Water-soluble compounds from Lignosus rhinocerus TM02 ® (xLr™) modulate ACE2 activity and inhibit its interaction with SARS-CoV-2 spike-protein

• Main Authors: Goh, Neng-Yao, Yap, Yeannie Hui-Yeng, Ng, Chyan Leong, Kong, Boon Hong, Ng, Szu-Ting, Tan, Chon-Seng, Razif, Muhammad Fazril Mohamad, Fung, Shin Yee
• Format: Article
• Published: Elsevier 2024
• Subjects: R Medicine
• Online Access: http://eprints.um.edu.my/45173/; https://doi.org/10.1016/j.fbio.2024.104232
• Institution: Universiti Malaya

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a coronavirus that causes COVID-19 by attaching its spike protein (S-protein) to the ACE2 receptor on host cells. This interaction is critical for viral entry and infection. Water-soluble compounds found in the medicinal mushroom Lignosus rhinocerus TM02 (R) (Tiger Milk mushroom) may potentially reduce the risk of SARS-CoV-2 infection by modulating human ACE2 activity, shielding it from binding with the S-protein. In this study, the cold-water-extract (xLr (TM)) and bioactive fractions of TM02 (R), a standardized L. rhinocerus cultivar, were evaluated for their potentials to modulate ACE2 activity and prevent SARS-CoV-2 spike protein-ACE2 binding. Both xLr (TM) and its high-molecular weight (HMW) fraction exhibited low ACE2 inhibitory activities (<20% inhibition), while the medium-molecular weight (MMW) fraction demonstrated both dose- and time-dependent inhibitions (IC50 = 1.161 +/- 0.148 mg mL(-1)). The low-molecular weight (LMW) fraction also demonstrated dose-dependent inhibition of ACE2 activity (IC50 = 1.818 +/- 0.233 mg mL(-1)), without affecting SARS-CoV-2 spike protein binding to the former. Molecular docking simulations revealed that xLr (TM) LMW molecules are able to bind to the ACE2 substrate enzymatic site, rather than the S-protein(RBD) binding site. xLr (TM), and its HMW and MMW fractions successfully suppressed SARS-CoV-2 spike protein-ACE2 binding in a dose-dependent manner (>95% inhibition at 10 mg mL(-1)). The observed inhibitory activities are likely attributed to its protein and/or polysaccharide-protein complexes, such as fungal immunomodulatory proteins (FIPs) or serine proteases. Overall, the water-soluble protein and polysaccharide-protein complexes found in the HMW and MMW of xLr (TM) have promising potential to reduce SARS-CoV-2 viral pathogenesis through its modulatory action on human ACE2.