scholarly journals Structure-Based Design, Synthesis and Biological Evaluation of Peptidomimetic Aldehydes as a Novel Series of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Wenhao Dai ◽  
Bing Zhang ◽  
Xia-Ming Jiang ◽  
Haixia Su ◽  
Jian Li ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Antiviral Drug ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Drug Candidates ◽  
Main Protease ◽  
Covalent Inhibitors ◽  
A Cell ◽  
Aldehyde Groups ◽  
Clinical Potential

ABSTRACTSARS-CoV-2 is the etiological agent responsible for the COVID-19 outbreak in Wuhan. Specific antiviral drug are urgently needed to treat COVID-19 infections. The main protease (Mpro) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, which makes it an attractive drug target. In an effort to rapidly discover lead compounds targeting Mpro, two compounds (11a and 11b) were designed and synthesized, both of which exhibited excellent inhibitory activity with an IC50 value of 0.05 μM and 0.04 μM respectively. Significantly, both compounds exhibited potent anti-SARS-CoV-2 infection activity in a cell-based assay with an EC50 value of 0.42 μM and 0.33 μM, respectively. The X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a and 11b were determined at 1.5 Å resolution, respectively. The crystal structures showed that 11a and 11b are covalent inhibitors, the aldehyde groups of which are bound covalently to Cys145 of Mpro. Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity which is promising drug leads with clinical potential that merits further studies.

scholarly journals Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Science ◽  
2020 ◽  
Vol 368 (6497) ◽  
pp. 1331-1335 ◽  
Author(s):  
Wenhao Dai ◽  
Bing Zhang ◽  
Xia-Ming Jiang ◽  
Haixia Su ◽  
Jian Li ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
X Ray ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Main Protease ◽  
Pharmacokinetic Properties ◽  
Key Enzyme ◽  
Low Toxicity ◽  
Aldehyde Groups

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

scholarly journals Synthesis, characterization and biological activity of organometallic derivatives of the antimalarial drug mefloquine as new antischistosomal drug candidates

MedChemComm ◽  
2018 ◽  
Vol 9 (11) ◽  
pp. 1905-1909 ◽  
Author(s):  
Faustine d'Orchymont ◽  
Jeannine Hess ◽  
Gordana Panic ◽  
Marta Jakubaszek ◽  
Lea Gemperle ◽  
...  
Keyword(s):  
Biological Activity ◽  
Antimalarial Drug ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Drug Candidates ◽  
Derivatives Of

The design, synthesis, characterization and biological evaluation of new ferrocenyl and ruthenocenyl derivatives of the antimalarial mefloquine is described.

New 5-benzylidenethiazolidin-4-one inhibitors of bacterial MurD ligase: Design, synthesis, crystal structures, and biological evaluation

2011 ◽  
Vol 46 (11) ◽  
pp. 5512-5523 ◽  
Author(s):  
Nace Zidar ◽  
Tihomir Tomašić ◽  
Roman Šink ◽  
Andreja Kovač ◽  
Delphine Patin ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Murd Ligase

scholarly journals Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors

2021 ◽  
Author(s):  
Julia Stille ◽  
Jevgenijs Tjutrins ◽  
Guanyu Wang ◽  
Felipe A. Venegas ◽  
Christopher Hennecker ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Antiviral Drugs ◽  
Design Synthesis ◽  
Design And Synthesis ◽  
Promising Target ◽  
Starting Point ◽  
Covalent Inhibitors ◽  
Screening Platform ◽  
And Function ◽  
Synthesis And Biological Evaluation

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro> has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in design and synthesis which led to submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

scholarly journals Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors

2020 ◽  
Author(s):  
Julia Stille ◽  
Jevgenijs Tjutrins ◽  
Guanyu Wang ◽  
Felipe A. Venegas ◽  
Christopher Hennecker ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Antiviral Drugs ◽  
Design Synthesis ◽  
Design And Synthesis ◽  
Promising Target ◽  
Starting Point ◽  
Covalent Inhibitors ◽  
Screening Platform ◽  
And Function ◽  
Synthesis And Biological Evaluation

