Despite the availability of effective vaccines, hepatitis B virus (HBV) infection remains a significant global public health issue, causing nearly 1 million deaths annually. Nucleoside analogs, which act as competitive inhibitors of viral DNA polymerase and have been approved for the treatment of chronic HBV infection, show no inhibitory effect on the expression of HBeAg or HBsAg. Furthermore, the rapid development of drug-resistant viruses has become a major challenge. Therefore, there is an urgent need to discover novel chemical entities with new mechanisms of action or new therapeutic targets against HBV. Based on structure-activity relationship studies and computer-aided design, structural modifications of PA led to the development of a highly effective and low-toxicity anti-HBV molecule—PA-XY1. Further mechanistic studies indicated that PA-XY1 significantly downregulates the expression of hepatocyte nuclear factor-4α (HNF-4α), a mechanism distinct from traditional interferon-based and nucleoside analog anti-HBV drugs. This novel discovery suggests that PA-XY1 may act on a new therapeutic target; however, the specific molecular target remains unclear. Therefore, it is essential to further investigate the molecular target of the anti-HBV lead compound PA-XY1 to support the development of novel anti-HBV drugs.

Jia Luo, Xiaoqing Xu, Weiqi Wang, Ling Qiao. Design and Synthesis of Molecular Probes for the Determination of the Target of the Anti-HBV Lead PA-XY1. International Journal of Frontiers in Medicine (2024), Vol. 6, Issue 12: 45-52. https://doi.org/10.25236/IJFM.2024.061207.

[1] Halegoua-De Marzio D, Hann H W. Then and now: The progress in hepatitis B treatment over the past 20 years[J]. World journal of gastroenterology, 2014, 20(2): 401-413.

[2] Lv J J, Yu S, Wang Y F, et al. Anti-hepatitis B virus norbisabolane sesquiterpenoids from Phyllanthus acidus and the establishment of their absolute configurations using theoretical calculations[J]. Journal of Organic Chemistry, 2014, 79(12): 5432-5447.

[3] Geoghegan K F, Johnson D S. Chemical proteomic technologies for drug target identification[J]. Annual Reports in Medicinal Chemistry, 2010, 45, 345-360.

[4] Saitoh T, Takeiri M, Gotoh Y, et al. Design and synthesis of biotinylated DHMEQ for direct identification of its target NF-κB components[J]. Bioorganic & Medicinal Chemistry Letters, 2011, 21(21): 6293-6296.

[5] Liao L X, Song X M, Wang L C, et al. Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy[J]. Proceedings of the National Academy of Sciences of the United States of America, 2017, 114(29): 5986E5994.

[6] Liu C X, Yin Q, Zhou H C, et al. Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells[J]. Nature Chemical Biology, 2012, 8(5): 486-493.

[7] Li D, Li C, Li L, et al. Natural Product Kongensin A is a Non-Canonical HSP90 Inhibitor that Blocks RIP3-dependent Necroptosis[J]. Cell Chemical Biology, 2016, 23(2): 257-266.

[8] Zhou Y Q, Li W C, Zhang X X, et al. Global profiling of cellular targets of gambogic acid by quantitative chemical proteomics[J]. Chemical Communications 2016, 52(97): 14035-14038.

[9] Zhou Y Q, Di Z G, Li X M, et al. Chemical proteomics reveal CD147 as a functional target of pseudolaric acid B in human cancer cells[J]. Chemical Communications, 2017, 53(62): 8671-8674.

[10] Guo H J, Xu J Q, Hao P L, et al. Competitive affinity-based proteome profiling and imaging to reveal potential cellular targets of betulinic acid[J]. Chemical Communications, 2017, 53(69): 9620-9623.