Witwit Haydar, Cubitt Beatrice, Khafaji Roaa, Castro Esteban M, Goicoechea Miguel, Lorenzo Maria M, Blasco Rafael, Martinez-Sobrido Luis, de la Torre Juan C
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
Viruses. 2025 Jan 13;17(1):92. doi: 10.3390/v17010092.
The ongoing monkeypox (mpox) disease outbreak has spread to multiple countries in Central Africa and evidence indicates it is driven by a more virulent clade I monkeypox virus (MPXV) strain than the clade II strain associated with the 2022 global mpox outbreak, which led the WHO to declare this mpox outbreak a public health emergency of international concern. The FDA-approved small molecule antiviral tecovirimat (TPOXX) is recommended to treat mpox cases with severe symptoms, but the limited efficacy of TPOXX and the emergence of TPOXX resistant MPXV variants has challenged this medical practice of care and highlighted the urgent need for alternative therapeutic strategies. In this study we have used vaccinia virus (VACV) as a surrogate of MPXV to assess the antiviral efficacy of combination therapy of TPOXX together with mycophenolate mofetil (MMF), an FDA-approved immunosuppressive agent that we have shown to inhibit VACV and MPXV, or the N-myristoyltransferase (NMT) inhibitor IMP-1088. Both MMF and IMP-1088 drugs exhibited strong dose-dependent antiviral activity against VACV and mpox, and potent synergistic effects in conjunction with TPOXX. Our findings support combination therapy of direct-acting (TPOXX) and host-targeted (MMF and IMP-1088) antivirals as a promising approach to treat mpox and prevent the emergence and spread of TPOXX-resistant MPXV variants.
目前正在爆发的猴痘疫情已蔓延至中非的多个国家，有证据表明，与2022年全球猴痘疫情相关的II型毒株相比，此次疫情是由更具毒性的I型猴痘病毒（MPXV）毒株引发的，这使得世界卫生组织宣布此次猴痘疫情为国际关注的突发公共卫生事件。美国食品药品监督管理局（FDA）批准的小分子抗病毒药物tecovirimat（TPOXX）被推荐用于治疗症状严重的猴痘病例，但TPOXX疗效有限以及TPOXX耐药MPXV变体的出现对这种治疗方法构成了挑战，并凸显了对替代治疗策略的迫切需求。在本研究中，我们使用痘苗病毒（VACV）作为MPXV的替代物，以评估TPOXX与霉酚酸酯（MMF）联合治疗的抗病毒效果，MMF是一种FDA批准的免疫抑制剂，我们已证明它能抑制VACV和MPXV，或N-肉豆蔻酰转移酶（NMT）抑制剂IMP-1088。MMF和IMP-1088药物对VACV和猴痘均表现出强烈的剂量依赖性抗病毒活性，并与TPOXX产生强大的协同效应。我们的研究结果支持直接作用抗病毒药物（TPOXX）与宿主靶向抗病毒药物（MMF和IMP-1088）联合治疗，作为治疗猴痘和预防TPOXX耐药MPXV变体出现和传播的一种有前景的方法。
