Small-molecule anti-COVID-19 drugs and a focus on China’s homegrown mindeudesivir (VV116)

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic agents that target severe acute respiratory syndrome coronavirus 2 to control viral infection. So far, a few small-molecule antiviral drugs, including nirmatrelvir–ritonavir (Paxlovid), remdesivir, and molnupiravir have been marketed for the treatment of COVID-19. Nirmatrelvir–ritonavir has been recommended by the World Health Organization as an early treatment for outpatients with mild-to-moderate COVID-19. However, the existing treatment options have limitations, and effective treatment strategies that are cost-effective and convenient for tackling COVID-19 are still needed. To date, four domestically developed oral anti-COVID-19 drugs have been granted conditional market approval in China. These drugs include azvudine, simnotrelvir–ritonavir (Xiannuoxin), leritrelvir, and mindeudesivir (VV116). Preclinical and clinical studies have explored the efficacy and tolerability of mindeudesivir and supported its early use in mild-to-moderate COVID-19 cases at high risk for progression. In this review, we discuss the most recent findings regarding the pharmacological mechanism and therapeutic effects focusing on mindeudesivir and other small-molecule antiviral agents for COVID-19. These findings will expand our understanding and highlight the potential widespread application of China’s homegrown anti-COVID-19 drugs.

Keywords

COVID-19 / antiviral drugs / mindeudesivir

References

[1] COVID-19 Cumulative Infection Collaborators. Estimating global, regional, and national daily and cumulative infections with SARS-CoV-2 through Nov 14, 2021: a statistical analysis. Lancet 2022; 399(10344): 2351–2380

[2] Boehm E, Kronig I, Neher RA, Eckerle I, Vetter P, Kaiser L; Geneva Centre for Emerging Viral Diseases. Novel SARS-CoV-2 variants: the pandemics within the pandemic. Clin Microbiol Infect 2021; 27(8): 1109–1117

[3] Viana R, Moyo S, Amoako DG, Tegally H, Scheepers C, Althaus CL, Anyaneji UJ, Bester PA, Boni MF, Chand M, Choga WT, Colquhoun R, Davids M, Deforche K, Doolabh D, du Plessis L, Engelbrecht S, Everatt J, Giandhari J, Giovanetti M, Hardie D, Hill V, Hsiao NY, Iranzadeh A, Ismail A, Joseph C, Joseph R, Koopile L, Kosakovsky Pond SL, Kraemer MUG, Kuate-Lere L, Laguda-Akingba O, Lesetedi-Mafoko O, Lessells RJ, Lockman S, Lucaci AG, Maharaj A, Mahlangu B, Maponga T, Mahlakwane K, Makatini Z, Marais G, Maruapula D, Masupu K, Matshaba M, Mayaphi S, Mbhele N, Mbulawa MB, Mendes A, Mlisana K, Mnguni A, Mohale T, Moir M, Moruisi K, Mosepele M, Motsatsi G, Motswaledi MS, Mphoyakgosi T, Msomi N, Mwangi PN, Naidoo Y, Ntuli N, Nyaga M, Olubayo L, Pillay S, Radibe B, Ramphal Y, Ramphal U, San JE, Scott L, Shapiro R, Singh L, Smith-Lawrence P, Stevens W, Strydom A, Subramoney K, Tebeila N, Tshiabuila D, Tsui J, van Wyk S, Weaver S, Wibmer CK, Wilkinson E, Wolter N, Zarebski AE, Zuze B, Goedhals D, Preiser W, Treurnicht F, Venter M, Williamson C, Pybus OG, Bhiman J, Glass A, Martin DP, Rambaut A, Gaseitsiwe S, von Gottberg A, de Oliveira T. Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa. Nature 2022; 603(7902): 679–686

[4] Cao Y, Wang J, Jian F, Xiao T, Song W, Yisimayi A, Huang W, Li Q, Wang P, An R, Wang J, Wang Y, Niu X, Yang S, Liang H, Sun H, Li T, Yu Y, Cui Q, Liu S, Yang X, Du S, Zhang Z, Hao X, Shao F, Jin R, Wang X, Xiao J, Wang Y, Xie XS. Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies. Nature 2022; 602(7898): 657–663

[5] Wang L, Møhlenberg M, Wang P, Zhou H. Immune evasion of neutralizing antibodies by SARS-CoV-2 Omicron. Cytokine Growth Factor Rev 2023; 70: 13–25

[6] Zheng L, Liu S, Lu F. Impact of national Omicron outbreak at the end of 2022 on the future outlook of COVID-19 in China. Emerg Microbes Infect 2023; 12(1): 2191738

