Hymecromone: a clinical prescription hyaluronan inhibitor for efficiently blocking COVID-19 progression
Shuai Yang, Yun Ling, Fang Zhao, Wei Li, Zhigang Song, Lu Wang, Qiuting Li, Mengxing Liu, Ying Tong, Lu Chen, Daoping Ru, Tongsheng Zhang, Kaicheng Zhou, Baolong Zhang, Peng Xu, Zhicong Yang, Wenxuan Li, Yuanlin Song, Jianqing Xu, Tongyu Zhu, Fei Shan, Wenqiang Yu, Hongzhou Lu, Shuai Yang, Yun Ling, Fang Zhao, Wei Li, Zhigang Song, Lu Wang, Qiuting Li, Mengxing Liu, Ying Tong, Lu Chen, Daoping Ru, Tongsheng Zhang, Kaicheng Zhou, Baolong Zhang, Peng Xu, Zhicong Yang, Wenxuan Li, Yuanlin Song, Jianqing Xu, Tongyu Zhu, Fei Shan, Wenqiang Yu, Hongzhou Lu
Abstract
Currently, there is no effective drugs for treating clinically COVID-19 except dexamethasone. We previously revealed that human identical sequences of SARS-CoV-2 promote the COVID-19 progression by upregulating hyaluronic acid (HA). As the inhibitor of HA synthesis, hymecromone is an approved prescription drug used for treating biliary spasm. Here, we aimed to investigate the relation between HA and COVID-19, and evaluate the therapeutic effects of hymecromone on COVID-19. Firstly, HA was closely relevant to clinical parameters, including lymphocytes (n = 158; r = -0.50; P < 0.0001), C-reactive protein (n = 156; r = 0.55; P < 0.0001), D-dimer (n = 154; r = 0.38; P < 0.0001), and fibrinogen (n = 152; r = 0.37; P < 0.0001), as well as the mass (n = 78; r = 0.43; P < 0.0001) and volume (n = 78; r = 0.41; P = 0.0002) of ground-glass opacity, the mass (n = 78; r = 0.48; P < 0.0001) and volume (n = 78; r = 0.47; P < 0.0001) of consolidation in patient with low level of hyaluronan (HA < 48.43 ng/mL). Furthermore, hyaluronan could directly cause mouse pulmonary lesions. Besides, hymecromone remarkably reduced HA via downregulating HAS2/HAS3 expression. Moreover, 89% patients with hymecromone treatment had pulmonary lesion absorption while only 42% patients in control group had pulmonary lesion absorption (P < 0.0001). In addition, lymphocytes recovered more quickly in hymecromone-treated patients (n = 8) than control group (n = 5) (P < 0.05). These findings suggest that hymecromone is a promising drug for COVID-19 and deserves our further efforts to determine its effect in a larger cohort.
Conflict of interest statement
Wenqiang Yu et al. are listed as inventors on patents’ applications related to this study. There are no other relationships or activities that could influence this submitted work.
© 2022. The Author(s).
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References
- Baj, A. et al. Breakthrough infections of E484K-harboring SARS-CoV-2 delta variant, Lombardy, Italy. Emerg. Infect. Dis.27, 3180 (2021).
- Kabinger F, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat. Struct. Mol. Biol. 2021;28:740–746. doi: 10.1038/s41594-021-00651-0.
- Owen DR, et al. An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19. Science. 2021;374:1586–1593. doi: 10.1126/science.abl4784.
- Hurt, A. C. & Wheatley, A. K. Neutralizing antibody therapeutics for COVID-19. Viruses13, 628 (2021).
- Xiang, R. et al. Recent advances in developing small-molecule inhibitors against SARS-CoV-2. Acta Pharm. Sin. B (2021).
- Cui W, Yang K, Yang H. Recent progress in the drug development targeting SARS-CoV-2 main protease as treatment for COVID-19. Front. Mol. Biosci. 2020;7:616341. doi: 10.3389/fmolb.2020.616341.
- Du L, Yang Y, Zhang X, Li F. Recent advances in nanotechnology-based COVID-19 vaccines and therapeutic antibodies. Nanoscale. 2022;14:1054–1074. doi: 10.1039/D1NR03831A.
- Li W, et al. SARS-CoV-2 RNA elements share human sequence identity and upregulate hyaluronan via NamiRNA-enhancer network. eBioMedicine. 2022;76:103861. doi: 10.1016/j.ebiom.2022.103861.
- Xu Z, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respiratory Med. 2020;8:420–422. doi: 10.1016/S2213-2600(20)30076-X.
- Hällgren R, Samuelsson T, Laurent TC, Modig J. Accumulation of hyaluronan (hyaluronic acid) in the lung in adult respiratory distress syndrome. Am. Rev. Respir. Dis. 1989;139:682–687. doi: 10.1164/ajrccm/139.3.682.
- Hellman U, et al. Presence of hyaluronan in lung alveoli in severe Covid-19: an opening for new treatment options? J. Biol. Chem. 2020;295:15418–15422. doi: 10.1074/jbc.AC120.015967.
