Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332

Zhao, Yao; Fang, Chao; Zhang, Qi; Zhang, Ruxue; Zhao, Xiangbo; Duan, Ying; Wang, Haofeng; Zhu, Yan; Lu, Feng; Zhao, Jinyi; Shao, Maolin; Yang, Xiuna; Zhang, Leike; Peng, Chao; Yang, Kailin; Ma, Dawei; Rao, Zihe; Yang, Haitao

doi:10.1007/s13238-021-00883-2

Cited by 194 publications

(229 citation statements)

References 17 publications

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“…The structure was solved by molecular replacement using a reported M pro structure (PDB ID: 6YB7( 29 )) as a search model. The overall fold of the structure is similar to those previously reported for M pro (RMSD = 0.41 Å for M pro complexed with PF-07321332 ( 8 , nirmatrelvir; PDB ID: 7VH8); 68 Supporting Information Figure S7 ).…”

Section: Resultssupporting

confidence: 79%

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Penicillin Derivatives Inhibit the SARS-CoV-2 Main Protease by Reaction with Its Nucleophilic Cysteine

et al. 2022

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The SARS-CoV-2 main protease (M pro ) is a medicinal chemistry target for COVID-19 treatment. Given the clinical efficacy of β-lactams as inhibitors of bacterial nucleophilic enzymes, they are of interest as inhibitors of viral nucleophilic serine and cysteine proteases. We describe the synthesis of penicillin derivatives which are potent M pro inhibitors and investigate their mechanism of inhibition using mass spectrometric and crystallographic analyses. The results suggest that β-lactams have considerable potential as M pro inhibitors via a mechanism involving reaction with the nucleophilic cysteine to form a stable acyl–enzyme complex as shown by crystallographic analysis. The results highlight the potential for inhibition of viral proteases employing nucleophilic catalysis by β-lactams and related acylating agents.

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Section: Resultssupporting

confidence: 79%

“…(E) C6 amido penicillin-derived side chain of the 20e -derived complex binds in the hydrophobic S2 M pro binding site. (F) Superimposition of active sites’ views of the M pro : 20e -derived complex and the M pro :PF-07321332 (slate blue: carbon-backbone of 8 , nirmatrelvir; PDB ID: 7VH8( 68 )) structures.…”

Section: Resultsmentioning

confidence: 99%

Penicillin Derivatives Inhibit the SARS-CoV-2 Main Protease by Reaction with Its Nucleophilic Cysteine

et al. 2022

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“…Notably, the presence of a mass shift of 500 Da after treatment with PF-07321332 indicated a covalent adduct formation (Fig. 1 e), in agreement with the results presented in the previous study [ 10 ]. Considering the lack of reactive group in GA and AA, covalent inhibition against 3CL pro is usually unlikely.…”

Section: Dear Editorsupporting

confidence: 92%

“…e–g Binding mode analysis between PF-07321332 ( e ), GA ( f ) or AA ( g ) and SARS-CoV-2 3CL pro using HPLC-Q-TOF MS. According to the published protocol [ 10 ], purified SARS-CoV-2 3CL pro (5 μM) was incubated with or without PF-07321332, GA or AA (500 μM) in TBS (10 mM Tris, 50 mM NaCl pH 8.0) at RT for 30 min. The desalted samples were analyzed by the quadrupole time-of-flight (Q-TOF) mass spectrum (Agilent, USA) for detecting the molecular weight of intact 3CL pro .…”

Section: Dear Editormentioning

confidence: 99%

“…The majority of current reported SARS-CoV-2 3CL pro inhibitors are peptidomimetic covalent inhibitors with a reactive warhead such as ketone, aldehyde or ketoamide [ 9 ]. A highlighting milestone is Nirmatrelvir (PF-07321332), a covalent inhibitor carrying a nitrile warhead that targets SARS-CoV-2 3CL pro , which plus Ritonavir has received its first conditional authorization on 31 December 2021 for the treatment of COVID-19 in the United Kingdom [ 10 ]. Nirmatrelvir has also been authorized for emergency use in the USA (December 2021), and more recently received a conditional authorization in the EU (January 2022).…”