[7] Yang H, Rao Z. Structural biology of SARS-CoV-2 and implications for therapeutic development. Nat Rev Microbiol 2021; 19(11): 685–700

[8] Li G, Hilgenfeld R, Whitley R, De Clercq E. Therapeutic strategies for COVID-19: progress and lessons learned. Nat Rev Drug Discov 2023; 22(6): 449–475

[9] Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19—final report. N Engl J Med 2020; 383(19): 1813–1826

[10] Gottlieb RL, Vaca CE, Paredes R, Mera J, Webb BJ, Perez G, Oguchi G, Ryan P, Nielsen BU, Brown M, Hidalgo A, Sachdeva Y, Mittal S, Osiyemi O, Skarbinski J, Juneja K, Hyland RH, Osinusi A, Chen S, Camus G, Abdelghany M, Davies S, Behenna-Renton N, Duff F, Marty FM, Katz MJ, Ginde AA, Brown SM, Schiffer JT, Hill JA; GS-US-540-9012 (PINETREE) Investigators. Early remdesivir to prevent progression to severe Covid-19 in outpatients. N Engl J Med 2022; 386(4): 305–315

[11] Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, Baniecki M, Hendrick VM, Damle B, Simón-Campos A, Pypstra R, Rusnak JM; EPIC-HR Investigators. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med 2022; 386(15): 1397–1408

[12] Li P, Wang Y, Lavrijsen M, Lamers MM, de Vries AC, Rottier RJ, Bruno MJ, Peppelenbosch MP, Haagmans BL, Pan Q. SARS-CoV-2 Omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination. Cell Res 2022; 32(3): 322–324

[13] Yu B, Chang J. The first Chinese oral anti-COVID-19 drug azvudine launched. Innovation (Camb) 2022; 3(6): 100321

[14] Xie Y, Yin W, Zhang Y, Shang W, Wang Z, Luan X, Tian G, Aisa HA, Xu Y, Xiao G, Li J, Jiang H, Zhang S, Zhang L, Xu HE, Shen J. Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2. Cell Res 2021; 31(11): 1212–1214

[15] Cao Z, Gao W, Bao H, Feng H, Mei S, Chen P, Gao Y, Cui Z, Zhang Q, Meng X, Gui H, Wang W, Jiang Y, Song Z, Shi Y, Sun J, Zhang Y, Xie Q, Xu Y, Ning G, Gao Y, Zhao R. VV116 versus nirmatrelvir-ritonavir for oral treatment of Covid-19. N Engl J Med 2023; 388(5): 406–417

[16] Eastman RT, Roth JS, Brimacombe KR, Simeonov A, Shen M, Patnaik S, Hall MD. Remdesivir: a review of its discovery and development leading to emergency use authorization for treatment of COVID-19. ACS Cent Sci 2020; 6(5): 672–683

[17] US Food and Drug Administration. FDA approves first oral antiviral for treatment of COVID-19 in adults. Available at the website of FDA

[18] US Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for molnupiravir. Available at the website of FDA

[19] Gordon CJ, Tchesnokov EP, Woolner E, Perry JK, Feng JY, Porter DP, Götte M. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem 2020; 295(20): 6785–6797

[20] Cho A, Saunders OL, Butler T, Zhang L, Xu J, Vela JE, Feng JY, Ray AS, Kim CU. Synthesis and antiviral activity of a series of 1′-substituted 4-aza-7,9-dideazaadenosine C-nucleosides. Bioorg Med Chem Lett 2012; 22(8): 2705–2707

[21] CihlarTMackmanRL. Journey of remdesivir from the inhibition of hepatitis C virus to the treatment of COVID-19. Antivir Ther 2022; 27(2): 13596535221082773 doi:10.1177/13596535221082773

[22] Olender SA, Perez KK, Go AS, Balani B, Price-Haywood EG, Shah NS, Wang S, Walunas TL, Swaminathan S, Slim J, Chin B, De Wit S, Ali SM, Soriano Viladomiu A, Robinson P, Gottlieb RL, Tsang TYO, Lee IH, Hu H, Haubrich RH, Chokkalingam AP, Lin L, Zhong L, Bekele BN, Mera-Giler R, Phulpin C, Edgar H, Gallant J, Diaz-Cuervo H, Smith LE, Osinusi AO, Brainard DM, Bernardino JI; GS-US-540–5773, GS-US-540–5807 Investigators. Remdesivir for severe coronavirus disease 2019 (COVID-19) versus a cohort receiving standard of care. Clin Infect Dis 2021; 73(11): e4166–e4174

[23] WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet 2022; 399(10339): 1941–1953

