A Novel Glucocorticoid and Androgen Receptor Modulator Reduces Viral Entry and Innate Immune Inflammatory Responses in the Syrian Hamster Model of SARS-CoV-2 Infection.
A Novel Glucocorticoid and Androgen Receptor Modulator Reduces Viral Entry and Innate Immune Inflammatory Responses in the Syrian Hamster Model of SARS-CoV-2 Infection.
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DOI：
10.3389/fimmu.2022.811430
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发表时间：
2022
影响因子：
7.3
通讯作者：
Tjalkens RB
中科院分区：
文献类型：
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作者：
Rocha SM;Fagre AC;Latham AS;Cummings JE;Aboellail TA;Reigan P;Aldaz DA;McDermott CP;Popichak KA;Kading RC;Schountz T;Theise ND;Slayden RA;Tjalkens RB
尽管进行了大量研究，但严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的治疗选择仍然有限。这部分是由于缺乏增加宿主对病毒防御的治疗方法。SARS-CoV-2在肺组织中的复制与巨噬细胞的显著浸润和放大组织损伤的先天免疫炎症反应的激活有关。雄激素（AR）和糖皮质激素（GR）受体的拮抗剂已在COVID-19模型和临床研究中显示出疗效，因为病毒进入所需的细胞表面蛋白血管紧张素转换酶2（ACE 2）和跨膜蛋白酶丝氨酸2（TMPRSS 2）受这些受体的转录调节。我们假设GR和AR调节剂PT 150通过下调通过这些受体调节的关键基因的表达，可以降低SARS-CoV-2的感染性，并预防叙利亚金黄地鼠COVID-19模型中的炎性肺损伤。用2.5 × 104 TCID 50/ml当量的SARS-CoV-2（菌株2019-nCoV/USA-WA 1/2020）鼻内感染动物，并以30和100 mg/Kg/天的剂量经口灌胃给予PT 150，共7天。在感染后3、5和7天（DPI）检查动物的肺组织病理学、病毒载量和调节SARS-CoV-2感染进展的蛋白质的产生。结果表明，口服PT 150可引起SARS-CoV-2在肺中复制的剂量依赖性降低，以及ACE 2和TMPRSS 2的表达。在PT 150治疗的动物中，肺细胞过多和巨噬细胞和CD 4 + T细胞的浸润显著减少，组织损伤和IL-6的表达也显著减少。分子对接研究表明，PT 150结合到AR和GR的配体结合结构域的共激活剂界面，从而充当这些受体的变构调节剂和转录抑制剂。AR和GR的系统发育分析显示，在包括人类在内的多个物种中保持了高度的序列同一性，这表明在叙利亚仓鼠中观察到的作用机制和治疗效果可能预测患者的积极结局。因此，PT 150是进一步临床开发用于治疗SARS-CoV-2变异体的COVID-19的强有力候选物。
Despite significant research efforts, treatment options for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain limited. This is due in part to a lack of therapeutics that increase host defense to the virus. Replication of SARS-CoV-2 in lung tissue is associated with marked infiltration of macrophages and activation of innate immune inflammatory responses that amplify tissue injury. Antagonists of the androgen (AR) and glucocorticoid (GR) receptors have shown efficacy in models of COVID-19 and in clinical studies because the cell surface proteins required for viral entry, angiotensin converting enzyme 2 (ACE2) and the transmembrane protease, serine 2 (TMPRSS2), are transcriptionally regulated by these receptors. We postulated that the GR and AR modulator, PT150, would reduce infectivity of SARS-CoV-2 and prevent inflammatory lung injury in the Syrian golden hamster model of COVID-19 by down-regulating expression of critical genes regulated through these receptors. Animals were infected intranasally with 2.5 × 104 TCID50/ml equivalents of SARS-CoV-2 (strain 2019-nCoV/USA-WA1/2020) and PT150 was administered by oral gavage at 30 and 100 mg/Kg/day for a total of 7 days. Animals were examined at 3, 5 and 7 days post-infection (DPI) for lung histopathology, viral load and production of proteins regulating the progression of SARS-CoV-2 infection. Results indicated that oral administration of PT150 caused a dose-dependent decrease in replication of SARS-CoV-2 in lung, as well as in expression of ACE2 and TMPRSS2. Lung hypercellularity and infiltration of macrophages and CD4+ T-cells were dramatically decreased in PT150-treated animals, as was tissue damage and expression of IL-6. Molecular docking studies suggest that PT150 binds to the co-activator interface of the ligand-binding domain of both AR and GR, thereby acting as an allosteric modulator and transcriptional repressor of these receptors. Phylogenetic analysis of AR and GR revealed a high degree of sequence identity maintained across multiple species, including humans, suggesting that the mechanism of action and therapeutic efficacy observed in Syrian hamsters would likely be predictive of positive outcomes in patients. PT150 is therefore a strong candidate for further clinical development for the treatment of COVID-19 across variants of SARS-CoV-2.