新型冠状病毒感染口服治疗药物的研究进展

doi:10.5246/jcps.2024.11.078

摘要/Abstract

摘要：

2019年疫情爆发以来, 新冠病毒(SARS-CoV-2)从原始株依次经历了阿尔法(Alpha, α)、贝塔(Beta, β)、伽马(Gamma, γ)、德尔塔(Delta, δ)和奥密克戎(Omicron, ο)的5次大变异, 其传播力和致病性发生了很大的变化。目前的Omicron变异株传染性变强, 毒力变弱, 几乎不侵害肺部, 重症率和病死率比以前大大下降。SARS-CoV-2已经变异为一种常见的呼吸道病毒, 新冠病毒感染演变为一个常见的呼吸道传染病, 所以口服治疗药物的使用就显得尤为重要。口服小分子抗新冠病毒药不仅可以使轻中症患者不发展成重症, 而且可以减低重症患者的死亡率, 已经成为临床治疗新冠病毒感染的主力军。已有8款新冠口服药批准上市, 其中5款为3CL蛋白酶抑制剂, 分别为奈玛特韦/利托那韦片、先诺特韦/利托那韦片、阿泰特韦/利托那韦片、恩赛特韦片和来瑞特韦片; 另外3款为RNA聚合酶抑制剂, 分别为莫诺拉韦胶囊、阿兹夫定片和氘瑞米德韦片。已上市的口服治疗新冠病毒感染药物主要是3CL蛋白酶抑制剂和RNA聚合酶抑制剂, 临床的药品供应得到了充分的保障。随着感染后群体免疫屏障的建立, 加上口服小分子抗新冠病毒药的使用, 全球的COVID-19疫情对人类社会已经不能构成严重威胁。

关键词: 新冠病毒感染, 奥密克戎变异株, 口服治疗药物, 研究进展

Abstract:

SARS-CoV-2 has undergone five major transformations from its original strain, evolving through Alpha, Beta, Gamma, Delta, and now Omicron. The Omicron variant stands out for its high transmissibility, reduced severity, mild symptoms, and low mortality. Today, Omicron infections have become akin to common upper respiratory tract infections, underscoring the critical role of oral therapeutic drugs in clinical settings. These small-molecule oral antivirals are game-changers, effectively preventing mild and moderate cases from escalating to severe conditions and significantly reducing mortality among severe cases. They have emerged as the frontline defenders in the fight against SARS-CoV-2. Currently, eight oral antiviral drugs have been approved for use, including four 3CL protease inhibitors (nirmatrelvir/ritonavir, simnotrelvir/ritonavir, atilotrelvir/ritonavir, ensitrelvir, and leritrelvir), and three RNA polymerase inhibitors (molnupiravir, azvudine, and deuterium remdesivir). These medications are readily available and have ensured an uninterrupted clinical supply. With the establishment of a robust post-infection immune barrier and the widespread clinical use of oral antiviral drugs, the global threat posed by the COVID-19 pandemic has significantly diminished. The relentless march of scientific progress and medical innovation has turned the tide, making COVID-19 a manageable part of our lives.

Key words: SARS-CoV-2 infections, Omicron variants, Oral therapeutic drugs, Research progress

Supporting:

王立, 芮萌, 彭军, 凌云. 新型冠状病毒感染口服治疗药物的研究进展[J]. 中国药学(英文版), 2024, 33(11): 1082-1089.

Li Wang, Meng Rui, Jun Peng, Yun Ling. Advancements in oral therapeutic drugs for treating SARS-CoV-2 infections: A comprehensive review[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(11): 1082-1089.

