N-Terminal Finger Stabilizes the S1 Pocket for the Reversible Feline Drug GC376 in the SARS-CoV-2 Mpro Dimer

Arutyunova, Elena; Khan, Muhammad Bashir; Fischer, Conrad; Lu, Jimmy; Lamer, Tess; Vuong, Wayne; Belkum, Marco J. van; McKay, Roy T.; Tyrrell, D. Lorne; Vederas, John C.; Young, Howard S.; Lemieux, M. Joanne

doi:10.1016/j.jmb.2021.167003

Cited by 31 publications

(47 citation statements)

References 49 publications

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“…For the capping group (P3), the indole N–H and the carbonyl of the amide make an H-bond donor and acceptor pair of bonds with Glu166, which is consistent with 3 and with indole GC-376 analogs. 39 , 44 In this protomer ( Figure 5 ), the O of the methoxy is within H-bonding distance with Gln189 (3.0 Å N to O). The ligand plot of chain C is shown in Figure S1 .…”

Section: Resultsmentioning

confidence: 92%

Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability

et al. 2021

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Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against a broad spectrum of coronaviruses. Described in this Article are novel α-acyloxymethylketone warhead peptidomimetic compounds with a six-membered lactam glutamine mimic in P1. Compounds with potent SARS-CoV-2 3CL protease and in vitro viral replication inhibition were identified with low cytotoxicity and good plasma and glutathione stability. Compounds 15e , 15h , and 15l displayed selectivity for SARS-CoV-2 3CL protease over CatB and CatS and superior in vitro SARS-CoV-2 antiviral replication inhibition compared with the reported peptidomimetic inhibitors with other warheads. The cocrystallization of 15l with SARS-CoV-2 3CL protease confirmed the formation of a covalent adduct. α-Acyloxymethylketone compounds also exhibited antiviral activity against an alphacoronavirus and non-SARS betacoronavirus strains with similar potency and a better selectivity index than remdesivir. These findings demonstrate the potential of the substituted heteroaromatic and aliphatic α-acyloxymethylketone warheads as coronavirus inhibitors, and the described results provide a basis for further optimization.

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Section: Resultsmentioning

confidence: 92%

Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability

et al. 2021

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“…IC 50 and K i values quantitatively reflect the potency and affinity of a drug and are therefore important parameters to consider when undergoing inhibitor design. First, we determined the catalytic parameters of FIPV M pro using our synthetic peptide FRETsubstrate (Supplementary Table S2) (Arutyunova et al, 2021).…”

Section: Gc376 Has Higher Affinity To Felinementioning

confidence: 99%

“…With the success GC376 has had in treating FIP in cats, it was then postulated to be an effective inhibitor to treat SARS-CoV-2 infections ( Vuong et al, 2020 ). We have previously reported that the prodrug GC376 and drug GC373 are potent inhibitors of SARS-CoV and SARS-CoV-2 M pro with K i values in the nanomolar range ( Arutyunova et al, 2021 ). The crystal structures of SARS-CoV and SARS-CoV-2 M pro in complex with the feline drugs revealed the inhibitor forming a covalent bond with Cys145 as a hemithioacetal in the active site ( Vuong et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…The crystal structures of SARS-CoV and SARS-CoV-2 M pro in complex with the feline drugs revealed the inhibitor forming a covalent bond with Cys145 as a hemithioacetal in the active site ( Vuong et al, 2020 ). The varied effectiveness of GC376 against M pro of different coronaviruses suggests structural differences in drug binding ( Kim et al, 2012 ; Arutyunova et al, 2021 ). Despite the research invested in the feline drugs with regard to FIP, no crystal structure of FIPV M pro with GC376 or GC373 has been solved to date.…”

Section: Introductionmentioning

confidence: 99%

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Crystallization of Feline Coronavirus Mpro With GC376 Reveals Mechanism of Inhibition

Chen

Khan

et al. 2022

Front. Chem.

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Coronaviruses infect a variety of hosts in the animal kingdom, and while each virus is taxonomically different, they all infect their host via the same mechanism. The coronavirus main protease (Mpro, also called 3CLpro), is an attractive target for drug development due to its essential role in mediating viral replication and transcription. An Mpro inhibitor, GC376, has been shown to treat feline infectious peritonitis (FIP), a fatal infection in cats caused by internal mutations in the feline enteric coronavirus (FECV). Recently, our lab demonstrated that the feline drug, GC373, and prodrug, GC376, are potent inhibitors of SARS-CoV-2 Mpro and solved the structures in complex with the drugs; however, no crystal structures of the FIP virus (FIPV) Mpro with the feline drugs have been published so far. Here, we present crystal structures of FIPV Mpro-GC373/GC376 complexes, revealing the inhibitors covalently bound to Cys144 in the active site, similar to SARS-CoV-2 Mpro. Additionally, GC376 has a higher affinity for FIPV Mpro with lower nanomolar Ki values compared to SARS-CoV and SARS-CoV-2 Mpro. We also show that improved derivatives of GC376 have higher potency for FIPV Mpro. Since GC373 and GC376 represent strong starting points for structure-guided drug design, determining the crystal structures of FIPV Mpro with these inhibitors are important steps in drug optimization and structure-based broad-spectrum antiviral drug discovery.

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“…3CLpro functions as a main protease responsible for the maturation of the viral nonstructural proteins (nsps) by cleaving the large polyprotein at 11 sites from nsp5 to nsp16. The junctions of those nsps show an extensive homology and provide a good recognition site for 3CLpro [ 7 , 8 ]. Accordingly, synthetized peptides based on the amino acid sequences of the junctions were used as the substrate to evaluate the hydrolytic activity of 3CLpro in vitro [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Merbromin is a mixed-type inhibitor of 3-chyomotrypsin like protease of SARS-CoV-2

Chen

Zhang

Zeng

et al. 2022

Biochemical and Biophysical Research Communications

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N-Terminal Finger Stabilizes the S1 Pocket for the Reversible Feline Drug GC376 in the SARS-CoV-2 Mpro Dimer

Cited by 31 publications

References 49 publications

Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability

Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability

Crystallization of Feline Coronavirus Mpro With GC376 Reveals Mechanism of Inhibition

Merbromin is a mixed-type inhibitor of 3-chyomotrypsin like protease of SARS-CoV-2

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