- Liang J, Jiang D, Noble PW. Hyaluronan as a therapeutic target in human diseases. Adv. Drug Deliv. Rev. 2016;97:186–203. doi: 10.1016/j.addr.2015.10.017.
- Guan WJ, et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020;382:1708–1720. doi: 10.1056/NEJMoa2002032.
- Huang C, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. doi: 10.1016/S0140-6736(20)30183-5.
- Nagy N, et al. 4-methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy in inflammation, autoimmunity, and cancer. Front. Immunol. 2015;6:123.
- Richardson S, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323:2052–2059. doi: 10.1001/jama.2020.6775.
- Ruffell B, Johnson P. Hyaluronan induces cell death in activated T cells through CD44. J. Immunol. 2008;181:7044–7054. doi: 10.4049/jimmunol.181.10.7044.
- Zhao W, Zhong Z, Xie X, Yu Q, Liu J. Relation between chest CT findings and clinical conditions of coronavirus disease (COVID-19) pneumonia: a multicenter study. AJR Am. J. Roentgenol. 2020;214:1072–1077. doi: 10.2214/AJR.20.22976.
- Jacobs C, et al. Automatic detection of subsolid pulmonary nodules in thoracic computed tomography images. Med. Image Anal. 2014;18:374–384. doi: 10.1016/j.media.2013.12.001.
- Shi Y, et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ. 2020;27:1451–1454. doi: 10.1038/s41418-020-0530-3.
- Kultti A, et al. 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. Exp. Cell Res. 2009;315:1914–1923. doi: 10.1016/j.yexcr.2009.03.002.
- Andonegui-Elguera, S. et al. Molecular alterations prompted by SARS-CoV-2 infection: induction of hyaluronan, glycosaminoglycan and mucopolysaccharide metabolism. Arch. Med. Res.51, 645–653 (2020).
- Ding M, Zhang Q, Li Q, Wu T, Huang YZ. Correlation analysis of the severity and clinical prognosis of 32 cases of patients with COVID-19. Respir. Med. 2020;167:105981. doi: 10.1016/j.rmed.2020.105981.
- Esposito AJ, Bhatraju PK, Stapleton RD, Wurfel MM, Mikacenic C. Hyaluronic acid is associated with organ dysfunction in acute respiratory distress syndrome. Crit. Care. 2017;21:304. doi: 10.1186/s13054-017-1895-7.
- Ponti G, Maccaferri M, Ruini C, Tomasi A, Ozben T. Biomarkers associated with COVID-19 disease progression. Crit. Rev. Clin. Lab. Sci. 2020;57:389–399. doi: 10.1080/10408363.2020.1770685.
- Shi W, et al. A deep learning-based quantitative computed tomography model for predicting the severity of COVID-19: a retrospective study of 196 patients. Ann. Transl. Med. 2021;9:216. doi: 10.21037/atm-20-2464.
- Yang, S. et al. Clinical and CT features of early stage patients with COVID-19: a retrospective analysis of imported cases in Shanghai, China. Eur. Respir. J.55, 2000407 (2020).
- Zhang W, et al. The characteristics and predictive role of lymphocyte subsets in COVID-19 patients. Int. J. Infect. Dis. 2020;99:92–99. doi: 10.1016/j.ijid.2020.06.079.
- Wiersinga, W. J., Rhodes, A., Cheng, A. C., Peacock, S. J. & Prescott, H. C. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. J. Am. Med. Assoc.324, 782–793 (2020).
- Group, R. C. et al. Dexamethasone in hospitalized patients with Covid-19. N. Engl. J. Med.384, 693–704 (2021).
- Tomazini BM, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: The CoDEX Randomized Clinical Trial. J. Am. Med. Assoc. 2020;324:1307–1316. doi: 10.1001/jama.2020.17021.
- Luo P, et al. Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis. Am. J. Trop. Med Hyg. 2020;103:69–72. doi: 10.4269/ajtmh.20-0375.
- Gebhardt C, et al. Dermal hyaluronan is rapidly reduced by topical treatment with glucocorticoids. J. Investig. Dermatol. 2010;130:141–149. doi: 10.1038/jid.2009.210.
- Sainio A, et al. Metformin decreases hyaluronan synthesis by vascular smooth muscle cells. J. Investig. Med. 2020;68:383–391. doi: 10.1136/jim-2019-001156.
- Li Q, Wang L, Wang B, Lu H. The COVID-19-designated hospitals in China: preparing for public health emergencies. Emerg. Microbes Infect. 2021;10:998–1001. doi: 10.1080/22221751.2021.1931467.
- Shan F, et al. Abnormal lung quantification in chest CT images of COVID-19 patients with deep learning and its application to severity prediction. Med Phys. 2021;48:1633–1645. doi: 10.1002/mp.14609.
- Song YS, et al. Volume and mass doubling times of persistent pulmonary subsolid nodules detected in patients without known malignancy. Radiology. 2014;273:276–284. doi: 10.1148/radiol.14132324.
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