October 31, 2024
Keio University
Osaka University
A research group led by Associate Professor Daisuke Takahashi and Professor Kazunobu Toshima of the Department of Applied Chemistry, Faculty of Science and Technology, Keio University, and Assistant Professor Itsuki Anzai and Professor Tokiko Watanabe of the Research Institute for Microbial Diseases, Osaka University, has chemically synthesized analogs (carbohydrates) of sulfated tetrasaccharides, which form the basic structure of fucoidan found in components such as the slime of seaweed. The group evaluated their inhibitory activity against the enzyme heparanase, which is involved in the severity of COVID-19, and their infection inhibitory activity against the novel coronavirus (hereinafter, SARS-CoV-2). As a result, they revealed that these analogs possess both heparanase inhibitory activity and SARS-CoV-2 infection inhibitory activity, and found that they are promising as lead compounds for therapeutic drugs that suppress the severity of COVID-19.
Although it has been reported that naturally derived fucoidan exhibits SARS-CoV-2 infection inhibitory activity, it was not known which partial structure is important for expressing this activity because it is a polysaccharide with a heterogeneous structure. The research group had previously chemically synthesized 13 types of sulfated tetrasaccharides (fucoidan analogs) with various sulfation patterns and glycan structures, and had identified analogs with high binding activity to the spike protein, the surface antigen of SARS-CoV-2. In this study, they revealed that a new analog, created by changing the aglycone structure from an octyl group to a cholestanyl group among the previously identified analogs, exhibits high binding activity to the spike protein. Furthermore, they determined that this analog also inhibits the activity of heparanase, whose expression level increases in correlation with the severity of COVID-19. In addition, they found that this analog suppresses infection not only by the original Wuhan strain from the beginning of the COVID-19 pandemic but also by variant strains such as the Omicron BA.2 and BA.5 subvariants. From these findings, this research is expected to contribute to the development of new therapeutic drugs for COVID-19 that are effective against various variant strains and suppress disease severity.
The results of this research were published online on October 7, 2024, in “Angewandte Chemie International Edition,” a journal of the German Chemical Society.
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