Targeting MPXV I7L Protease: Promising New Antiviral Strategy for Mpox, Suggests Review

Although targeting the monkeypox virus (MPXV) I7L core protease is a promising antiviral strategy, its clinical translation is hindered by poorly understood safety and selectivity profiles. To bridge this gap, Hinpetch Daungsupawong of Laos and Viroj Wiwanitkit of Saveetha University in India reviewed these key challenges to outline a clear path toward effective treatments.

Therefore, the clinical review was designed as a scientific perspective and qualitative literature analysis, rather than an empirical trial, meaning it utilized no clinical population, sample size, trial duration, or clinical exclusion criteria. Instead, the authors evaluated published molecular data on I7L core protease inhibitors, focusing on translating in vitro potency to in vivo efficacy as the primary analytical endpoint.

Key Clinical Findings of the Study Includes:

• Inhibitor Profiles Compared: Investigators reviewed how the synthetic covalent inhibitor A68 demonstrates high in vitro potency, whereas natural compounds like shikonin and myricetin show only moderate enzymatic inhibition.

• Structural Binding Gaps: Researchers highlighted that shikonin suffers from unconfirmed structural binding and poor bioavailability, while myricetin lacks specificity data against the viral protease.

• Repurposing Toxicity Risks: Reviewers cautioned that repurposed compounds originally designed for coronavirus disease 2019 (COVID-19) require extensive off-target toxicity screening to prevent unintended interactions with human proteins.

• In Vivo Pharmacokinetic Obstacles: Analysts emphasized that preclinical animal testing is critical to evaluate whether these promising molecules can reach therapeutic concentrations in serum and target tissues.

• Synergistic Combination Therapies: Authors proposed that combining protease inhibitors with immunomodulators or vaccines can optimize treatment outcomes by simultaneously boosting immune responses and blocking replication.

The results suggest that targeting the I7L core protease represents a highly viable antiviral strategy, but translating this to a clinical reality requires addressing key research gaps in structure-function relationships, in vivo pharmacokinetics, and off-target safety profiles. Expanding compound databases and implementing synergistic combination regimens will be essential steps to accelerate the delivery of safe, optimized therapies for future outbreak control.

Thus, the review concludes clinicians should consider that managing monkeypox infections effectively may ultimately depend on a multi-pronged therapeutic approach that combines protease inhibitors with other antiviral strategies, such as vaccines and immunomodulatory agents, rather than relying on monotherapy.

Although the review is currently limited by the lack of living-organism data for these protease inhibitors, it highlights an urgent clinical opportunity to transition these compounds into animal model testing to resolve their precise in vivo safety, bioavailability, and therapeutic dosing schedules.

Reference

Daungsupawong H, Wiwanitkit V. Targeting the monkeypox virus: Protease inhibitors, selectivity, and in vivo efficacy. Indian J Allergy Asthma Immunol 2026;40:9-11.