Hymecromone: a clinical prescription hyaluronan inhibitor for efficiently blocking COVID-19 progression

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).

Figures

Fig. 1

The increase of hyaluronan is related to the severity in COVID-19 patients. a The plasma hyaluronan level of COVID-19 patients and normal healthy subjects were evaluated by ELISA. The classification of mild and severe of COVID-19 was based on pulmonary lesions of chest CT. b ROC of the plasma hyaluronan level in normal volunteers and COVID-19 patients. The 48.43 ng/mL of hyaluronan is the cutoff value to distinguish the normal subjects and COVID-19 patients. c Counts of lymphocytes upon admission plotted against hyaluronic acid. d Two-tailed Spearman’s correlation analysis was performed to evaluate the correlation between hyaluronan and lymphocyte counts. Data are presented by mean ± SD. The significant difference in (a) and (c) was analyzed by the Mann–Whitney test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; ns, not significant

Fig. 2

The plasma level of hyaluronan as a typical indicator of COVID-19 patients in the clinical setting. a C-reactive protein of COVID-19 patients is showing based on the threshold of 48.43 ng/mL of hyaluronan. b The relation of C-reactive protein against hyaluronic acid was determined by two-tailed Spearman’s correlation analysis. c D-dimer of COVID-19 patients is showing based on the threshold of 48.43 ng/mL of hyaluronan. d The relation of D-dimer against hyaluronic acid was determined by two-tailed Spearman’s correlation analysis. e Fibrinogen of COVID-19 patients are showing based on the threshold of 48.43 ng/mL of hyaluronan. f The relation of fibrinogen against hyaluronic acid was determined by two-tailed Spearman’s correlation analysis. Data in (a, c, and e) are presented by mean ± SD. The significant difference was confirmed by the Mann–Whitney test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; ns, not significant

Fig. 3

Correlation between hyaluronan and pulmonary lesions in COVID-19 patients with a low level of hyaluronan (HA a, b Scatter plot showing relation on the mass (a) and volume (b) of GGO against hyaluronic acid. c, d Scatter plot showing relation on the mass (c) and volume (d) of the consolidation region against hyaluronic acid. Mass and volume of pulmonary lesions were calculated via the automatic lung segmentation technology of AI based on CT images of severe COVID-19 patients. GGO was defined a range from −750 HU to −300 HU, and the consolidation region was defined from −300 HU to 50 HU. Two-tailed Spearman’s correlation analysis was performed to identify the relation of pulmonary lesions against hyaluronic acid

Fig. 4

Hyaluronan directly induces GGO and consolidation in adult mice. Represented CT images of lungs in mice with different treatments are shown. Adult C57BL/6 mice were used to assess whether hyaluronic acid induces pulmonary lesions. We directly delivered hyaluronan (200–400 kDa) to the trachea (n = 3), and 1× PBS treatment was as the control group (n = 3). Then, we monitored the lungs of mice in two groups via QuantumGX microCT at the fourth day

Fig. 5

Hymecromone decreases hyaluronan by downregulating hyaluronic acid synthases. a ELISA detected the hyaluronic acid level of culture medium in HEK293T and HUVEC treated with DMSO or hymecromone (200 μg/mL). The fold change of hyaluronic acid was normalized to DMSO. b RT-qPCR evaluated the mRNA levels of HAS1, HAS2, and HAS3 in HEK293T treated with DMSO or hymecromone (200 μg/mL). c RT-qPCR evaluated the mRNA levels of HAS1, HAS2, and HAS3 in HUVEC treated with DMSO or hymecromone (200 μg/mL). All experiments were repeated independently in triplicate. Data are presented by mean ± SD. The significant difference was confirmed by unpaired t test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; ns, not significant

Fig. 6

The Consort Diagram of recruited COVID-19 patients for this clinical trial. Among these patients, 94 patients were in the trial group while 50 patients were in the control group. Changes in lymphocytes, CRP, fibrinogen, and D-dimer were set as the primary endpoints and change in chest CT results was set as the secondary endpoint

Fig. 7

Represented CT images of COVID-19 patients with support or hymecromone treatment. The original CT results are shown in black-and-white images of two groups while the marked lesion regions of CT results are shown in color images of two groups. Red regions indicate GGO, and green regions indicate consolidation

Fig. 8

Hymecromone accelerate the recovery of COVID-19 patients from lymphocytopenia. Changes in lymphocytes (a), CRP (b), fibrinogen (c), and D-dimer (d) were calculated as the fold change of diverse clinical indicators per day in patients with lymphocytopenia. Data are presented by mean ± SEM. The significant difference was confirmed by the Mann–Whitney test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; ns, not significant