参考文献 33

[1]	Ridgway, H.; Ntallis, C.; Chasapis, C.T.; Kelaidonis, K.; Matsoukas, M.T.; Plotas, P.; Apostolopoulos, V.; Moore, G.; Tsiodras, S.; Paraskevis, D.; Mavromoustakos, T.; Matsoukas, J.M. Molecular epidemiology of SARS-CoV-2: the dominant role of arginine in mutations and infectivity. Viruses. 2013, 15, 309.
[2]	Alkhatib, M.; Salpini, R.; Carioti, L.; Ambrosio, F.A.; D’Anna, S.; Duca, L.; Costa, G.; Bellocchi, M.C.; Piermatteo, L.; Artese, A.; Santoro, M.M.; Alcaro, S.; Svicher, V.; Ceccherini-Silberstein, F. Update on SARS-CoV-2 omicron variant of concern and its peculiar mutational profile. Microbiol. Spectr. 2022, 10, e0273221.
[3]	Ren, S.Y.; Wang, W.B.; Gao, R.D.; Zhou, A.M. Omicron variant (B.1.1.529) of SARS-CoV-2: Mutation, infectivity, transmission, and vaccine resistance. World J. Clin. Cases. 2022, 10, 1–11.
[4]	Christensen, P.A.; Olsen, R.J.; Long, S.W.; Snehal, R.; Davis, J.J.; Ojeda Saavedra, M.; Reppond, K.; Shyer, M.N.; Cambric, J.; Gadd, R.; Thakur, R.M.; Batajoo, A.; Mangham, R.; Pena, S.; Trinh, T.; Kinskey, J.C.; Williams, G.; Olson, R.; Gollihar, J.; Musser, J.M. Signals of significantly increased vaccine breakthrough, decreased hospitalization rates, and less severe disease in patients with coronavirus disease 2019 caused by the omicron variant of severe acute respiratory syndrome coronavirus 2 in Houston, texas. Am. J. Pathol. 2022, 192, 642–652.
[5]	Deng, X.D.; Wang, T.H.; Xiang, M.L.; Ke, J.L.; Gao, Q. Reflections on constructing a community of shared future between doctors and patients under the background that COVID-19 is classified as a Class B infectious disease. Modern Hospitals. 2023, 23, 772–775.
[6]	Mo, Z.F. World Health Organization has declared that the coronavirus outbreak no longer constitutes a public health emergency of international concern. World Sci. 2023, 6, 52.
[7]	Malone, B.; Urakova, N.; Snijder, E.J.; Campbell, E.A. Structures and functions of coronavirus replication–transcription complexes and their relevance for SARS-CoV-2 drug design. Nat. Rev. Mol. Cell Biol. 2022, 23, 21–39.
[8]	Guigon, A.; Faure, E.; Lemaire, C.; Chopin, M.C.; Tinez, C.; Assaf, A.; Lazrek, M.; Hober, D.; Bocket, L.; Engelmann, I.; Alidjinou, E.K. Emergence of Q493R mutation in SARS-CoV-2 spike protein during bamlanivimab/etesevimab treatment and resistance to viral clearance. J. Infect. 2022, 84, 248–288.
[9]	Mahase, E. Covid-19: Pfizer’s paxlovid is 89% effective in patients at risk of serious illness, company reports. BMJ. 2021, 375, n2713.
[10]	Tao, K.M.; Tzou, P.; Nouhin, J.; Bonilla, H.; Jagannathan, P.; Shafer, R. SARS-CoV-2 antiviral therapy. Clin. Microbiol. Rev. 2021, 34, e0010921.
[11]	Chavda, V.P.; Patel, A.B.; Vaghasiya, D.D. SARS-CoV-2 variants and vulnerability at the global level. J. Med. Virol. 2022, 94, 2986–3005.
[12]	Ledford, H.; Maxmen, A. African clinical trial denied access to key COVID drug Paxlovid. Nature. 2022, 604, 412–413.
