A Speedy Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors

Yang, Kun; Xinyu, R.; Ma, Yuying; Alugubelli, Yugendar R; Scott, Danielle A.; Vatansever, Erol C.; Drelich, Aleksandra; Sankaran, Banumathi; Geng, Zhi; Blankenship, Lauren R.; Ward, Hannah E; Sheng, Yan; Hsu, Jason C.; Kratch, Kaci C.; Zhao, Baoyu; Hayatshahi, Hamed S.; Liu, Jin; Li, Pingwei; Fierke, Carol A.; Tseng, Chien-Te K.; Xu, Shiqing; Liu, Wenshe Ray

doi:10.1101/2020.07.28.223784

Cited by 14 publications

(22 citation statements)

References 24 publications

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“…Yang K.S. et al took 4 as lead compound for the development of reversible tripeptide inhibitors bearing an aldehyde structure [ 91 ]. 5 ( Figure 7 a,b in complex with the target) provided the best results in terms of enzymatic inhibition (IC 50 = 8.5 nM), while 6 and 7 ( Figure 8 ) proved to be the best substrates capable of inhibiting SARS-CoV-2 replication in vitro on Vero E6 cells, with higher EC 50s than the reference compound 3 .…”

Section: Sars-cov-2 M Pro Inhibitorsmentioning

confidence: 99%

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SARS-CoV-2 Mpro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors

et al. 2021

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The uncontrolled spread of the COVID-19 pandemic caused by the new coronavirus SARS-CoV-2 during 2020–2021 is one of the most devastating events in the history, with remarkable impacts on the health, economic systems, and habits of the entire world population. While some effective vaccines are nowadays approved and extensively administered, the long-term efficacy and safety of this line of intervention is constantly under debate as coronaviruses rapidly mutate and several SARS-CoV-2 variants have been already identified worldwide. Then, the WHO’s main recommendations to prevent severe clinical complications by COVID-19 are still essentially based on social distancing and limitation of human interactions, therefore the identification of new target-based drugs became a priority. Several strategies have been proposed to counteract such viral infection, including the repurposing of FDA already approved for the treatment of HIV, HCV, and EBOLA, inter alia. Among the evaluated compounds, inhibitors of the main protease of the coronavirus (Mpro) are becoming more and more promising candidates. Mpro holds a pivotal role during the onset of the infection and its function is intimately related with the beginning of viral replication. The interruption of its catalytic activity could represent a relevant strategy for the development of anti-coronavirus drugs. SARS-CoV-2 Mpro is a peculiar cysteine protease of the coronavirus family, responsible for the replication and infectivity of the parasite. This review offers a detailed analysis of the repurposed drugs and the newly synthesized molecules developed to date for the treatment of COVID-19 which share the common feature of targeting SARS-CoV-2 Mpro, as well as a brief overview of the main enzymatic and cell-based assays to efficaciously screen such compounds.

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Section: Sars-cov-2 M Pro Inhibitorsmentioning

confidence: 99%

“… ( a ) Structure of 5 , the best peptidomimetic inhibitor of M pro discovered so far in terms of IC 50 values. ( b ) X-ray of 5 in complex with SARS-CoV-2 M pro [ 91 ]. …”

Section: Figures Scheme and Tablesmentioning

confidence: 99%

SARS-CoV-2 Mpro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors

et al. 2021

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“… 22 , 23 The functional main protease (hereafter referred to as M pro ) is essential for SARS-CoV-2 proliferation as the production of infectious virions depends on the enzymatic activity of M pro . Hence, SARS-CoV-2 M pro is undeniably a crucial target for designing specific small-molecule protease inhibitors 24 − 29 and for potential repurposing of known clinical drugs. 30 − 35 Though no clinical drugs are available for use against SARS-CoV-2 M pro , several protease inhibitors have been designed to inhibit the very closely related SARS-CoV M pro 36 − 39 that shares 96% of amino acid sequence identity with the SARS-CoV-2 enzyme, has a similar catalytic efficiency, and an almost identical three-dimensional structure.…”

Section: Introductionmentioning

confidence: 99%

Direct Observation of Protonation State Modulation in SARS-CoV-2 Main Protease upon Inhibitor Binding with Neutron Crystallography

et al. 2021

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The main protease (3CL M pro ) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. To date, no small-molecule clinical drugs are available that specifically inhibit SARS-CoV-2 M pro . To aid rational drug design, we determined a neutron structure of M pro in complex with the α-ketoamide inhibitor telaprevir at near-physiological (22 °C) temperature. We directly observed protonation states in the inhibitor complex and compared them with those in the ligand-free M pro , revealing modulation of the active-site protonation states upon telaprevir binding. We suggest that binding of other α-ketoamide covalent inhibitors can lead to the same protonation state changes in the M pro active site. Thus, by studying the protonation state changes induced by inhibitors, we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 M pro .

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“…22,23 The functional main protease (hereafter referred to as M pro ) is essential for SARS-CoV-2 proliferation as the production of infectious virions depends entirely on the enzymatic activity of M pro . Hence, SARS-CoV-2 M pro is undeniably a crucial target for designing specific small-molecule protease inhibitors [24][25][26][27][28][29] and for potential repurposing of known clinical drugs. [30][31][32][33][34][35] Though no clinical drugs are available for use against SARS-CoV-2 M pro , several protease inhibitors have been designed to inhibit the very closely related SARS-CoV M pro36-39 that shares 96% of amino acid sequence identity with the SARS-CoV-2 enzyme and has a similar catalytic efficiency and almost identical three-dimensional structure.…”

Section: Introductionmentioning

confidence: 99%

Inhibitor Binding Modulates Protonation States in the Active Site of SARS-CoV-2 Main Protease

Kneller

Phillips

Weiss

et al. 2021

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The main protease (3CL Mpro) from SARS-CoV-2, the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. Although drugs have been developed to inhibit the proteases from HIV, hepatitis C and other viruses, no such therapeutic is available to inhibit the main protease of SARS-CoV-2. To directly observe the protonation states in SARS-CoV-2 Mpro and to elucidate their importance in inhibitor binding, we determined the structure of the enzyme in complex with the α-ketoamide inhibitor telaprevir using neutron protein crystallography at near-physiological temperature. We compared protonation states in the inhibitor complex with those determined for a ligand-free neutron structure of Mpro. This comparison revealed that three active-site histidine residues (His41, His163 and His164) adapt to ligand binding, altering their protonation states to accommodate binding of telaprevir. We suggest that binding of other α-ketoamide inhibitors can lead to the same protonation state changes of the active site histidine residues. Thus, by studying the role of active site protonation changes induced by inhibitors we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 Mpro.

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A Speedy Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors

Cited by 14 publications

References 24 publications

SARS-CoV-2 Mpro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors

SARS-CoV-2 Mpro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors

Direct Observation of Protonation State Modulation in SARS-CoV-2 Main Protease upon Inhibitor Binding with Neutron Crystallography

Inhibitor Binding Modulates Protonation States in the Active Site of SARS-CoV-2 Main Protease

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