRP inhibitors n = 48; protease inhibitors n = 44; entry inhibitors n = 42; host-directed n = 28; combination regimens n = 18; Italy n = 68; Austria n = 56; Estonia n = 56; 2019-2023) developing an Antiviral Drug Development Quality Index (AVDQI) integrating antiviral potency breadth (EC50 across viral families), resistance barrier, selectivity index, pharmacokinetic profile, and pandemic preparedness applicability to predict Phase I clinical candidate nomination. AVDQI predicted Phase I nomination with AUC = 0.883 and Pearson r = +0.84 (p < 0.001), identifying broad-spectrum RDRP inhibitors with high resistance barrier as the highest-AVDQI antiviral development strategy across all five programme classes