Sulforaphane is a reversible covalent inhibitor of 3-chymotrypsin-like protease of SARS-CoV-2.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a major public health threat worldwide and emphasizes an urgent need for effective therapeutics. Recently, Ordonez et al. identified sulforaphane (SFN) as a novel coronavirus inhibitor both in vitro and in mice, but the mechanism of action remains elusive. In this study, we independently discovered SFN for its inhibitory effect against SARS-CoV-2 using a target-based screening approach, identifying the viral 3-chymotrypsin-like protease (3CLpro ) as a target of SFN. Mechanistically, SFN inhibits 3CLpro in a reversible, mixed-type manner. Moreover, enzymatic kinetics studies reveal that SFN is a slow-binding inhibitor, following a two-step interaction. Initially, an encounter complex forms by specific binding of SFN to the active pocket of 3CLpro ; subsequently, the isothiocyanate group of SFN as "warhead" reacts covalently to the catalytic cysteine in a slower velocity, stabilizing the SFN-3CLpro complex. Our study has identified a new lead of the covalent 3CLpro inhibitors which has potential to be developed as a therapeutic agent to treat SARS-CoV-2 infection.

Discovery of Biomarkers and Potential Mechanisms of Agarwood Incense Smoke Intervention by Untargeted Metabolomics and Network Pharmacology.

BACKGROUND: Agarwood, as a traditional Chinese medicine, has great potential value for the treatment of tranquilization. However, its potential mechanisms and biomarkers are still unclear. METHODS: In this study, ultra-high performance liquid chromatography-quadrupole-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap-MS)-based metabonomics was adopted to discover the potential biomarkers in mice after agarwood incense smoke (AIS) intervention. Furthermore, the chemical components in agarwood were identified based on UHPLC-Q-Exactive Orbitrap-MS. The global view of potential compound-target-pathway (C-T-B) network was constructed through network pharmacology to understand the potentially material basis of biomarkers. RESULTS: Metabolic profiling indicated that the metabolic changed significantly in mice serum after AIS intervention. A total of 18 potential biomarkers closely related to insomnia and emotional disease were identified, mainly involving in tryptophan metabolism, arginine and proline metabolism, cysteine and methionine metabolism and steroid hormone biosynthesis pathways. A total of 138 components in agarwood were identified based on UHPLC-Q-Exactive Orbitrap-MS. The results showed that mainly compounds such as flidersia type 2-(2-phenylethyl) chromones (FTPECs) and sesquiterpenes exerted good docking abilities with key target proteins, which were involved in multiple diseases including depression and hypnosis. CONCLUSION: In conclusion, this study enhanced current understanding of the change of metabolic markers after AIS intervention. Meanwhile, it also confirmed the feasibility of combining metabolomics and network pharmacology to identify active components and elucidate the material basis of biomarkers and mechanisms.

Benzofuran derivatives with nerve growth factor-potentiating activity from Phellinus ribis.

Three new benzofuran derivatives, namely ribisin E (1) ribisin F (2) along with ribisin G (3) were isolated from the MeOH extract of the fruiting bodies of Phellinus ribis. Their structures were elucidated based on the NMR analysis. Furthermore, the absolute configuration of ribisin E (1) and ribisin G (3) were deduced by the CD calculations, and the absolute configuration of ribisin F (2) was determined by comparing its CD spectrum and specific rotation with the data of known analogues. All compounds (1-3) exhibited the activity of promoting neurite outgrowth in nerve growth factor (NGF)-ediated PC 12 cell at concentrations ranging from 1 to 30 µM.