Adeyinka Olawale S, Barrera Michael D, Metibemu Damilohun S, Boghdeh Niloufar, Anderson Carol A, Baha Haseebullah, Crown Olamide, Falode John Adeolu, Bleach Janard L, Bliss Amanda R, Hampton Tamia P, Ojobor Jane-Frances Chinenye, Alem Farhang, Narayanan Aarthi, Ogungbe Ifedayo Victor
Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, Alabama 35899, United States.
Department of Biology, College of Science, George Mason University, Fairfax, Virginia 22030, United States.
ACS Infect Dis. 2025 Jan 10;11(1):181-196. doi: 10.1021/acsinfecdis.4c00701. Epub 2024 Dec 31.
New World alphaviruses, including Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV), are mosquito-transmitted viruses that cause disease in humans. These viruses are endemic to the western hemisphere, and disease in humans may lead to encephalitis and long-term neurological sequelae. There are currently no FDA-approved vaccines or antiviral therapeutics available for the prevention or treatment of diseases caused by these viruses. The alphavirus nonstructural protein 2 (nsP2) functions as a protease, which is critical for the establishment of a productive viral infection by enabling accurate processing of the nsP123 polyprotein. Owing to the essential role played by nsP2 in the alphavirus infectious process, it is also a valuable therapeutic target. In this article, we report the synthesis and evaluation of novel small molecule inhibitors that target the alphavirus nsP2 protease via a covalent mode of action. The two lead compounds demonstrated robust inhibition of viral replication . These inhibitors interfered with the processing of the nsP123 polyprotein as determined using VEEV TC-83 as a model pathogen and are active against EEEV and WEEV. The compounds were found to be nontoxic in two different mouse strains and demonstrated antiviral activity in a VEEV TC-83 lethal challenge mouse model. Cumulatively, the outcomes of this study provide a compelling rationale for the preclinical development of nsP2 protease inhibitors as direct-acting antiviral therapeutics against alphaviruses.
新大陆甲病毒，包括委内瑞拉马脑炎病毒（VEEV）、东部马脑炎病毒（EEEV）和西部马脑炎病毒（WEEV），是通过蚊子传播的病毒，可导致人类患病。这些病毒在西半球流行，人类感染该病毒可能会引发脑炎和长期神经后遗症。目前尚无美国食品药品监督管理局（FDA）批准的用于预防或治疗由这些病毒引起疾病的疫苗或抗病毒疗法。甲病毒非结构蛋白2（nsP2）具有蛋白酶功能，通过对nsP123多蛋白进行精确加工，对建立有效的病毒感染至关重要。由于nsP2在甲病毒感染过程中发挥着重要作用，它也是一个有价值的治疗靶点。在本文中，我们报告了通过共价作用模式靶向甲病毒nsP2蛋白酶的新型小分子抑制剂的合成与评估。这两种先导化合物对病毒复制表现出强大的抑制作用。以VEEV TC-83作为模型病原体进行测定时，这些抑制剂干扰了nsP123多蛋白的加工过程，并且对EEEV和WEEV具有活性。研究发现这些化合物在两种不同的小鼠品系中无毒，并在VEEV TC-83致死性攻击小鼠模型中表现出抗病毒活性。总体而言，本研究结果为nsP2蛋白酶抑制剂作为抗甲病毒的直接作用抗病毒疗法的临床前开发提供了令人信服的理论依据。
