Boon Adrianus C M, L Bricker Traci, Fritch Ethan J, Leist Sarah R, Gully Kendra, Baric Ralph S, Graham Rachel L, Troan Brigid V, Mahoney Matthew, Janetka James W
bioRxiv. 2024 Feb 12:2024.02.09.579701. doi: 10.1101/2024.02.09.579701.
We have developed a novel class of peptidomimetic inhibitors targeting several host cell human serine proteases including transmembrane protease serine 2 (TMPRSS2), matriptase and hepsin. TMPRSS2 is a membrane associated protease which is highly expressed in the upper and lower respiratory tract and is utilized by SARS-CoV-2 and other viruses to proteolytically process their glycoproteins, enabling host cell receptor binding, entry, replication, and dissemination of new virion particles. We have previously shown that compound MM3122 exhibited sub nanomolar potency against all three proteases and displayed potent antiviral effects against SARS-CoV-2 in a cell-viability assay. Herein, we demonstrate that MM3122 potently inhibits viral replication in human lung epithelial cells and is also effective against the EG.5.1 variant of SARS-CoV-2. Further, we have evaluated MM3122 in a mouse model of COVID-19 and have demonstrated that MM3122 administered intraperitoneally (IP) before (prophylactic) or after (therapeutic) SARS-CoV-2 infection had significant protective effects against weight loss and lung congestion, and reduced pathology. Amelioration of COVID-19 disease was associated with a reduction in pro-inflammatory cytokines and chemokines production after SARS-CoV-2 infection. Prophylactic, but not therapeutic, administration of MM3122 also reduced virus titers in the lungs of SARS-CoV-2 infected mice. Therefore, MM3122 is a promising lead candidate small molecule drug for the treatment and prevention of infections caused by SARS-CoV-2 and other coronaviruses.
SARS-CoV-2 and other emerging RNA coronaviruses are a present and future threat in causing widespread endemic and pandemic infection and disease. In this paper, we have shown that the novel host-cell protease inhibitor, MM3122, blocks SARS-CoV-2 viral replication and is efficacious as both a prophylactic and therapeutic drug for the treatment of COVID-19 in mice. Targeting host proteins and pathways in antiviral therapy is an underexplored area of research but this approach promises to avoid drug resistance by the virus, which is common in current antiviral treatments.
我们开发了一类新型拟肽抑制剂，其靶向几种宿主细胞人丝氨酸蛋白酶，包括跨膜蛋白酶丝氨酸2（TMPRSS2）、matriptase和hepsin。TMPRSS2是一种膜相关蛋白酶，在上、下呼吸道中高度表达，被严重急性呼吸综合征冠状病毒2（SARS-CoV-2）和其他病毒用于蛋白水解处理其糖蛋白，从而实现宿主细胞受体结合、进入、复制以及新病毒粒子的传播。我们之前已表明，化合物MM3122对所有这三种蛋白酶均表现出亚纳摩尔效力，并且在细胞活力测定中对SARS-CoV-2显示出强效抗病毒作用。在此，我们证明MM3122能有效抑制人肺上皮细胞中的病毒复制，并且对SARS-CoV-2的EG.5.1变体也有效。此外，我们在新型冠状病毒肺炎（COVID-19）小鼠模型中评估了MM3122，证明在SARS-CoV-2感染之前（预防性）或之后（治疗性）腹腔注射（IP）MM3122对体重减轻和肺充血具有显著保护作用，并减轻了病理变化。COVID-19疾病的改善与SARS-CoV-2感染后促炎细胞因子和趋化因子产生的减少有关。预防性而非治疗性给予MM3122也降低了SARS-CoV-2感染小鼠肺部的病毒滴度。因此，MM3122是一种有前景的先导候选小分子药物，可用于治疗和预防由SARS-CoV-2和其他冠状病毒引起 的感染。
SARS-CoV-2和其他新出现的RNA冠状病毒是当前和未来导致广泛地方性和大流行性感染及疾病的威胁。在本文中，我们已表明新型宿主细胞蛋白酶抑制剂MM3122可阻断SARS-CoV-2病毒复制，并且作为预防性和治疗性药物对小鼠COVID-19的治疗均有效。在抗病毒治疗中靶向宿主蛋白和途径是一个未充分探索的研究领域，但这种方法有望避免病毒产生耐药性，而病毒耐药性在当前抗病毒治疗中很常见。
