SARS-CoV-2 Main Protease Active Site Ligands in the Human Metabolome

Abstract

In late 2019, a global pandemic occurred. The causative agent was identified as a member of the Coronaviridae family, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we present an analysis on the substances identified in the human metabolome capable of binding the active site of the SARS-CoV-2 main protease (Mpro). The substances present in the human metabolome have both endogenous and exogenous origins. The aim of this research was to find molecules whose biochemical and toxicological profile was known that could be the starting point for the development of antiviral therapies. Our analysis revealed numerous metabolites—including xenobiotics—that bind this protease, which are essential to the lifecycle of the virus. Among these substances, silybin, a flavolignan compound and the main active component of silymarin, is particularly noteworthy. Silymarin is a standardized extract of milk thistle, Silybum marianum, and has been shown to exhibit antioxidant, hepatoprotective, antineoplastic, and antiviral activities. Our results—obtained in silico and in vitro—prove that silybin and silymarin, respectively, are able to inhibit Mpro, representing a possible food-derived natural compound that is useful as a therapeutic strategy against COVID-19.

Oxidative Stress-Related Mechanisms in SARS-CoV-2 Infections

“…Rutin (a polyphenolic flavonoid) may able a potential inhibitor as it is able to form several hydrogen bonds and σ - π stacking interactions with various amino acids of Mpro in anchoring and blocking the substrate into the active pocket of the catalytic center [ 157 ]. In vivo and in silico studies have demonstrated that silymarin and its derivative silybin (a flavonoid from the group of flavonolignans) are able to inhibit SARS-CoV-2 main protease [ 158 ]. Another authors found luteolin to be effective in blocking the S2 protein of SARS-CoV [ 159 ].…”

Identification of potential anti-COVID-19 drug leads from Medicinal Plants through Virtual High-Throughput Screening

“…It is very interesting to note that for Chelidonium majus L., the only herbal source of Chelidimerine, significant in vitro inhibitory activity against cysteine proteinases has already been reported (133). In addition, some Physalin derivatives have very recently been introduced as potent M pro inhibitors (78,134,135) and Hinokiflavone which belongs to biflavonoid compounds, has already been identified as the antiviral potential of H1N1 influenza inhibitor (55). Even more interesting is the fact that, 5 out of 13 phytochemicals -two flavonoid glycosides (6 and 7 in Figure 2), two biflavonoid compounds (8 and 13), and Pongamoside A (11)contain the flavonoid scaffold which is well-known for its striking antiviral potential against diverse coronaviruses (9,55,60,63,(66)(67)(68)(69)71,76,(82)(83)(84)87).…”

Current Potential Therapeutic Approaches against SARS-CoV-2: A Review

“…3CLpro (also known as Mpro) is the major betacoronavirus protease necessary for viral RNA translation in polyprotein synthesis [ 10 , 30 ]. Recently, the x-ray structures and α-ketoamide complex of SARS-CoV-2 3CLpro have been reported [ 10 , 30 , 61 ].…”

“…3CLpro (also known as Mpro) is the major betacoronavirus protease necessary for viral RNA translation in polyprotein synthesis [ 10 , 30 ]. Recently, the x-ray structures and α-ketoamide complex of SARS-CoV-2 3CLpro have been reported [ 10 , 30 , 61 ]. Two compound pulmonary tropism pyridine-containing α-ketoamides, called 13a and 13b, exerted pharmacokinetic properties at sufficient concentration in the lungs and bronchial-alveolar liquid lavage of mice within 4 to 24 h of administration [ 47 ].…”