Dihydroisocoumarins of Hydrangea macrophylla var. thunbergii inhibit binding of the SARS-CoV-2 spike protein to ACE2

Abstract

ABSTRACT Binding of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the cognate angiotensin-converting enzyme 2 (ACE2) receptor is the initial step in the viral infection process. In this study, we screened an in-house extract library to identify food materials with inhibitory activity against this binding using enzyme-linked immunosorbent assays and attempted to ascertain their active constituents. Hydrangea macrophylla var. thunbergii leaves were identified as candidate materials. Its active compounds were purified using conventional chromatographic methods and identified as naringenin and dihydroisocoumarins (hydrangenol and phyllodulcin), which have affinities for the ACE2 receptor and inhibit ACE2 receptor–spike S1 binding. Given that boiled water extracts of H. macrophylla leaves are commonly consumed as sweet tea in Japan, we speculated that this tea could be used as a potential natural resource to reduce the risk of SARS-CoV-2 infection.