Exploration of the protein and pharmacological landscape of monkeypox virus treatment: from entry point to end point.

The re-emergence of monkeypox virus (MPXV), renamed mpox, as a global health emergency in 2022 has intensified the search for robust therapeutic interventions. This review summarizes the virological, structural, and pharmacological dimensions of MPXV, with a focus on the virus's lifecycle from host cell entry to dissemination. MPXV's double-stranded DNA genome exhibits clade-specific plasticity, with variations in genes like OPG065 and MOPICE driving virulence, immune evasion, and host adaptation. Key viral proteins, including entry facilitators A27L and L1R, envelope protein F13L (VP37), and immune modulators such as B19R and C12L, serve as critical targets for antiviral strategies. Structural insights from cryo-EM and X-ray crystallography reveal conserved motifs across orthopoxviruses, enabling pan-orthopox drug design. Current therapeutics, such as tecovirimat (targeting VP37 to block egress), brincidofovir, and cidofovir (inhibiting DNA polymerase E9L), offer symptomatic relief but face hurdles like resistance mutations (e.g., A314V in E9L) and suboptimal efficacy in immunocompromised patients. Emerging resistance underscores the need for vigilant genomic surveillance. Novel modalities, including monoclonal antibodies against antigenic proteins like A35R and M1R, cytokine-based immunotherapies, and host-directed agents modulating autophagy or interferon pathways, show promise. Computational approaches integrating AI-driven screening, molecular dynamics simulations, and multi-omics have pinpointed repurposed candidates like lumacaftor and conivaptan as VP37 inhibitors. This integrative framework advocates for combination therapies, personalized regimens based on clade profiling, and global collaboration to mitigate MPXV's adaptive potential. By bridging virology and pharmacology, the review charts pathways for innovative drug development to combat this zoonotic threat effectively.