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Volume 41 Issue 2
April 2026

    . doi: 10.1016/j.virs.2026.04.006
    Citation: Guimin Dai, Wenjie Chen, Wenying Cao, Guigen Zhang. A natural five-amino-acid insert at the S2’ cleavage site of MERS-CoV spike enhances viral membrane fusion .VIROLOGICA SINICA, 2026, 41(2) : 485-489.  http://dx.doi.org/10.1016/j.virs.2026.04.006
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    MERS冠状病毒刺突蛋白S2’酶切位点5氨基酸的天然插入促进其介导的膜融合

    • a 中山大学中山医学院病原生物与生物安全学系;

    • b 中山大学人类病毒学研究所、中山大学热带病防治研究教育部重点实验室

    • 1.一株骆驼来源的MERS冠状病毒（MERS-CoV）的刺突蛋白S2’酶切位点含有一个5氨基酸（TSGVF）的天然插入。
      2. 假病毒进入实验表明，刺突蛋白S2’酶切位点含有TSGVF插入增强假病毒进入不同细胞系的效率。
      3. 相比较而言，含有TSGVF插入的假病毒进入细胞过程中对TMPRSS2蛋白酶抑制剂具有更强的抵抗力。
      4. 刺突蛋白S2’酶切位点含有TSGVF天然插入增强病毒-细胞膜融合及刺突蛋白介导的细胞合胞体的形成。

    A natural five-amino-acid insert at the S2’ cleavage site of MERS-CoV spike enhances viral membrane fusion

    • Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China

    • Highlights
      1       A novel 5-aa insert, TSGVF, is present at the S2' cleavage site of the spike protein of MERS-CoV from dromedary camels.
      2 Pseudovirus-based entry assays showed that the TSGVF insert increases viral entry efficiency in different human cells.
      3 Pseudovirus with TSGVF insert at the S2' cleavage site showed strong resistance to TMPRSS2 inhibitor.
      4 The natural occurrence of TSGVF insert at the spike S2' cleavage site enhances viral membrane fusion and syncytia formation.
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      1. Bonnin A, Danneels A, Dubuisson J, Goffard A, Belouzard S. 2018. HCoV-229E spike protein fusion activation by trypsin-like serine proteases is mediated by proteolytic processing in the S2' region. Journal of General Virology 99: 908-912.

      2. Burkard C, Verheije MH, Wicht O, van Kasteren SI, van Kuppeveld FJ, Haagmans BL, Pelkmans L, Rottier PJM, Bosch BJ, de Haan CAM. 2014. Coronavirus Cell Entry Occurs through the Endo-/Lysosomal Pathway in a Proteolysis-Dependent Manner. Plos Pathogens 10, e1004502.

      3. Casassus B. 2025. MERS: France confirms first cases in 12 years. BMJ-British Medical Journal 391, r2577.

      4. Chen J, Yang XL, Si HR, Gong QC, Que TC, Li J, Li Y, Wu CG, Zhang W, Chen Y, Luo Y, Zhu Y, Li B, Luo DS, Hu B, Lin HF, Jiang RD, Jiang TT, Li Q, Liu MQ, Xie SZ, Su J, Zheng XS, Li A, Yao YL, Yang Y, Chen PY, Wu AQ, He MH, Lin XH, Tong YG, Hu YL, Shi ZL, Zhou P. 2023. A bat MERS-like coronavirus circulates in pangolins and utilizes human DPP4 and host proteases for cell entry. Cell 186: 850-863.

      5. Hassan AM, Muhlemann B, Al-Subhi TL, Rodon J, El-Kafrawy SA, Memish Z, Melchert J, Bleicker T, Mauno T, Perlman S, Zumla A, Jones TC, Muller MA, Corman VM, Drosten C, Azhar EI. 2025. Ongoing Evolution of Middle East Respiratory Syndrome Coronavirus, Saudi Arabia, 2023-2024. Emerging Infectious Diseases 31: 57-65.

      6. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. 2020. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181: 271-280.

      7. Karani A, Ombok C, Situma S, Breiman R, Mureithi M, Jaoko W, Njenga MK, Ngere I. 2025. Low-Level Zoonotic Transmission of Clade C MERS-CoV in Africa: Insights from Scoping Review and Cohort Studies in Hospital and Community Settings. Viruses-Basel 17, 125.

      8. Kleine-Weber H, Elzayat MT, Hoffmann M, Pohlmann S. 2018. Functional analysis of potential cleavage sites in the MERS-coronavirus spike protein. Scientific Reports 8, 16597.

      9. Lau SKP, Li KSM, Li X, Tsang KY, Sridhar S, Woo PCY. 2022. Fatal Pneumonia Associated With a Novel Genotype of Human Coronavirus OC43. Frontiers in Microbiology 12, 795449.

      10. Millet JK, Goldstein ME, Labitt RN, Hsu HL, Daniel S, Whittaker GR. 2016. A camel-derived MERS-CoV with a variant spike protein cleavage site and distinct fusion activation properties. Emerging Microbes & Infections 5, e126.

      11. Millet JK, Whittaker GR. 2014. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. Proceedings of the National Academy of Sciences of the United States of America, 111: 15214-15219.

      12. Raj VS, Mou HH, Smits SL, Dekkers DHW, Muller MA, Dijkman R, Muth D, Demmers JAA, Zaki A, Fouchier RAM, Thiel V, Drosten C, Rottier PJM, Osterhaus ADME, Bosch BJ, Haagmans BL. 2013. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature, 495: 251-254.

      13. Su S, Wong G, Shi WF, Liu J, Lai ACK, Zhou JY, Liu WJ, Bi YH, Gao GF. 2016. Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses. Trends in Microbiology, 24: 490-502.

      14. Xia S, Jiao FK, Chen J, Wang LJ, Lu TY, Wang Q, Xu W, Wang XL, Sun F, Zhi Y, Zhou P, Jiang SB, Lu L. 2025. MERS-related coronavirus circulating in pangolins exhibits strong fusogenicity in human cells and high sensitivity to fusion inhibitors. Cell Reports Medicine, 6, 102277.

      15. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus ADME, Fouchier RAM. 2012. Isolation of a Novel Coronavirus from a Man with Pneumonia in Saudi Arabia. New England Journal of Medicine, 367: 1814-1820.

      16. Zhou H, Chen X, Hu T, Li J, Song H, Liu YR, Wang PH, Liu D, Yang J, Holmes EC, Hughes AC, Bi YH, Shi WF. 2020. A Novel Bat Coronavirus Closely Related to SARS-CoV-2 Contains Natural Insertions at the S1/S2 Cleavage Site of the Spike Protein (vol 30, 2196.e1, 2020). Current Biology, 30: 3896-3896.

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    • Electronic Supplementary Material

      10.1016j.virs.2026.04.006-ESM.docx

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      A natural five-amino-acid insert at the S2’ cleavage site of MERS-CoV spike enhances viral membrane fusion

        Corresponding author: Guigen Zhang, zhanggg5@mail.sysu.edu.cn
      • Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
      • Received Date: 27 October 2025
      • Accepted Date: 14 April 2026

      Abstract: Highlights
      1       A novel 5-aa insert, TSGVF, is present at the S2' cleavage site of the spike protein of MERS-CoV from dromedary camels.
      2 Pseudovirus-based entry assays showed that the TSGVF insert increases viral entry efficiency in different human cells.
      3 Pseudovirus with TSGVF insert at the S2' cleavage site showed strong resistance to TMPRSS2 inhibitor.
      4 The natural occurrence of TSGVF insert at the spike S2' cleavage site enhances viral membrane fusion and syncytia formation.

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