Targeting Influenza Virus RdRp PB2 Subunit: Advances in Inhibitor Development for Antiviral Therapy

Qianhao Qin

doi:10.54097/e3g0fk77

Authors

Qianhao Qin

DOI:

https://doi.org/10.54097/e3g0fk77

Keywords:

Influenza virus; RNA-dependent RNA polymerase; PB2 subunit; Influenza polymerase inhibitors.

Abstract

Influenza remains a significant global health challenge, causing seasonal outbreaks and occasional pandemics. Current antiviral treatments are often limited by the virus’s rapid mutation and the emergence of drug resistance. The RNA-dependent RNA polymerase (RdRp) complex, composed of PA, PB1, and PB2 subunits, is crucial for viral replication, with PB2 playing a key role in binding host pre-mRNA during viral RNA synthesis. Targeting PB2 has become an attractive strategy for developing novel antivirals. In recent years, several small-molecule inhibitors have been identified that specifically disrupt PB2’s function, offering a promising approach to halting viral replication. This review explores the discovery and development of PB2 inhibitors, focusing on their structure-activity relationships and mechanisms of action. It also evaluates their effectiveness against various influenza strains, including drug-resistant variants, and highlights challenges in advancing PB2-targeted therapies. By analyzing current progress, this review aims to provide insights for future research in developing more effective antiviral strategies against influenza.

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References

[1] Liao Hui, Li Yinyan, Yu Luqiang, et al. Design, synthesis and structure-activity relationship of dihydrobenzoquinolines as novel inhibitors against influenza A virus. European Journal of Medicinal Chemistry, 2022, 244: 114799. DOI: https://doi.org/10.1016/j.ejmech.2022.114799

[2] Zhou Zhen, Liu Tian, Zhang Jun, et al. Influenza A virus polymerase: an attractive target for next-generation anti-influenza therapeutics. Drug Discovery Today, 2018, 23(3): 503-518. DOI: https://doi.org/10.1016/j.drudis.2018.01.028

[3] World Health Organization. Virus detections by subtype reported to FluNet. September 14, 2024. Retrieved on September 14, 2024. Retrieved from: https://www.who.int/

[4] Principi Nicola, Esposito Susanna. Drugs for influenza treatment: is there significant news? Frontiers in Pharmacology, 2020, 11: 1-15.

[5] Mills Christina E, Robins James M and Lipsitch Marc. Transmissibility of 1918 pandemic influenza. Nature, 2004, 432(16): 904-906. DOI: https://doi.org/10.1038/nature03063

[6] Moscona Anne. Neuraminidase inhibitors for influenza. The New England Journal of Medicine, 2005, 353: 1363-1373. DOI: https://doi.org/10.1056/NEJMra050740

[7] Moscona Anne. Global transmission of oseltamivir-resistant influenza. The New England Journal of Medicine, 2009, 360(10): 953-956. DOI: https://doi.org/10.1056/NEJMp0900648

[8] Feng Jingjing, Guo Fuyuan, Li Ping, et al. Discovery of a macrocyclic influenza cap-dependent endonuclease inhibitor. Journal of Medicinal Chemistry, 2024, 67(4): 2570-2583. DOI: https://doi.org/10.1021/acs.jmedchem.3c01715

[9] Takashita Emi, Kawakami Chika, Morita Hiroki, et al. Detection of influenza A (H3N2) viruses exhibiting reduced susceptibility to the novel cap-dependent endonuclease inhibitor baloxavir in Japan. Eurosurveillance, 2019, 24(3): 1800698. DOI: https://doi.org/10.2807/1560-7917.ES.2019.24.3.1800698

[10] Yoshino Ryo, Yasuo Nobuhiro, Sekijima Masakazu. Molecular dynamics simulation reveals the mechanism by which the influenza cap-dependent endonuclease acquires resistance against baloxavir marboxil. Scientific Reports, 2019, 9: 17464. DOI: https://doi.org/10.1038/s41598-019-53945-1

[11] Chen Fang, Yang Li, Zhai Liang, et al. Methyl brevifolin carboxylate, a novel influenza virus PB2 inhibitor from Canarium Album (Lour.) Raeusch. Chemical Biology & Drug Design, 2020, 96(5): 1280-1291. DOI: https://doi.org/10.1111/cbdd.13740

[12] Fan Haibo, Walker Andrew P, Carrique Lilia, et al. Structures of influenza A virus RNA polymerase offer insight into viral genome replication. Nature, 2019, 573: 287-290. DOI: https://doi.org/10.1038/s41586-019-1530-7

[13] Li Xinhong, Xu Yijie, Li Wei, et al. Design, synthesis, biological evaluation, and molecular dynamics simulation of influenza polymerase PB2 inhibitors. Molecules, 2023, 28, 1849. DOI: https://doi.org/10.3390/molecules28041849

[14] Chen Wenteng, Shao Jiaan, Ying Zhimin, et al. Approaches for discovery of small-molecular antivirals targeting the influenza A virus PB2 subunit. Drug Discovery Today, 2022, 27(6): 631-638. DOI: https://doi.org/10.1016/j.drudis.2022.02.024

[15] Clark Michael P, Ledeboer Mark W, Davies Ian, et al. Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2. Journal of Medicinal Chemistry, 2014, 57: 6668–6678.

[16] Farmer Leslie J, Clark Michael P, Boyd Michael J, et al. Discovery of novel, orally bioavailable β-aminoacid azaindole inhibitors of influenza PB2. ACS Medicinal Chemistry Letters, 2017, 8(2): 256-260. DOI: https://doi.org/10.1021/acsmedchemlett.6b00486

[17] Shinya Kawaoka, Kiso Masaki and Yamayoshi Shuichi. The X-Stand structure of baloxavir marboxil: a new antiviral drug with a novel mechanism of action against influenza A and B virus. Journal of Virology, 2014, 88(12): 7100-7110.

[18] Inoue Kazuhiro and Matsumoto Kazuhiko. Baloxavir marboxil for the treatment of influenza: clinical efficacy and safety profile. The Lancet Infectious Diseases, 2020, 20(5): 539-550.

[19] Chen Xiaoxin, Ma Qinhai, Zhao Manyu, et al. Preclinical study of ZSP1273, a potent antiviral inhibitor of cap binding to the PB2 subunit of influenza A polymerase. Pharmaceuticals, 2023, 16(3): 365-395. DOI: https://doi.org/10.3390/ph16030365

[20] McGowan David C, Balemans Wouter, Embrechts Wouter, et al. Design, synthesis, and biological evaluation of novel indoles targeting the influenza PB2 cap binding region. Journal of Medicinal Chemistry, 2019, 62: 9680-9690. DOI: https://doi.org/10.1021/acs.jmedchem.9b01091