ABSTRACT
BACKGROUND: The 3C-like proteases (3CLpros) are cysteine-rich homodimeric proteins and can be covalently modified by numerous natural and synthetic compounds, which in turn, block the proteolytic activity or the formation of enzymatically active dimeric forms. Although herbal medicines have been widely used to treat COVID-19, identification of the key herbal constituents that can covalently modify the 3CLpros in ß-coronaviruses (CoVs) remains a big challenge. AIMS: To construct a comprehensive approach for efficient discovering the covalent SARS-CoV-2 3CLpro inhibitors from herbal medicines. To decipher the key anti-SARS-CoV-2 3CLpro constituents in Ginkgo biloba extract 50 (GBE50) and to study their anti-SARS-CoV-2 3CLpro mechanisms. METHODS: SARS-CoV-2 3CLpro inhibition assay including time-dependent inhibition assays and inactivation kinetic analyses were conducted using a fluorescence-based biochemical assay. The constituents in GBE50 were analyzed by UHPLC-Q-Exactive Orbitrap HRMS. The peptides modified by herbal constituents were characterized by using nanoLC-MS/MS. RESULTS: Following testing the anti-SARS-CoV-2 3CLpro effects of 104 herbal medicines, it was found that Ginkgo biloba extract 50 (GBE50) potently inhibited SARS-CoV-2 3CLpro in dose- and time-dependent manners. A total of 38 constituents were identified from GBE50 by UHPLC-Q-Exactive Orbitrap HRMS, while 26 peptides modified by 18 constituents were identified by chemoproteomic profiling. The anti-SARS-CoV-2 3CLpro effects of 18 identified covalent inhibitors were then validated by performing time-dependent inhibition assays. The results clearly demonstrated that most tested constituents showed time-dependent inhibition on SARS-CoV-2 3CLpro, while gallocatechin and sciadopitysin displayed the most potent anti-SARS-CoV-2 3CLpro effects. CONCLUSION: Collectively, GBE50 and some constituents in this herbal product could strongly inhibit SARS-CoV-2 3CLpro in dose- and time-dependent manner. Gallocatechin and sciadopitysin were identified as potent SARS-CoV-2 3CLpro inhibitors, which offers promising lead compounds for the development of novel anti-SARS-CoV-2 drugs.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Antiviral Agents/pharmacology , Peptides , Plant Extracts , Tandem Mass SpectrometryABSTRACT
- Alzheimer's disease (AD) is an irreversible degenerative illness of the central nervous system with characteristic histological alterations, known as amyloid plaques and plaques and tangles in the brain induces neurotoxicity and synaptic dysfunction, ev
ABSTRACT
Respiratory viral infections are a major public health concern because of their global occurrence, ease of spread and considerable morbidity and mortality. Medical treatments for viral respiratory diseases primarily involve providing relief from symptoms like pain and discomfort rather than treating the infection. Very few antiviral medications have been approved with restrictive usage, high cost, unwanted side effects and limited availability. Plants with their unique metabolite composition and high remedial values offer unique preventive and therapeutic efficacy in treatment of viral infections. The present review is focused on the types and mode of action of plant secondary metabolites that have been used successfully ί in the treatment of infections caused by respiratory viruses like Influenza, SARS, MERS, RSV etc. Plant metabolites such as phenolics, alkaloids, terpenoids and oligosaccharides inhibit attachment and entry of the virus. Others such as flavonoids, viz quercetin and baicalein, alkaloids viz sanguinarine, berberine and emetine, specific lipids and fatty acids prevent viral replication and protein synthesis. These metabolites have the potential to be used as lead molecules that can be optimized to develop potent drugs for effectively combating pandemics caused by respiratory viruses.