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Nat Commun
. 2025 Jul 9;16(1):6326.
doi: 10.1038/s41467-025-61431-8. Host protein ARF1 is a proviral factor for SARS-CoV-2 and a candidate broad-spectrum therapeutic target
Cunhuan Zhang # 1 2 , Yuan-Qin Min # 1 3 , Heng Xue 1 2 , Haiyan Zhang 1 3 , Kunpeng Liu 1 2 , Yichao Tian 1 2 , Ziying Yang 1 2 , Zihan Zhao 1 2 , Hang Yang 1 3 , Chao Shan 1 3 , Xiulian Sun 4 5 , Yun-Jia Ning 6 7 8
Affiliations
SARS-CoV-2 and its emerging variants pose continuing threats to public health. SARS-CoV-2 assembles at the ER-Golgi intermediate compartment (ERGIC), where the viral membrane (M) protein highly accumulates to act as the central driver. However, how M is concentrated in the ERGIC, which hosts factor(s), may be involved, and whether they could be exploited as broad-spectrum antiviral targets remains unclear. Here, we identify an M-interacting host protein, ARF1, as a proviral factor that bolsters the propagation of SARS-CoV-2 and its variants in cultured cells and the viral infection and pathogenicity in female K18-hACE2 mice. By its N-terminal helix, ARF1 interacts with M and facilitates M's ERGIC accumulation and thus M-driven virion production. Consistently, pharmacological ARF1 inhibition by small molecules disrupts both ARF1 and M concentration at the ERGIC, blocking virion assembly and propagation. Furthermore, a designed peptide mimicking the M-targeted motif of ARF1 competitively blocks M-ARF1 interaction, M accumulation at the ERGIC, and viral assembly and propagation in vitro. Moreover, the peptidomimetic inhibitor exhibits therapeutic efficacy against SARS-CoV-2 infection and pathogenicity in vivo. These findings provide critical insights into the basic biology of SARS-CoV-2 and demonstrate the potential to develop pan-SARS-CoV-2 therapeutics by targeting ARF1 and/or the ARF1-M interaction interface.
. 2025 Jul 9;16(1):6326.
doi: 10.1038/s41467-025-61431-8. Host protein ARF1 is a proviral factor for SARS-CoV-2 and a candidate broad-spectrum therapeutic target
Cunhuan Zhang # 1 2 , Yuan-Qin Min # 1 3 , Heng Xue 1 2 , Haiyan Zhang 1 3 , Kunpeng Liu 1 2 , Yichao Tian 1 2 , Ziying Yang 1 2 , Zihan Zhao 1 2 , Hang Yang 1 3 , Chao Shan 1 3 , Xiulian Sun 4 5 , Yun-Jia Ning 6 7 8
Affiliations
- PMID: 40634337
- PMCID: PMC12241596
- DOI: 10.1038/s41467-025-61431-8
SARS-CoV-2 and its emerging variants pose continuing threats to public health. SARS-CoV-2 assembles at the ER-Golgi intermediate compartment (ERGIC), where the viral membrane (M) protein highly accumulates to act as the central driver. However, how M is concentrated in the ERGIC, which hosts factor(s), may be involved, and whether they could be exploited as broad-spectrum antiviral targets remains unclear. Here, we identify an M-interacting host protein, ARF1, as a proviral factor that bolsters the propagation of SARS-CoV-2 and its variants in cultured cells and the viral infection and pathogenicity in female K18-hACE2 mice. By its N-terminal helix, ARF1 interacts with M and facilitates M's ERGIC accumulation and thus M-driven virion production. Consistently, pharmacological ARF1 inhibition by small molecules disrupts both ARF1 and M concentration at the ERGIC, blocking virion assembly and propagation. Furthermore, a designed peptide mimicking the M-targeted motif of ARF1 competitively blocks M-ARF1 interaction, M accumulation at the ERGIC, and viral assembly and propagation in vitro. Moreover, the peptidomimetic inhibitor exhibits therapeutic efficacy against SARS-CoV-2 infection and pathogenicity in vivo. These findings provide critical insights into the basic biology of SARS-CoV-2 and demonstrate the potential to develop pan-SARS-CoV-2 therapeutics by targeting ARF1 and/or the ARF1-M interaction interface.