ABSTRACT The 2022 global mpox outbreak and subsequent viral evolution have exposed critical limitations in current therapeutic strategies, which predominantly rely on repurposed smallpox drugs targeting a narrow range of viral proteins. This review provides a timely and comprehensive evaluation of the mpox antiviral landscape, spanning from established clinical agents to cutting‐edge preclinical candidates. We critically analyse the ‘clinical translation gap’ observed in recent clinical trials (e.g., STOMP and PALM007), attributing the limited efficacy in mild cases to host immunopathological responses versus primary viral replication. Highlighting a strategic paradigm shift, we also discuss the 2025 breakthrough in covalent inhibitors targeting the conserved CorePro. Furthermore, we explore the integration of AI‐assisted drug design and host‐targeted therapies (HTTs) to elevate resistance barriers. By synthesising these emerging targets and multidimensional strategies, this review serves as a strategic roadmap for developing next‐generation anti‐mpox therapeutics with optimised efficacy and broader resistance profiles.
Hou et al. (Mon,) studied this question.