[24] Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, Hu Y, Luo G, Wang K, Lu Y, Li H, Wang S, Ruan S, Yang C, Mei C, Wang Y, Ding D, Wu F, Tang X, Ye X, Ye Y, Liu B, Yang J, Yin W, Wang A, Fan G, Zhou F, Liu Z, Gu X, Xu J, Shang L, Zhang Y, Cao L, Guo T, Wan Y, Qin H, Jiang Y, Jaki T, Hayden FG, Horby PW, Cao B, Wang C. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020; 395(10236): 1569–1578

[25] Saravolatz LD, Depcinski S, Sharma M. Molnupiravir and nirmatrelvir-ritonavir: oral coronavirus disease 2019 antiviral drugs. Clin Infect Dis 2023; 76(1): 165–171

[26] Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, Leist SR, Schäfer A, Dinnon KH 3rd, Stevens LJ, Chappell JD, Lu X, Hughes TM, George AS, Hill CS, Montgomery SA, Brown AJ, Bluemling GR, Natchus MG, Saindane M, Kolykhalov AA, Painter G, Harcourt J, Tamin A, Thornburg NJ, Swanstrom R, Denison MR, Baric RS. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med 2020; 12(541): eabb5883

[27] Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, Martín-Quirós A, Caraco Y, Williams-Diaz A, Brown ML, Du J, Pedley A, Assaid C, Strizki J, Grobler JA, Shamsuddin HH, Tipping R, Wan H, Paschke A, Butterton JR, Johnson MG, De Anda C; MOVe-OUT Study Group. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med 2022; 386(6): 509–520

[28] National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. Available at the website of NIH

[29] Owen DR, Allerton CMN, Anderson AS, Aschenbrenner L, Avery M, Berritt S, Boras B, Cardin RD, Carlo A, Coffman KJ, Dantonio A, Di L, Eng H, Ferre R, Gajiwala KS, Gibson SA, Greasley SE, Hurst BL, Kadar EP, Kalgutkar AS, Lee JC, Lee J, Liu W, Mason SW, Noell S, Novak JJ, Obach RS, Ogilvie K, Patel NC, Pettersson M, Rai DK, Reese MR, Sammons MF, Sathish JG, Singh RSP, Steppan CM, Stewart AE, Tuttle JB, Updyke L, Verhoest PR, Wei L, Yang Q, Zhu Y. An oral SARS-CoV-2 M^pro inhibitor clinical candidate for the treatment of COVID-19. Science 2021; 374(6575): 1586–1593

[30] Mengist HM, Fan X, Jin T. Designing of improved drugs for COVID-19: crystal structure of SARS-CoV-2 main protease M^pro. Signal Transduct Target Ther 2020; 5(1): 67

[31] Zhao Y, Fang C, Zhang Q, Zhang R, Zhao X, Duan Y, Wang H, Zhu Y, Feng L, Zhao J, Shao M, Yang X, Zhang L, Peng C, Yang K, Ma D, Rao Z, Yang H. Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332. Protein Cell 2022; 13(9): 689–693

[32] Lamontagne F, Agarwal A, Rochwerg B, Siemieniuk RA, Agoritsas T, Askie L, Lytvyn L, Leo YS, Macdonald H, Zeng L, Amin W, da Silva ARA, Aryal D, Barragan FAJ, Bausch FJ, Burhan E, Calfee CS, Cecconi M, Chacko B, Chanda D, Dat VQ, De Sutter A, Du B, Freedman S, Geduld H, Gee P, Gotte M, Harley N, Hashimi M, Hunt B, Jehan F, Kabra SK, Kanda S, Kim YJ, Kissoon N, Krishna S, Kuppalli K, Kwizera A, Lado Castro-Rial M, Lisboa T, Lodha R, Mahaka I, Manai H, Mendelson M, Migliori GB, Mino G, Nsutebu E, Preller J, Pshenichnaya N, Qadir N, Relan P, Sabzwari S, Sarin R, Shankar-Hari M, Sharland M, Shen Y, Ranganathan SS, Souza JP, Stegemann M, Swanstrom R, Ugarte S, Uyeki T, Venkatapuram S, Vuyiseka D, Wijewickrama A, Tran L, Zeraatkar D, Bartoszko JJ, Ge L, Brignardello-Petersen R, Owen A, Guyatt G, Diaz J, Kawano-Dourado L, Jacobs M, Vandvik PO. A living WHO guideline on drugs for covid-19. BMJ 2020; 370: m3379

