Synergistic effect of combinational SHEN26 and PF07817883 in SARS-CoV-2 infection

Jiacheng Huang; Yujian Yang; Tiefeng Xu; Jianwei Liang; Xin Wang; Guanguan Li; Lihong Liu; Keda Shi; Zhao Lv; Xikui Sun; Chunmei Li; Xumu Zhang; Qifan Zhou; Sidi Yang; Deyin Guo

doi:10.1016/j.virs.2026.09.006

October 2026

. doi: 10.1016/j.virs.2026.09.006

Citation: Jiacheng Huang, Yujian Yang, Tiefeng Xu, Jianwei Liang, Xin Wang, Guanguan Li, Lihong Liu, Keda Shi, Zhao Lv, Xikui Sun, Chunmei Li, Xumu Zhang, Qifan Zhou, Sidi Yang, Deyin Guo. Synergistic effect of combinational SHEN26 and PF07817883 in SARS-CoV-2 infection .VIROLOGICA SINICA, 2026, 41(5) : 1261-1264. http://dx.doi.org/10.1016/j.virs.2026.09.006

SHEN26与PF07817883联合用药在抗SARS-CoV-2病毒感染中的协同效应

黄佳程 ^a,b ,
杨玉剑 ^c ,
徐铁凤 ^d ,
梁健威 ^a ,
王欣 ^a ,
李官官 ^e ,
刘利红 ^a ,
施科达 ^d ,
吕朝 ^f ,
孙西魁 ^a ,
李春梅 ^f ,
张绪穆 ^c ,
周启璠 ^c,, ,
杨斯迪 ^a,, ,
郭德银 ^a,b,,

a. 广州国家实验室, 广州国际生物岛, 广东省广州市, 邮编:510005;
b. 中山大学, 中山医学院, 人类病毒学研究所病原生物学与生物安全系热带病控制教育部重点实验室, 广东省广州市, 邮编:510080;
c. 南方科技大学, 坪山生物医药研究院, 小分子药物发现与合成重点实验室, 广东省深圳市, 邮编:518055;
d. 广州医科大学附属第一医院, 广州呼吸健康研究所, 呼吸疾病临床研究中心呼吸疾病国家重点实验室, 广东省广州市, 邮编:510145;
e. 深圳安泰维生物医药有限公司, 广东省深圳市, 邮编:518118;
f. 中山大学深圳校区, 中山医学院, 感染与免疫研究中心(CIIS), 广东省深圳市, 邮编:518107

通讯作者： 周启璠, zhouqf@sustech.edu.cn; 杨斯迪, yang_sidi@gzlab.ac.cn; 郭德银, guo_deyin@gzlab.ac.cn
收稿日期： 2026-04-30
录用日期： 2026-09-09

摘要

SARS-CoV-2持续传播，加之新出现的病毒变异株和突破性感染不断出现，进一步凸显了开发能够与疫苗形成互补的新型抗病毒策略的迫切需求。采用作用机制互补的药物进行联合治疗，是一种有望提高抗病毒疗效、扩大对不同病毒变异株覆盖范围并降低耐药发生风险的治疗策略。本研究系统评估了RNA依赖的RNA聚合酶（RdRp）抑制剂ATV014（SHEN26）和第二代主蛋白酶（Mpro）抑制剂PF07817883（Ibuzatrelvir）单独应用及联合应用的抗病毒活性。研究结果表明，ATV014与PF07817883联合用药在体外和体内均表现出协同抗病毒作用，进一步证明了同时靶向病毒复制过程中两个关键环节的双机制治疗策略能够更有效地抑制病毒复制，并减轻COVID-19相关病理损伤。本研究结果为该联合方案作为一种具有临床应用前景的抗病毒治疗策略提供了实验依据，尤其支持其在高危患者早期治疗中的进一步开发与应用。
- ARS-CoV-2
- , SHEN26
- , Ibuzatrelvir
- , 联合用药

Synergistic effect of combinational SHEN26 and PF07817883 in SARS-CoV-2 infection

Jiacheng Huang ^a,b ,
Yujian Yang ^c ,
Tiefeng Xu ^d ,
Jianwei Liang ^a ,
Xin Wang ^a ,
Guanguan Li ^e ,
Lihong Liu ^a ,
Keda Shi ^d ,
Zhao Lv ^f ,
Xikui Sun ^a ,
Chunmei Li ^f ,
Xumu Zhang ^c ,
Qifan Zhou ^c,, ,
Sidi Yang ^a,, ,
Deyin Guo ^a,b,,

a. Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou 510005, China;
b. 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;
c. Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, College of Science, Academy for Advanced Interdisciplinary Studies and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518055, China;
d. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510145, China;
e. Shenzhen AntiV Pharma Co. Ltd., Shenzhen 518118, China;
f. MOE Key Laboratory of Tropical Disease Control, Zhongshan School of Medicine, Sun Yat-sen University Shenzhen Campus, Sun Yat-Sen University, Shenzhen 518107, China

Corresponding author: Qifan Zhou, zhouqf@sustech.edu.cn Sidi Yang, yang_sidi@gzlab.ac.cn Deyin Guo, guo_deyin@gzlab.ac.cn
Received Date: 30 April 2026
Accepted Date: 09 September 2026

Abstract

Highlights
1 ATV014 (SHEN26) and PF07817883 exhibited potent synergistic antiviral activity against SARS-CoV-2 in vitro.
2 In vivo, the combination showed synergistic antiviral and tissue-repair effects superior to either monotherapy.
3 The therapeutic potential of combining a RdRp inhibitor with a main protease inhibitor as a complementary antiviral strategy.

