State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730046, China.
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
Virology. 2024 Dec;600:110283. doi: 10.1016/j.virol.2024.110283. Epub 2024 Oct 31.
African swine fever virus (ASFV) is the causative agent of African swine fever (ASF), a hemorrhagic illness with high fatality rates in domestic pigs that has resulted in a substantial socio-economic loss and threatens the global pork industry. Very few safe and efficient vaccines or compounds against ASF are commercially available, thus developing new antiviral strategies is urgently required. Targeted protein degradation (TPD) has emerged as one of the most innovative strategies for drug discovery. In this study, we generate Nanobody-based TRIM-aways specifically binding with and targeting ASFV-encoded structural proteins p30, p54, and p72 for degradation. Furthermore, nanobody-based trim-aways exhibit robust viral structural protein degradation capabilities in ASFV-infected iPAM and MA104 cells through both proteasomal and lysosomal pathways, concurrently demonstrating potent anti-ASFV activity with less viral production. Our study highlights the Nanobody-based TRIM-away targeting viral protein degradation as a potential candidate for the development of a novel antiviral strategy against ASF.
非洲猪瘟病毒（ASFV）是非洲猪瘟（ASF）的病原体，ASF 是一种高致死率的猪出血性疾病，给全球养猪业造成了巨大的经济损失和威胁。目前，市场上可获得的针对 ASF 的安全有效的疫苗或化合物非常少，因此迫切需要开发新的抗病毒策略。靶向蛋白降解（TPD）已成为药物发现最具创新性的策略之一。在这项研究中，我们生成了基于纳米抗体的 TRIM-aways，它们特异性结合并靶向 ASFV 编码的结构蛋白 p30、p54 和 p72 进行降解。此外，基于纳米抗体的 TRIM-aways 通过蛋白酶体和溶酶体途径在感染 ASFV 的 iPAM 和 MA104 细胞中显示出强大的病毒结构蛋白降解能力，同时具有较低的病毒产量和强大的抗 ASFV 活性。我们的研究强调了基于纳米抗体的靶向病毒蛋白降解的 TRIM-aways 作为开发针对 ASF 的新型抗病毒策略的潜在候选物。
