Antiviral drug discovery for enterovirus 71: structure-based optimization of direct and host-targeted strategies

Enterovirus 71 (EV71) is a major pathogen causing severe and fatal hand, foot, and mouth disease. Its strong neurotropism and rapid evolution pose an ongoing threat to infants and young children. To date, no specific antiviral drug against EV71 has been approved, leaving a critical gap in clinical management. This review summarizes recent progress in the search for anti-EV71 drugs. The structural features of EV71 and key steps in its life cycle, including entry and replication, are first described. The evolution of drug discovery technologies is then traced, from traditional cytopathic effect-based screening to modern platforms such as computer-assisted virtual screening, reporter-carrying pseudovirus systems, and high-content imaging. Next, two main antiviral strategies are discussed: direct-acting agents that target the viral capsid, protease, and polymerase, and host-targeted approaches that modulate virus-dependent pathways including metabolism, signal transduction, and immune responses. In addition, the review highlights recent medicinal chemistry efforts in structure-based optimization of EV71 inhibitors, covering side-chain modifications, cyclization, prodrug design, and covalent binding engineering. By summarizing the mechanisms, optimization strategies, and current state of candidate drugs, this review aims to provide a practical reference for the development of antivirals against EV71 and other enteroviruses.