Molecular Therapeutic Development Against SARS-CoV-2: Structural Insights and Comparative Cellular Antiviral Evaluation with Established Antivirals

The continuous evolution of SARS-CoV-2 and the practical limitations of current monotherapies, such as narrow therapeutic windows and rapid drug degradation, underscore the urgent need for innovative antiviral strategies. This study evaluates a novel niclosamide–nafamostat cocrystal (NNC), a dual-action supramolecular system engineered to combine two pharmacologically complementary agents within a single crystalline lattice. Fabricated via a solution precipitation method, successful cocrystallization and structural integration were verified through complementary spectroscopic and solid-state analyses. Results revealed a distinct multi-component phase held together by a stable network of intermolecular hydrogen bonds. In biological evaluations against the virus, the cocrystal demonstrated exceptional antiviral potency, dramatically outperforming standard clinical references including remdesivir, chloroquine, and lopinavir. Dose-dependent profiles showed that the cocrystal sustains near-complete viral suppression well into sub-micromolar thresholds where conventional monotherapies completely lose their effectiveness. Furthermore, cytotoxicity assays revealed a unique safety profile characterized by a stable cell-viability plateau, ensuring that host cells remain highly viable even at maximum therapeutic concentrations. This optimal balance of extreme potency and low acute toxicity yielded an outstanding selectivity index that completely outclasses the reference standards. By simultaneously targeting host-mediated viral entry and downstream endosomal acidification while overcoming the individual solubility and stability flaws of its parent drugs, the cocrystal establishes a highly cooperative antiviral architecture. These findings validate pharmaceutical cocrystallization as a powerful strategy for optimizing drug performance and provide a strong foundation for future preclinical development.