Rodriguez Galvan Joaquin, de Vries Maren, Belblidia Shiraz, Fisher Ashley, Prescott Rachel A, Crosse Keaton M, Hearing Patrick, Mangel Walter F, Duerr Ralf, Dittmann Meike
New York University Grossman School of Medicine, Microbiology Department, New York, NY, USA.
New York University Grossman School of Medicine, Department of Medicine, New York, NY, USA.
EMBO J. 2025 Sep 8. doi: 10.1038/s44318-025-00546-6.
Serine protease inhibitors (SERPINs) are involved in various physiological processes and diseases, such as inflammation, cancer metastasis, and neurodegeneration. Their role in viral infections is poorly understood, as their expression patterns during infection and the range of proteases they target have yet to be fully characterized. Here, we show widespread expression of human SERPINs in response to respiratory virus infections, both in bronchioalveolar lavages from COVID-19 patients and in polarized human airway epithelial cultures. Using in silico docking of 10 SERPINs to 48 host proteases, we confirm known targets and predict new interactions. Protease activity assays validated selected interactions, confirming the newly predicted host targets for PAI-1 (SERPINE1) and PAI-2 (SERPINB2). PAI-1 inhibits cathepsin L, essential for SARS-CoV-2 maturation, and suppresses multi-cycle replication of both ancestral SARS-CoV-2 WA-1 and its variant Omicron BA.1. In addition, we identify PAI-2 as an antiviral SERPIN that reduces infectivity of human adenovirus 5 by directly inhibiting the adenoviral protease. Our study leverages in silico docking using full-length 3D protein structures to uncover new SERPIN targets, offering a range of candidate targets for therapeutic interventions.
丝氨酸蛋白酶抑制剂（SERPINs）参与多种生理过程和疾病，如炎症、癌症转移和神经退行性变。它们在病毒感染中的作用尚不清楚，因为它们在感染期间的表达模式以及所靶向的蛋白酶范围尚未完全明确。在此，我们发现人类SERPINs在应对呼吸道病毒感染时广泛表达，无论是在新冠肺炎患者的支气管肺泡灌洗液中，还是在极化的人气道上皮培养物中。通过对10种SERPINs与48种宿主蛋白酶进行计算机模拟对接，我们证实了已知靶点并预测了新的相互作用。蛋白酶活性测定验证了所选的相互作用，确认了PAI-1（SERPINE1）和PAI-2（SERPINB2）新预测的宿主靶点。PAI-1抑制组织蛋白酶L，这对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的成熟至关重要，并抑制原始SARS-CoV-2 WA-1及其变体奥密克戎BA.1的多轮复制。此外，我们确定PAI-2是一种抗病毒SERPIN，它通过直接抑制腺病毒蛋白酶来降低人腺病毒5的感染性。我们的研究利用全长3D蛋白质结构的计算机模拟对接来发现新的SERPIN靶点，为治疗干预提供了一系列候选靶点。