[33] Charness ME, Gupta K, Stack G, Strymish J, Adams E, Lindy DC, Mohri H, Ho DD. Rebound of SARS-CoV-2 infection after nirmatrelvir-ritonavir treatment. N Engl J Med 2022; 387(11): 1045–1047

[34] Sun L, Peng Y, Yu W, Zhang Y, Liang L, Song C, Hou J, Qiao Y, Wang Q, Chen J, Wu M, Zhang D, Li E, Han Z, Zhao Q, Jin X, Zhang B, Huang Z, Chai J, Wang JH, Chang J. Mechanistic insight into antiretroviral potency of 2′-deoxy-2′-β-fluoro-4′-azidocytidine (FNC) with a long-lasting effect on HIV-1 prevention. J Med Chem 2020; 63(15): 8554–8566

[35] Yu B, Chang J. Azvudine (FNC): a promising clinical candidate for COVID-19 treatment. Signal Transduct Target Ther 2020; 5(1): 236

[36] Wang RR, Yang QH, Luo RH, Peng YM, Dai SX, Zhang XJ, Chen H, Cui XQ, Liu YJ, Huang JF, Chang JB, Zheng YT. Azvudine, a novel nucleoside reverse transcriptase inhibitor showed good drug combination features and better inhibition on drug-resistant strains than lamivudine in vitro. PLoS One 2014; 9(8): e105617

[37] Ren Z, Luo H, Yu Z, Song J, Liang L, Wang L, Wang H, Cui G, Liu Y, Wang J, Li Q, Zeng Z, Yang S, Pei G, Zhu Y, Song W, Yu W, Song C, Dong L, Hu C, Du J, Chang J. A randomized, open-label, controlled clinical trial of azvudine tablets in the treatment of mild and common COVID-19, a pilot study. Adv Sci (Weinh) 2020; 7(19): 2001435

[38] Zhu KW. Efficacy and safety evaluation of azvudine in the prospective treatment of COVID-19 based on four phase III clinical trials. Front Pharmacol 2023; 14: 1228548

[39] Sun Y, Jin L, Dian Y, Shen M, Zeng F, Chen X, Deng G. Oral azvudine for hospitalised patients with COVID-19 and pre-existing conditions: a retrospective cohort study. EClinicalMedicine 2023; 59: 101981

[40] Gao Y, Luo Z, Ren S, Duan Z, Han Y, Liu H, Gao Z, Zhang X, Hu Z, Ma Y. Antiviral effect of azvudine and nirmatrelvir-ritonavir among hospitalized patients with COVID-19. J Infect 2023; 86(6): e158–e160

[41] Dian Y, Meng Y, Sun Y, Deng G, Zeng F. Azvudine versus Paxlovid for oral treatment of COVID-19 in Chinese patients with pre-existing comorbidities. J Infect 2023; 87(2): e24–e27

[42] Wang F, Xiao W, Tang Y, Cao M, Shu D, Asakawa T, Xu Y, Jiang X, Zhang L, Wang W, Tang J, Huang Y, Yang Y, Yang Y, Tang R, Shen J, Lu H. Efficacy and safety of SIM0417 (SSD8432) plus ritonavir for COVID-19 treatment: a randomised, double-blind, placebo-controlled, phase 1b trial. Lancet Reg Health West Pac 2023; 38: 100835

[43] Chen X, Li P, Huang J, Yang Y, Zhang H, Wang Z, Zhu Z, Wang J, Zhang J, Chen K, He H, Long C, Chen S. Discovery of novel bicyclic[3.3.0]proline peptidyl α-ketoamides as potent 3CL-protease inhibitors for SARS-CoV-2. Bioorg Med Chem Lett 2023; 90: 129324

[44] Zhu KW. Deuremidevir and simnotrelvir-ritonavir for the treatment of COVID-19. ACS Pharmacol Transl Sci 2023; 6(9): 1306–1309

[45] ChenXHuangXMaQ. Petr KuzmičZhouBXuJLiuBJiangHZhangWYangCWuSHuangJLiHLongCZhaoXXuHShengYGuoYNiuCXueLXuYLiuJZhangTJamesSpencerDengWChenSXiongXYangZZhongN. Inhibition mechanism and antiviral activity of an α-ketoamide based SARS-CoV-2 main protease inhibitor. 2023, PREPRINT (Version 1) Available at Research Square. doi: 10.21203/rs.3.rs-2634509/v1

[46] Wei D, Hu T, Zhang Y, Zheng W, Xue H, Shen J, Xie Y, Aisa HA. Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2. Bioorg Med Chem 2021; 46: 116364

