A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein

• 成果类型: Article
• 署名作者: Van Damme, Ellen; Abeywickrema, Pravien; Yin, Yanting; Xie, Jiexiong; Jacobs, Sofie; Mann, Mandeep Kaur; Doijen, Jordi; Miller, Robyn; Piassek, Madison; Marsili, Simone; Subramanian, Murali; Gottlieb, Leah; Abdelnabi, Rana; Van Gool, Michiel; van den Broeck, Nick; De Pauw, Ines; Diels, Annick; Vermeulen, Peter; Temmerman, Koen; Scobey, Trevor; Mattocks, Melissa; Schaefer, Alexandra; Jochmans, Dirk; De Jonghe, Steven; Leyssen, Pieter; Chiu, Winston; Toro, Mayra Diosa; Zwaagstra, Marleen; Leijs, Anouk A.; De Gruyter, Heidi L. M.; Buyck, Christophe; van den Heede, Klaas; Jacobs, Frank; van den Eynde, Christel; Thijs, Laura; Raeymaekers, Valerie; Miller, Seth; Del Rosario, Amanda; Neyts, Johan; Peeters, Danielle; Baric, Ralph S.; van Kuppeveld, Frank J. M.; Snijder, Eric J.; van Hemert, Martijn J.; Monshouwer, Mario; Sharma, Sujata; Draghia-Akli, Ruxandra; Koul, Anil; Van Loock, Marnix
• 署名单位: Johnson & Johnson; Johson & Johnson Belgium; Janssen Pharmaceuticals; Johnson & Johnson; Janssen Pharmaceuticals; Johnson & Johnson; Janssen Pharmaceuticals; Johnson & Johnson; Johnson & Johnson Spain; Johnson & Johnson; Janssen Pharmaceuticals; KU Leuven; Johnson & Johnson; Janssen Pharmaceuticals; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Utrecht University; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Johnson & Johnson; Johson & Johnson Belgium; Janssen Pharmaceuticals; Gilead Sciences; Royal Netherlands Academy of Arts & Sciences; Royal Netherlands Institute of Southeast Asian & Caribbean Studies (KITLV-KNAW)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1701
• DOI: 10.1038/s41586-025-08651-6
• 发表日期: 2025-04-10
• 关键词: antiviral activity; transmission; replication

摘要

The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly1,2. Here we describe the identification of JNJ-9676, a small-molecule inhibitor targeting the coronavirus M protein. JNJ-9676 demonstrates in vitro nanomolar antiviral activity against SARS-CoV-2, SARS-CoV and sarbecovirus strains from bat and pangolin zoonotic origin. Using cryogenic electron microscopy (cryo-EM), we determined a binding pocket of JNJ-9676 formed by the transmembrane domains of the M protein dimer. Compound binding stabilized the M protein dimer in an altered conformational state between its long and short forms, preventing the release of infectious virus. In a pre-exposure Syrian golden hamster model, JNJ-9676 (25 mg per kg twice per day) showed excellent efficacy, illustrated by a significant reduction in viral load and infectious virus in the lung by 3.5 and 4 log10-transformed RNA copies and 50% tissue culture infective dose (TCID50) per mg lung, respectively. Histopathology scores at this dose were reduced to the baseline. In a post-exposure hamster model, JNJ-9676 was efficacious at 75 mg per kg twice per day even when added at 48 h after infection, when peak viral loads were observed. The M protein is an attractive antiviral target to block coronavirus replication, and JNJ-9676 represents an interesting chemical series towards identifying clinical candidates addressing the current and future coronavirus pandemics.