[13]	Mohapatra, R.K.; Kandi, V.; Sarangi, A.K.; Verma, S.; Tuli, H.S.; Chakraborty, S.; Chakraborty, C.; Dhama, K. The recently emerged BA.4 and BA.5 lineages of Omicron and their global health concerns amid the ongoing wave of COVID-19 pandemic-Correspondence. Int. J. Surg. 2022, 103, 106698.
[14]	Vangeel, L.; Chiu, W.; De Jonghe, S.; Maes, P.; Slechten, B.; Raymenants, J.; André, E.; Leyssen, P.; Neyts, J.; Jochmans, D. Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antiviral Res. 2022, 198, 105252.
[15]	Owen, D.R.; Allerton, C.M.N.; Anderson, A.S.; Aschenbrenner, L.; Avery, M.; Berritt, S.; Boras, B.; Cardin, R.D.; Carlo, A.; Coffman, K.J.; Dantonio, A.; Di, L.; Eng, H.; Ferre, R.; Gajiwala, K.S.; Gibson, S.A.; Greasley, S.E.; Hurst, B.L.; Kadar, E.P.; Kalgutkar, A.S.; Lee, J.C.; Lee, J.; Liu, W.; Mason, S.W.; Noell, S.; Novak, J.J.; Obach, R.S.; Ogilvie, K.; Patel, N.C.; Pettersson, M.; Rai, D.K.; Reese, M.R.; Sammons, M.F.; Sathish, J.G.; Singh, R.S.P.; Steppan, C.M.; Stewart, A.E.; Tuttle, J.B.; Updyke, L.; Verhoest, P.R.; 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, 1586–1593.
[16]	Alugubelli, Y.R.; Geng, Z.Z.; Yang, K.S.; Shaabani, N.; Khatua, K.; Ma, X.R.; Vatansever, E.C.; Cho, C.C.; Ma, Y.; Xiao, J.; Blankenship, L.R.; Yu, G.; Sankaran, B.; Li, P.; Allen, R.; Ji, H.; Xu, S.; Liu, W.R. A systematic exploration of boceprevir-based main protease inhibitors as SARS-CoV-2 antivirals. Eur. J. Med. Chem. 2022, 240, 114596.
[17]	National Health Commission, State Administration of Traditional Chinese Medicine. Diagnosis and treatment of COVID-19 (The ninth edition) [EB/OL]. (2022-03-14) [2022-03-15]. This article can be found online at https://www.gov.cn/zhengce/zhengceku/2022-03/15/content_5679257.htm.
[18]	Sasaki, M.; Tabata, K.; Kishimoto, M.; Itakura, Y.; Kobayashi, H.; Ariizumi, T.; Uemura, K.; Toba, S.; Kusakabe, S.; Maruyama, Y.; Iida, S.; Nakajima, N.; Suzuki, T.; Yoshida, S.; Nobori, H.; Sanaki, T.; Kato, T.; Shishido, T.; Hall, W.W.; Orba, Y.; Sato, A.; Sawa, H. S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters. Sci. Transl. Med. 2023, 15, eabq4064.
[19]	Mukae, H.; Yotsuyanagi, H.; Ohmagari, N.; Doi, Y.; Imamura, T.; Sonoyama, T.; Fukuhara, T.; Ichihashi, G.; Sanaki, T.; Baba, K.; Takeda, Y.; Tsuge, Y.; Uehara, T. A randomized phase 2/3 study of ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection: results of the phase 2a part. Antimicrob. Agents Chemother. 2022, 66, e0069722.
[20]	Feng, X.; Guan, Q. Ensitrelvir, Xocova. Chin. J. Med. Chem. 2023, 33, 159.
[21]	Lu, L.; Wu, Q.; Wang, F. XIANNUOXIN^®: China’s first anti-SARS-CoV-2 drug targeting 3C-like protease. Progr. Pharmac. Sci. 2023, 47, 484–488.
[22]	Cao, B.; Wang, Y.; Lu, H.; Huang, C.; Yang, Y.; Shang, L.; Chen, Z.; Jiang, R.; Liu, Y.; Lin, L.; Peng, P.; Wang, F.; Gong, F.; Hu, H.; Cheng, C.; Yao, X.; Ye, X.; Zhou, H.; Shen, Y.; Liu, C.; Wang, C.; Yi, Z.; Hu, B.; Xu, J.; Gu, X.; Shen, J.; Xu, Y.; Zhang, L.; Fan, J.; Tang, R.; Wang, C. Oral simnotrelvir for adult patients with mild-to-moderate covid-19. N. Engl. J. Med. 2024, 390, 230–241.
