Teratogenicity assessment of new antiviral drugs using 3D morphogenesis models

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.