Section: Dear Editormentioning

confidence: 99%

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Ginkgolic acid and anacardic acid are reversible inhibitors of SARS-CoV-2 3-chymotrypsin-like protease

Gao

Zhou

et al. 2022

Cell Biosci

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Because of the emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different regions of the world, the battle with infectious coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been seesawing. Therefore, the identification of antiviral drugs is of particular importance. In order to rapidly identify inhibitors for SARS-CoV-2 3-chymotrypsin-like protease (3CLpro), an enzyme essential for viral replication, we combined the fluorescence polarization (FP) technique with biotin-avidin system (BAS) and developed a novel sandwich-like FP screening assay. Through high-throughput screening, two hits of 3CLpro inhibitors, ginkgolic acid (GA) and anacardic acid (AA) were identified, which showed IC50 values of 11.29 ± 0.48 and 12.19 ± 0.50 μM, respectively. Their binding modes were evaluated by HPLC-Q-TOF–MS. There was no mass increase detected for SARS-CoV-2 3CLpro incubated with either GA or AA, indicating the absence of covalent adducts. The kinetic analysis clearly demonstrated that both GA and AA inhibit SARS-CoV-2 3CLpro via reversible and mixed-inhibition manner. Our results argue against conclusion that GA and AA act as irreversible and covalent inhibitors against SARS-CoV-2 3CLpro, which is based on the studies by Chen et al.

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Synthesis, SARS‐CoV‐2 3CL main protease inhibitor, anti‐inflammatory, and wound‐healing effects of a zinc(II)‐thiosemicarbazone complex

Arslan

Kaya

Ülküseven

2023

Applied Organom Chemis

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A new zinc(II) complex with tetradentate thiosemicarbazone (2) was synthesized to investigate the effectiveness against SARS-CoV-2 virus and its antiinflammatory effects on BEAS-2B human bronchial epithelial cells. Structural confirmation was performed by IR, 1 H and 13 C NMR, and ESI-MS spectroscopies. The results showed that the complex 2 molecule inhibits 3CL main protease enzyme. It was found that complex 2 had a proliferative effect at low doses. TNF-α stimulation significantly increased IL8 gene expression 3.42 ± 0.107 fold in BEAS-2B cells (p = 0.037). However, it was found that all concentrations of complex 2 highly suppressed IL8 gene expression in the control group and TNF-α-stimulated BEAS-2B cells (p = 0.009). The healing rate of complex 2 was higher than the control and BEAS-2B cells induced by TNF-α at the 24 and 48 h after wound formation. It is known that the biological efficiency of metal-thiosemicarbazone complexes was adjusted depending on substituent and metal. In this context, complex 2 may be considered as a precursor molecule in the investigation of the antiviral and anti-inflammatory effects of those formed with the element zinc. Investigation of the selectivity of the inhibitory effect of complex 2 on the 3CL main protease is important for a more detailed understanding of its antiviral effect potential. Although the 3CL main protease enzyme was concentrated in antiviral effective molecule screening studies against SARS-CoV-2 virus, the fact that complex 2 also has antiinflammatory and wound-healing effects is a distinguishing feature from other inhibitory effective molecules.

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Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332

Cited by 194 publications

References 17 publications

Penicillin Derivatives Inhibit the SARS-CoV-2 Main Protease by Reaction with Its Nucleophilic Cysteine

Penicillin Derivatives Inhibit the SARS-CoV-2 Main Protease by Reaction with Its Nucleophilic Cysteine

Ginkgolic acid and anacardic acid are reversible inhibitors of SARS-CoV-2 3-chymotrypsin-like protease

Synthesis, SARS‐CoV‐2 3CL main protease inhibitor, anti‐inflammatory, and wound‐healing effects of a zinc(II)‐thiosemicarbazone complex

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