Angum M. M. Ibrahim, Ranadheer Reddy Challa, Bhaskar Vallamkonda, V. V. Sesha Mohan, Dharani Prasad P, Shaik Kareemulla, Malarkodi Velraj
INTRODUCTION: Viral infections continue to pose a significant health problem to all parts of the world because of a high rate of mutation and the ability to resist traditional single-target antivirals. Multi-target inhibition of core viral proteins (main protease, RNA-dependent RNA polymerase, and spike glycoprotein) with plant metabolites as the target of drug discovery is a promising alternative. This review presented a systematic review of the antiviral potential and mechanism of plantderived compounds published from 2020 to 2025. MATERIALS AND METHODS: The systematic search of the literature was performed with the help of PubMed, Scopus, Web of Science, Science Direct, and EMBASE in accordance with PRISMA 2020. Peer-reviewed articles that reported precise molecular targets, quantifiable antiviral activity (IC50, EC50 or %inhibition), and mechanistic information were included. Qualitative synthesis of data was done because of heterogeneity in methodology. RESULTS: Sixty studies were eligible. Flavonoids (quercetin, kaempferol) had an inhibitory effect on viral protease and polymerase with an IC50 value of 2-12 μM. The terpenoids (glycyrrhizin, betulinic acid) inhibited spike-ACE2 binding and viral fusion with up to 80% infectivity in vitro. The polymerases of hepatitis and influenza viruses were inhibited by polyphenols (EGCG, resveratrol). The bioavailability increased 150-200% with nano formulations, which enhanced therapeutic potency. DISCUSSION: Metabolites of plants have direct antiviral and host immunomodulatory properties. Nevertheless, a lack of clinical validation and inconsistency in the standardization of phytochemicals are critical issues. CONCLUSION: Plant-based metabolites are highly promising, multi-target antiviral leads. Nanotechnology, together with standardized pharmacological assessment and enhanced regulatory validation, has the potential to hasten clinical translation of plant metabolites into safe, broad-spectrum antiviral therapies.