Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs

  title={Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs},
  author={Kanchan Anand and John Ziebuhr and Parvesh Wadhwani and Jeroen R. Mesters and Rolf Hilgenfeld},
  pages={1763 - 1767}
A novel coronavirus has been identified as the causative agent of severe acute respiratory syndrome (SARS. [] Key Method We determined crystal structures for human coronavirus (strain 229E) Mpro and for an inhibitor complex of porcine coronavirus [transmissible gastroenteritis virus (TGEV)] Mpro, and we constructed a homology model for SARS coronavirus (SARS-CoV) Mpro. The structures reveal a remarkable degree of conservation of the substrate-binding sites, which is further supported by recombinant SARS-CoV…

Identification of novel inhibitors of the SARS coronavirus main protease 3CLpro.

Isothermal titration microcalorimetric experiments indicate that these inhibitors bind reversibly to 3CL(pro) in an enthalpically favorable fashion, implying that they establish strong interactions with the protease molecule, thus defining attractive molecular scaffolds for further optimization.

Structures of Two Coronavirus Main Proteases: Implications for Substrate Binding and Antiviral Drug Design

A Michael acceptor inhibitor (named N3) was found to demonstrate in vitro inactivation of IBV Mpro and potent antiviral activity against IBV in chicken embryos and provides a feasible animal model for designing wide-spectrum inhibitors against CoV-associated diseases.

Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

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.

Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19

The ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment are presented.

The substrate specificity of SARS coronavirus 3C-like proteinase

  • K. FanLiang Ma L. Lai
  • Chemistry, Biology
    Biochemical and Biophysical Research Communications
  • 2005

Molecular design of inhibitors against the Mproprotein of the severe acute respiratory syndrome (SARS) virus

The structure of Mpro has been optimized using an MMFF94s force field and docked with AG7088, an inhibitor of the human rhinovirus 3C protease, which proposes a new high affinity ligand for SARS Mpro, with inhibitory properties independent of slight structural changes in the protease.

Cinanserin Is an Inhibitor of the 3C-Like Proteinase of Severe Acute Respiratory Syndrome Coronavirus and Strongly Reduces Virus Replication In Vitro

It is demonstrated that the old drug cinanserin is an inhibitor of SARS-CoV replication, acting most likely via inhibition of the 3CL proteinase.



Conservation of substrate specificities among coronavirus main proteases.

The data show that the differential cleavage kinetics of sites within pp1a/pp1ab are a conserved feature of coronavirus main proteases and lead to predict similar processing kinetics for the replicase polyproteins of all coronaviruses.

Mutational analysis of the active centre of coronavirus 3C-like proteases.

It is concluded that both the catalytic systems and substrate-binding pockets of coronavirus main proteases differ from those of other RNA virus 3C and 3C-like proteases.

Structure-assisted design of mechanism-based irreversible inhibitors of human rhinovirus 3C protease with potent antiviral activity against multiple rhinovirus serotypes.

Cocrystal-structure-assisted optimization of 3C-protease-directed Michael acceptors has yielded molecules having extremely rapid in vitro inactivation of the viral protease, potent antiviral activity against multiple rhinovirus serotypes and low cellular toxicity.

Characterization of a Novel Coronavirus Associated with Severe Acute Respiratory Syndrome

Phylogenetic analyses and sequence comparisons showed that SARS-CoV is not closelyrelated to any of the previouslycharacterized coronaviruses.

Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra α-helical domain

The crystal structure of the 33.1 kDa transmissible gastroenteritis (corona)virus Mpro is reported and illustrates that RNA viruses have evolved unprecedented variations of the classical chymotrypsin fold.

Characterization of a human coronavirus (strain 229E) 3C-like proteinase activity

The putative HCV 229E 3C-like proteinase domain is expressed as part of a beta-galactosidase fusion protein in Escherichia coli and it is shown that the expressed protein has proteolytic activity and the substitution of one amino acid within the predictedproteinase domain abolishes, or at least significantly reduces, this activity.

Identification of a novel coronavirus in patients with severe acute respiratory syndrome.

The novel coronavirus might have a role in causing SARS and was detected in a variety of clinical specimens from patients with SARS but not in controls.

Biosynthesis, purification, and characterization of the human coronavirus 229E 3C-like proteinase

The biosynthesis of the human coronavirus 229E 3C-like proteinase in Escherichia coli and the enzymatic properties, inhibitor profile, and substrate specificity of the purified protein are described.

A novel coronavirus associated with severe acute respiratory syndrome.

A novel coronavirus is associated with this outbreak of severe acute respiratory syndrome, and the evidence indicates that this virus has an etiologic role in SARS.


NIAD supports a broad spectrum of both basic and applied research in virology to expand the understanding of the biology, pathogenesis, and the immunology of viral diseases, leading to their