References
1. Allerton, C.M.N., Arcari, J.T., Aschenbrenner, L.M., Avery, M., Bechle, B.M., Behzadi, M.A., Boras, B., Buzon, L.M., Cardin, R.D., Catlin, N.R., Carlo, A.A., Coffman, K.J., Dantonio, A., Di, L., Eng, H., Farley, K.A., Ferre, R.A., Gernhardt, S.S., Gibson, S.A., Greasley, S.E., Greenfield, S.R., Hurst, B.L., Kalgutkar, A.S., Kimoto, E., Lanyon, L.F., Lovett, G.H., Lian, Y., Liu, W., Alsina, L.A.M., Noell, S., Obach, R.S., Owen, D.R., Patel, N.C., Rai, D.K., Reese, M.R., Rothan, H.A., Sakata, S., Sammons, M.F., Sathish, J.G., Sharma, R., Steppan, C.M., Tuttle, J.B., Verhoest, P.R., Wei, L., Yang, Q., Yurgelonis, I., Zhu, Y., 2024. A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19. J. Med. Chem. 67, 13550-13571.
2. Bai, J., Asakawa, T., Yuan, W., Lin, Y., Ju, H., Xu, D., Yang, M., Li, S., Li, G., Guo, D., Lu, H., Zhang, X., 2025. Efficacy and safety of SHEN26, a novel oral small molecular RdRp inhibitor for COVID-19 treatment: a multicenter, randomized, double-blinded, placebo-controlled, phase II clinical trial. Virol. J. 22, 16.
3. Cao, L., Li, Y., Yang, S., Li, G., Zhou, Q., Sun, J., Xu, T., Yang, Yang, Liao, R., Shi, Y., Yang, Yujian, Zhu, T., Huang, S., Ji, Y., Cong, F., Luo, Y., Zhu, Y., Luan, H., Zhang, H., Chen, J., Liu, X., Luo, R., Liu, L., Wang, P., Yu, Y., Xing, F., Ke, B., Zheng, H., Deng, X., Zhang, W., Lin, C., Shi, M., Li, C.-M., Zhang, Y., Zhang, L., Dai, J., Lu, H., Zhao, J., Zhang, X., Guo, D., 2022. The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants. Sci. Transl. Med. 14, eabm7621.
4. Gidari, A., Sabbatini, S., Schiaroli, E., Bastianelli, S., Pierucci, S., Busti, C., Saraca, L.M., Capogrossi, L., Pasticci, M.B., Francisci, D., Gidari, A., Sabbatini, S., Schiaroli, E., Bastianelli, S., Pierucci, S., Busti, C., Saraca, L.M., Capogrossi, L., Pasticci, M.B., Francisci, D., 2023. Synergistic Activity of Remdesivir-Nirmatrelvir Combination on a SARS-CoV-2 In Vitro Model and a Case Report. Viruses 15, 1577.
5. Hirsch, C., Kreuzberger, N., Skoetz, N., Monsef, I., Kluge, S., Spinner, C.D., Malin, J.J., 2025. Efficacy and safety of antiviral therapies for the treatment of persistent COVID-19 in immunocompromised patients since the Omicron surge: a systematic review. J. Antimicrob. Chemother. 80, 633-644.
6. Mortezavi, M., Sloan, A., Singh, R.S.P., Chen, L.F., Kim, J.H., Shojaee, N., Toussi, S.S., Prybylski, J., Baniecki, M.L., Bergman, A., Banerjee, A., Allerton, C., Alami, N.N., 2024. Virologic Response and Safety of Ibuzatrelvir, A Novel SARS-CoV-2 Antiviral, in Adults With COVID-19. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 80, 673-680.
7. Soares, V.C., Moreira, I.B.G., Dias, S.S.G., 2025. SARS-CoV-2 Infection and Antiviral Strategies: Advances and Limitations. Viruses 17, 1064.
8. Xia, S., Lan, Q., Zhu, Y., Wang, C., Xu, W., Li, Y., Wang, L., Jiao, F., Zhou, J., Hua, C., Wang, Q., Cai, X., Wu, Y., Gao, J., Liu, H., Sun, G., Munch, J., Kirchhoff, F., Yuan, Z., Xie, Y., Sun, F., Jiang, S., Lu, L., 2021. Structural and functional basis for pan-CoV fusion inhibitors against SARS-CoV-2 and its variants with preclinical evaluation. Signal Transduct. Target. Ther. 6, 288.
9. Xia, S., Liu, M., Wang, C., Xu, W., Lan, Q., Feng, S., Qi, F., Bao, L., Du, L., Liu, S., Qin, C., Sun, F., Shi, Z., Zhu, Y., Jiang, S., Lu, L., 2020. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res. 30, 343-355.
10. Zhou, Q., Yang, S., Cao, L., Yang, Y., Xu, T., Chen, Q., Lu, H., Li, Y., Guo, D., Zhang, X., 2023. Preclinical characterization and anti-SARS-CoV-2 efficacy of ATV014: an oral cyclohexanecarboxylate prodrug of 1'-CN-4-aza-7,9-dideazaadenosine C-nucleoside. Signal Transduct. Target. Ther. 8, 27.
Proportional views
Electronic Supplementary Material

10.1016j.virs.2026.09.006-ESM.docx