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in design and synthesis which led to submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

scholarly journals Boceprevir, calpain inhibitors II and XII, and GC-376 have broad-spectrum antiviral activity against coronaviruses in cell culture

2020 ◽  
Author(s):  
Yanmei Hu ◽  
Chunlong Ma ◽  
Tommy Szeto ◽  
Brett Hurst ◽  
Bart Tarbet ◽  
...  
Keyword(s):  
Cell Culture ◽  
Antiviral Activity ◽  
Cathepsin L ◽  
Antiviral Drug ◽  
Antiviral Effect ◽  
Neutralization Assay ◽  
Drug Candidates ◽  
Main Protease ◽  
Human Coronaviruses ◽  
Calpain Inhibitors

AbstractAs the COVID-19 pandemic continues to fold out, the morbidity and mortality are increasing daily. Effective treatment for SARS-CoV-2 is urgently needed. We recently discovered four SARS-CoV-2 main protease (Mpro) inhibitors including boceprevir, calpain inhibitors II and XII and GC-376 with potent antiviral activity against infectious SARS-CoV-2 in cell culture. Despite the weaker enzymatic inhibition of calpain inhibitors II and XII against Mpro compared to GC-376, calpain inhibitors II and XII had more potent cellular antiviral activity. This observation promoted us to hypothesize that the cellular antiviral activity of calpain inhibitors II and XII might also involve the inhibition of cathepsin L in addition to Mpro. To test this hypothesis, we tested calpain inhibitors II and XII in the SARS-CoV-2 pseudovirus neutralization assay in Vero E6 cells and found that both compounds significantly decreased pseudoviral particle entry into cells, indicating their role in inhibiting cathepsin L. The involvement of cathepsin L was further confirmed in the drug time-of-addition experiment. In addition, we found that these four compounds not only inhibit SARS-CoV-2, but also SARS-CoV, MERS-CoV, as well as human coronaviruses (CoVs) 229E, OC43, and NL63. The mechanism of action is through targeting the viral Mpro, which was supported by the thermal shift binding assay and enzymatic FRET assay. We further showed that these four compounds have additive antiviral effect when combined with remdesivir. Altogether, these results suggest that boceprevir, calpain inhibitors II and XII, and GC-376 are not only promising antiviral drug candidates against existing human coronaviruses, but also might work against future emerging CoVs.

scholarly journals The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro)

2021 ◽  
Author(s):  
Ali Ebrahim ◽  
Blake T Riley ◽  
Desigan Kumaran ◽  
Babak Andi ◽  
Martin R Fuchs ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Antiviral Drug ◽  
Conformational Ensemble ◽  
Temperature Dependent ◽  
Density Maps ◽  
Main Protease ◽  
Promising Target ◽  
Conformational Landscape ◽  
Catalytic Dyad ◽  
New Strategies

The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or Mpro, is a promising target for development of novel antiviral therapeutics. Previous X-ray crystal structures of Mpro were obtained at cryogenic temperature or room temperature only. Here we report a series of high-resolution crystal structures of unliganded Mpro across multiple temperatures from cryogenic to physiological, and another at high humidity. We interrogate these datasets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a temperature-dependent conformational landscape for Mpro, including a mobile water interleaved between the catalytic dyad, mercurial conformational heterogeneity in a key substrate-binding loop, and a far-reaching intramolecular network bridging the active site and dimer interface. Our results may inspire new strategies for antiviral drug development to counter-punch COVID-19.

scholarly journals A Genetic Trap in Yeast for Inhibitors of SARS-CoV-2 Main Protease

mSystems ◽  
2021 ◽  
Author(s):  
Hanna Alalam ◽  
Sunniva Sigurdardóttir ◽  
Catarina Bourgard ◽  
Ievgeniia Tiukova ◽  
Ross D. King ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
Drug Candidates ◽  
Main Protease ◽  
Vaccination Campaigns

The COVID-19 pandemic may continue for several years before vaccination campaigns can put an end to it globally. Thus, the need for discovery of new antiviral drug candidates will remain.

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