[47] Zhang R, Zhang Y, Zheng W, Shang W, Wu Y, Li N, Xiong J, Jiang H, Shen J, Xiao G, Xie Y, Zhang L. Oral remdesivir derivative VV116 is a potent inhibitor of respiratory syncytial virus with efficacy in mouse model. Signal Transduct Target Ther 2022; 7(1): 123

[48] Pharmaceuticals and Medical Devices Agency. Tokyo: Pharmaceuticals and medical devices agency; c2022. Gilead sciences. section 2.6.4 pharmacokinetics written summary of remdesivir common technical document. 2020. Available at the website of Pharmaceuticals and Medical Devices Agency

[49] Qian HJ, Wang Y, Zhang MQ, Xie YC, Wu QQ, Liang LY, Cao Y, Duan HQ, Tian GH, Ma J, Zhang ZB, Li N, Jia JY, Zhang J, Aisa HA, Shen JS, Yu C, Jiang HL, Zhang WH, Wang Z, Liu GY. Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects. Acta Pharmacol Sin 2022; 43(12): 3130–3138

[50] National Health Commission of the People’s Republic of China. A transcript of Press Conference of The Joint Prevention and Control Mechanism of the State Council, 13 May 2022. Available at the website of NHC

[51] Shen Y, Ai J, Lin N, Zhang H, Li Y, Wang H, Wang S, Wang Z, Li T, Sun F, Fan Z, Li L, Lu Y, Meng X, Xiao H, Hu H, Ling Y, Li F, Li H, Xi C, Gu L, Zhang W, Fan X. An open, prospective cohort study of VV116 in Chinese participants infected with SARS-CoV-2 Omicron variants. Emerg Microbes Infect 2022; 11(1): 1518–1523

[52] Extance A. Covid-19: what is the evidence for the antiviral molnupiravir?. BMJ 2022; 377: o926

[53] WangLBergerNADavisPBKaelberDCVolkowNDXuR. COVID-19 rebound after Paxlovid and Molnupiravir during January–June 2022. medRxiv 2022; doi: 10.1101/2022.06.21.22276724

[54] Aggarwal NR, Molina KC, Beaty LE, Bennett TD, Carlson NE, Mayer DA, Peers JL, Russell S, Wynia MK, Ginde AA. Real-world use of nirmatrelvir-ritonavir in outpatients with COVID-19 during the era of omicron variants including BA.4 and BA.5 in Colorado, USA: a retrospective cohort study. Lancet Infect Dis 2023; 23(6): 696–705

[55] Ledford H. Long-COVID treatments: why the world is still waiting. Nature 2022; 608(7922): 258–260

[56] Ayoubkhani D, Bermingham C, Pouwels KB, Glickman M, Nafilyan V, Zaccardi F, Khunti K, Alwan NA, Walker AS. Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study. BMJ 2022; 377: e069676

[57] McCarthy MW. VV116 as a potential treatment for COVID-19. Expert Opin Pharmacother 2023; 24(6): 675–678

[58] Zhao J, Zhang G, Zhang Y, Yi D, Li Q, Ma L, Guo S, Li X, Guo F, Lin R, Luu G, Liu Z, Wang Y, Cen S. 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides: SARS-CoV-2 RNA-dependent RNA polymerase inhibitors. Antiviral Res 2021; 196: 105209

[59] Brown AJ, Won JJ, Graham RL, Dinnon KH 3rd, Sims AC, Feng JY, Cihlar T, Denison MR, Baric RS, Sheahan TP. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res 2019; 169: 104541

[60] Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, Leist SR, Schäfer A, Dinnon KH 3rd, Stevens LJ, Chappell JD, Lu X, Hughes TM, George AS, Hill CS, Montgomery SA, Brown AJ, Bluemling GR, Natchus MG, Saindane M, Kolykhalov AA, Painter G, Harcourt J, Tamin A, Thornburg NJ, Swanstrom R, Denison MR, Baric RS. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med 2020; 12(541): eabb5883

Acknowledgements

This work was supported by the National Major Scientific and Technological Special Project for “Significant New Drugs Development”(No. 2017ZX09304007), the National Natural Science Foundation of China (Nos. 82088102 and 81970728), the Science and Technology Commission of Shanghai Municipality (Nos. 22Y31900300 and 23XD1432600), and the Innovative Research Team of High-Level Local Universities in Shanghai. Yu Xu is supported by the “National Top Young Talents” program.

Compliance with ethics guidelines

Conflicts of interest Qiuyu Cao, Yi Ding, Yu Xu, Mian Li, Ruizhi Zheng, Zhujun Cao, Weiqing Wang, Yufang Bi, Guang Ning, Yiping Xu, and Ren Zhao declare that they have no conflicts of interest.

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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