Abstract:
As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (Mpro) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug. Serious drug-drug interactions can occur with Paxlovid for patients who are also taking other medications metabolized by CYP4503A4, particularly transplant or otherwise immunocompromised patients who are most at risk for SARS-CoV-2 infection and the development of severe symptoms. Developing an alternative antiviral with improved pharmacological properties is critical for treatment of these patients. By using a computational and structure-guided approach, we were able to optimize a 100 to 250 μM screening hit to a potent nanomolar inhibitor and lead compound, Mpro61. In this study, we further evaluate Mpro61 as a lead compound, starting with examination of its mode of binding to SARS-CoV-2 Mpro. In vitro pharmacological profiling established a lack of off-target effects, particularly CYP450 3A4 inhibition, as well as potential for synergy with the currently approved alternate antiviral, molnupiravir. Development and subsequent testing of a capsule formulation for oral dosing of Mpro61 in B6-K18-hACE2 mice demonstrated favorable pharmacological properties, efficacy, and synergy with molnupiravir, and complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate.
摘要:
随着SARS-CoV-2病毒的持续传播和变异,重要的是不仅要关注通过疫苗接种预防传播,还要关注用直接作用抗病毒药物(DAA)治疗感染.Paxlovid的批准,SARS-CoV-2主要蛋白酶(Mpro)DAA,对患者的治疗具有重要意义。此DAA的限制,然而,抗病毒成分,Nirmatrelvir,快速代谢,需要包含CYP4503A4代谢抑制剂,利托那韦,以提高活性药物的水平。对于同时服用CYP4503A4代谢的其他药物的患者,尤其是移植或其他免疫功能低下的患者,Paxlovid可能会发生严重的药物相互作用。SARS-CoV-2感染和严重症状发展的风险最大。开发具有改善的药理学性质的替代抗病毒药物对于治疗这些患者至关重要。通过使用计算和结构指导的方法,我们能够优化100至250μM的筛选命中有效的纳摩尔抑制剂和先导化合物,Mpro61.在这项研究中,我们进一步评估了作为先导化合物的Mpro61,首先检查其与SARS-CoV-2Mpro的结合方式。体外药理学分析建立了缺乏脱靶效应,特别是CYP4503A4抑制,以及与目前批准的替代抗病毒药物协同作用的潜力,Molnupiravir.在B6-K18-hACE2小鼠中口服Mpro61的胶囊制剂的开发和随后的测试证明了有利的药理特性,功效,以及与莫努比拉韦的协同作用,并从SARS-CoV-2的后续挑战中完全恢复,从而将Mpro61确立为有希望的潜在临床前候选药物。