ABSTRACT

PT150 is a clinical-stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an antidepressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 µM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) modulating molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.

摘要

PT150 是一种临床阶段的分子，口服，具有很强的安全性，已完成其最初用作抗抑郁药的 1 期和 2 期临床试验。它有针对 COVID-19 的有效 IND。已发现 PT150 和多种病毒家族中的其他同类成员具有抗病毒活性；因此，现在它在人支气管上皮细胞中针对 SARS-CoV-2 进行了测试，结果显示有效的 90% 抑制性抗病毒浓度 (EC90) 为 5.55 µM。PT150是新型糖皮质激素受体（GR）和雄激素受体（AR）调节分子扩展平台的成员。在体内，它们的主要净效应是全身性糖皮质激素拮抗作用之一，但它们也在细胞水平上表现出直接下调 AR 和轻微的 GR 激动作用。我们假设抗 SARS-CoV-2 活性部分取决于 AR 通过减少 TMPRSS2 表达和调节 ACE2 活性而下调。鉴于目前认为高皮质醇血症是 COVID-19 进展的一个重要辅助因素，我们还假设其通过皮质醇的全身拮抗作用发挥附加作用，从而发挥有效的免疫调节作用。