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The antineoplastic drug carmofur is shown to inhibit the SARS-CoV-2 main protease (Mpro). Here, the X-ray crystal structure of Mpro in complex with carmofur reveals that the carbonyl reactive group of carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC50 = 24.30 μM) and is a promising lead compound to develop new antiviral treatment for COVID-19.A crystal structure of SARS-CoV-2 with inhibitor carmofur reveals the mechanism of action of this compound and opens the way to develop more potent drugs.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CL pro ) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CL pro . Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CL pro s, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands. SARS-CoV-2 3CL protease (3CL pro ) is essential for coronavirus replication and of great interest as an antiviral drug target. Here, the authors show that the naturally occurring flavonoid myricetin is a non-peptidomimetic and covalent inhibitor of 3CL pro , and they solve crystal structures of 3CL pro with myricetin and derivatives, which reveal that the pyrogallol group covalently modifies the catalytic cysteine.

The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (M pro ), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent M pro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in M pro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger M pro inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of M pro with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta -corona viruses. Ebselen is an organoselenium drug that inhibits the SARS-CoV-2 main protease (M pro ). Here, the authors co-crystallised M pro with ebselen and an ebselen derivative and observed an enzyme bound organoselenium covalent adduct in the crystal structures, which was also confirmed by mass spectrometry analysis.

The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp. The antiparasitic drug suramin directly inhibits SARS-CoV-2 RNA-dependent RNA polymerase by blocking binding of the RNA template–primer duplex and entry of nucleotide triphosphate to the catalytic site.

A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019–2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19) 1 – 4 . Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (M pro ) of SARS-CoV-2: M pro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2 5 , 6 . We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of M pro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds—including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds—as inhibitors of M pro . Six of these compounds inhibited M pro , showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 μM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available. A programme of structure-assisted drug design and high-throughput screening identifies six compounds that inhibit the main protease of SARS-CoV-2, demonstrating the ability of this strategy to isolate drug leads with clinical potential.

The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CL pro ) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CL pro with an enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that simnotrelvir is a potent pan-CoV 3CL pro inhibitor but has high selectivity. It effectively blocks replications of SARS-CoV-2 variants in cell-based assays and exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2 Delta infection in which it not only significantly reduces lung viral loads but also eliminates the virus from brains. The discovery of simnotrelvir thereby highlights the utility of structure-based development of marked protease inhibitors for providing a small molecule therapeutic effectively combatting human coronaviruses. In this study, the authors report the structure-based discovery and preclinical evaluation of 2 simnotrelvir, an orally bioavailable 3CLpro inhibitor that blocks replication of SARS-CoV-2 variants in 3 vitro, shows robust efficacy in a mouse model and good safety and pharmacokinetic profiles in rats 4 and monkeys.

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARSCoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 μmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three \"hot\" spots on PLpro, including the substratebinding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.

Coronavirus, a large family of positive-sense RNA viruses, are responsible for both mild and severe respiratory illnesses, ranging from the common cold to life-threatening conditions. Despite significant advances in vaccine and antiviral development, the high mutability of human coronaviruses (HCoVs), such as SARS-CoV-2, presents a major challenge in treating these infections. Effective, broad-spectrum antiviral drugs are urgently needed to address both current and future HCoV outbreaks. Here, we conducted high-throughput screening of a natural product library containing 3407 compounds to identify potential antiviral agents against HCoV-OC43 and HCoV-229E. We identified several natural products with inhibitory effects on HCoV-229E, HCoV-OC43, and the SARS-CoV-2 variants Delta (B.1.617.2) and Omicron (BA.5) in vitro without evident cytotoxicity. Among these, dibenzoylmethane (DBM) not only demonstrated broad-spectrum anticoronavirus activity in vitro but also effectively inhibited HCoV-OC43 replication in a BALB/c mouse model. Pharmacokinetic analysis revealed that DBM, when administered orally, maintained effective concentrations in the blood over an extended period, suggesting its suitability for oral administration. Mechanistically, DBM was found to regulate caspase-6, a host factor that suppresses interferon signalling and promotes HCoV replication. These findings highlight DBM as a promising candidate for the development of therapeutics targeting HCoVs, offering potential for treating infections by both established and emerging HCoVs.