UNC0638 inhibits SARS-CoV-2 entry by blocking cathepsin L maturation
Yongjun Chen, Yujin Shi, Xiaoyan Zuo, Xiaojing Dong, Xia Xiao, Funding acquisition, Validation | Lan Chen, Conceptualization, Investigation | Zichun Xiang, Conceptualization, Resources, Supervision | Lili Ren, Conceptualization Zhuo Zhou, Wensheng Wei, Xiaobo Lei, Jianwei Wang
Journal of Virology, doi:10.1128/jvi.00741-25
Since the outbreak of SARS-CoV-2, viral mutations have posed significant challenges in identifying therapeutic targets and developing broad-spectrum antiviral drugs. Post-translational modifications of genes involved in interferon production and signaling pathways play a crucial role in regulating interferon responses. In this study, we employed CRISPR-Cas9 screening based on adenine base editors to investigate functional amino acids in 1,278 innate immune-related genes. This approach, which converts A-T base pairs into G-C base pairs to probe the functional importance of specific amino acids, allowed us to identify 17 vital factors involved in SARS-CoV-2 infection. Among the candidate genes, genetic knockdown of EHMT2 exhibited the strongest antiviral effect. Further analysis revealed that UNC0638, a selective inhibitor of EHMT2, significantly reduced the endosomal entry of SARS-CoV-2 in pseudovirus assays. The observed inhibitory effect was consistently observed across multiple SARS-CoV-2 variants, including Alpha, Beta, Delta, and Omicron. Mechanistically, UNC0638 reduced mature cathepsin L (CTSL) levels, impairing the proteolytic cleavage of SARS-CoV-2 spike protein and subsequent membrane fusion, a critical step for viral entry. Our findings uncover EHMT2 as a host dependency factor and reveal the antiviral mecha nism of EHMT2 inhibitors through CTSL maturation blockade. These results advance the understanding of host factors in SARS-CoV-2 infection and provide a strategic framework for developing host-targeted antiviral therapies.
IMPORTANCE In this study, we demonstrated that knockdown or knockout of EHMT2 inhibited SARS-CoV-2 infection, and inhibitors of EHMT2, including UNC0638, UNC0642, and BIX01294 showed similar restrictive effects. Mechanistically, the EHMT2 inhibitor UNC0638 restricts spike-mediated cell entry by inhibiting the maturation of CTSL, a critical protease required for SARS-CoV-2 entry via the endosomal pathway. Importantly, CTSL is not only essential for SARS-CoV-2 but also plays a key role in the entry of other coronaviruses that utilize similar pathways. Therefore, EHMT2 inhibitors could have broader applications as pan-coronavirus therapeutic agents. KEYWORDS SARS-CoV-2, EHMT2, UNC0638, viral entry, cathepsin L C oronaviruses (CoV) are enveloped, positive-sense RNA viruses with genomes of approximately 26-32 kb long with a short untranslated region at both 5′ and 3′ terminal (1-3). The genome encodes four structural proteins: spike (S) protein, envelope protein, nucleocapsid (N) protein, and membrane (M) protein, along with 16 non-structural proteins (NSP1-16) and approximately eight accessory proteins (1-3). Seven coronaviruses are known to infect humans, including severe acute respira tory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2, human coronavirus HKUI (HCoV-HKU1), HCoV-NL63, HCoV-OC43, and HCoV-229E (3). The first three are highly pathogenic and cause..
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