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.

Role of the extracellular matrix in COVID-19

“…Hellman et al [ 13 ] reported that fatal cases of COVID-19 were associated with the accumulation of hyaluronic acid in the alveolar spaces of the lungs and occurrences of hypoxemia and respiratory failure. A mouse model has also been shown to develop lesions in the lungs due to HA[ 15 ]. In a prospective study, the authors found that the COVID-19 cytokine milieu stimulates aberrant synthesis and degradation of HA, and HA fragments present at elevated levels in COVID-19 patient plasma directly induce endothelial barrier dysfunction[ 16 ].…”

Viral miRNA-mediated activation of hyaluronan production as a drug target against COVID-19

“…We have confirmed that hymecromone could inhibit hyaluronan production in HEK293T and MRC5 cells 4 , thereby demonstrating its potential to treat COVID-19 by reducing hyaluronan. Through a subsequent clinical trial, we also found that hymecromone could improve clinical manifestations (such as lymphopenia and pulmonary lesions) 9 . Assuredly, many more lives could be saved if the efficacy of hymecromone against COVID-19 is confirmed in a larger sample.…”

“…Furthermore, since hyaluronan is closely associated with currently known indicators (such as C-reactive protein, and lymphocytes) of COVID-19 progression 9 , it may also be used to distinguish different stages of COVID-19. The recent appearance of the Omicron variant has resulted in many asymptomatic infections of SARS-CoV-2 worldwide.…”

Vascular Endothelial Glycocalyx Damage and Potential Targeted Therapy in COVID-19

“…The small HA fragments bound to their receptors CD44 and layilin to activate the Rho-associated protein kinase (ROCK) signaling pathway, which were known to disrupt the endothelial barrier integrity [ 106 ]. Hymecromone, a synthetic inhibitor of HA, has been shown to improve lymphopenia and lung lesions, promoting the recovery of clinical manifestations in SARS-CoV-2-infected patients [ 127 ]. These studies indicated the role for HA in the vascular pathology of COVID-19, and more components that induce endothelial dysfunction need to be further confirmed.…”