[23]	Li, B.; Liu, C.W.; Li, Z.H.; Wang, L.; Jiang, W.H. Preparation and structural identification of the chiral isomers of SMA-1, the key starting material of leritrelvir. Chin. J. Med. Chem. 2023, 33, 904–909.
[24]	Ding, Y.H.; Liu, L. Phase I study, and dosing regimen selection for a pivotal COVID-19 trial of GST-HG171. Antimicrob. Agents Chemother. 2024, 68, e0111523.
[25]	Zhang, J.L.; Li, Y.H.; Wang, L.L.; Liu, H.Q.; Lu, S.Y.; Liu, Y.; Li, K.; Liu, B.; Li, S.Y.; Shao, F.M.; Wang, K.; Sheng, N.; Li, R.; Cui, J.J.; Sun, P.C.; Ma, C.X.; Zhu, B.; Wang, Z.; Wan, Y.H.; Yu, S.S.; Che, Y.S.; Wang, C.Y.; Wang, C.; Zhang, Q.Q.; Zhao, L.M.; Peng, X.Z.; Cheng, Z.S.; Chang, J.B.; Jiang, J.D. Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective in treating COVID-19 patients. Signal Transduct. Target. Ther. 2021, 6, 414.
[26]	Pourkarim, F.; Pourtaghi-Anvarian, S.; Rezaee, H. Molnupiravir: a new candidate for COVID-19 treatment. Pharmacol. Res. Perspect. 2022, 10, e00909.
[27]	Fischer, W.A.; Eron, J.J.; Holman, W.; Cohen, M.S.; Fang, L.; Szewczyk, L.J.; Sheahan, T.P.; Baric, R.; Mollan, K.R.; Wolfe, C.R.; Duke, E.R.; Azizad, M.M.; Borroto-Esoda, K.; Wohl, D.A.; Coombs, R.W.; James Loftis, A.; Alabanza, P.; Lipansky, F.; Painter, W.P. A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci. Transl. Med. 2022, 14, eabl7430.
[28]	Ren, Z.G.; Luo, H.; Yu, Z.J.; Song, J.C.; Liang, L.; Wang, L.; Wang, H.Y.; Cui, G.Y.; Liu, Y.; Wang, J.; Li, Q.Q.; Zeng, Z.H.; Yang, S.K.; Pei, G.Z.; Zhu, Y.H.; Song, W.B.; Yu, W.Q.; Song, C.J.; Dong, L.H.; Hu, C.S.; Du, J.F.; Chang, J.B. A randomized, open-label, controlled clinical trial of azvudine tablets in the treatment of mild and common COVID-19, a pilot study. Adv. Sci. 2020, 7, e2001435.
[29]	Shen, Y.Z.; Ai, J.W.; Lin, N.; Zhang, H.C.; Li, Y.; Wang, H.Y.; Wang, S.; Wang, Z.; Li, T.; Sun, F.; Fan, Z.Y.; Li, L.Q.; Lu, Y.F.; Meng, X.M.; Xiao, H.; Hu, H.L.; Ling, Y.; Li, F.; Li, H.D.; Xi, C.M.; Gu, L.P.; Zhang, W.H.; Fan, X.H. An open, prospective cohort study of VV116 in Chinese participants infected with SARS-CoV-2 omicron variants. Emerg. Microbes Infect. 2022, 11, 1518–1523.
[30]	McCarthy, M.W. VV116 as a potential treatment for COVID-19. Expert. Opin Pharmacother. 2023, 24, 675–678.
[31]	Fan, X.; Dai, X.; Ling, Y.; Wu, L.; Tang, L.; Peng, C.; Huang, C.; Liu, H.; Lu, H.; Shen, X.; Zhang, W.; Wang, F.; Li, G.; Li, M.; Huang, Y.; Zhang, H.; Li, M.; Ren, F.; Li, Y.; Liu, C.; Zhou, Z.; Sun, W.; Yi, Y.; Zhou, D.; Gao, H.; Pan, Q.; Liu, H.; Zhao, J.; Ding, Z.; Ma, Y.; Li, W.; Wang, Q.; Wang, X.; Bai, Y.; Jiang, X.; Ma, J.; Xie, B.; Zhang, K.; Li, L. Oral VV116 versus placebo in patients with mild-to-moderate COVID-19 in China: a multicentre, double-blind, phase 3, randomised controlled study. Lancet Infect. Dis. 2024, 24, 129–139.
[32]	Feng, X.; Guan, Q. Renmindevir. Chin. J. Med. Chem. 2023, 33, 160.
[33]	Chatterjee, S.; Bhattacharya, M.; Nag, S.; Dhama, K.; Chakraborty, C. A detailed overview of SARS-CoV-2 omicron: its sub-variants, mutations and pathophysiology, clinical characteristics, immunological landscape, immune escape, and therapies. Viruses. 2023, 15, 167.