Teratogenicity assessment of new antiviral drugs using 3D morphogenesis models

建议书摘要 已知各种药物具有致畸性，在治疗过程中使用会导致流产或出生缺陷。 怀孕了。然而，许多其他药物的致畸性尚不清楚，特别是那些最近推出的药物 被推向市场。由于正在进行的新冠肺炎大流行/地方病，许多调查人员正在开发新的 抗SARS-CoV-2的抗病毒药物。目前，有三种抗病毒药物被批准或获准紧急使用 FDA授权的药物，即瑞昔维韦、莫那普拉韦和帕昔洛韦。然而，关于它们的致畸性的研究 少之又少。由于新冠肺炎仍然坚持免疫逃逸变体的出现，包括 那些有生育潜力的人可能需要抗病毒治疗。为医生提供适当的建议 对于他们的病人，抗病毒药物的致畸作用应该得到充分的研究。之前，我们发明了 基于小鼠和人类干细胞的3D形态发生模型，概括了早期 体外胚胎发生可作为灵敏、特异地检测各种致畸因素的有效工具 化学制品。我们使用这些形态发生模型进行的初步研究表明，抗新冠肺炎 药物，特别是瑞司他韦和莫努比拉韦，在接近其浓度的情况下会损害胚胎发育。 人的治疗性血浆水平。这些观察结果需要对致畸的进一步研究。 抗病毒药物的潜力，如本申请中所建议的。具体地说，我们将(1)表征分子 新型抗病毒药物对形态发生模型的影响，(2)探讨其可能的致畸机制 新的抗病毒药物，以及(3)用小鼠全胚胎检测新的抗病毒药物的致畸作用。 文化。拟议的实验应该会产生与它们的致畸潜力有关的有价值的信息， 如浓度-效应关系和作用的分子机制，并有助于设计和 以有效的方式解释基于动物和人类的研究。

Proposal Abstract Various drugs are known to be teratogenic, causing miscarriages or birth defects, when used during pregnancy. However, teratogenicity is unclear for many other drugs, particularly those that were recently marketed. Because of the ongoing COVID-19 pandemic/endemic, many investigators are developing new antiviral drugs against SARS-CoV-2. Currently, three antivirals are approved or granted the emergency use authorization by the FDA, namely remdesivir, molnupiravir, and Paxlovid. Yet studies on their teratogenicity are scarce. As COVID-19 still persists with the emergence of immune escape variants, many people, including those of childbearing potential, may require antiviral treatment. For physicians to provide proper advice for their patients, the teratogenicity of the antivirals should be studied sufficiently. Previously, we invented the mouse and human stem cell-based 3D morphogenesis models, which recapitulate the key features of early embryogenesis in vitro and can serve as effective tools to sensitively and specifically detect various teratogenic chemicals. Our Preliminary Studies using these morphogenesis models suggest that the anti-COVID-19 drugs, particularly remdesivir and molnupiravir, impair embryogenesis at the concentrations close to their therapeutic plasma levels in human. These observations necessitate further investigations into the teratogenic potential of the antivirals, as proposed in this application. Specifically, we will (1) characterize the molecular impact of the new antivirals on the morphogenesis models, (2) explore the possible teratogenic mechanisms of the new antivirals, and (3) examine the teratogenic effects of the new antivirals with the mouse whole embryo culture. The proposed experiments should yield valuable information pertinent to their teratogenic potential, such as the concentration-effect relationship and molecular mechanisms of actions, and help in the design and interpretation of animal- and human-based studies in an effective manner.