scholarly journals Selective Covalent Targeting of SARS-CoV-2 Main Protease by Enantiopure Chlorofluoroacetamide

2021 ◽  
Author(s):  
Daiki Yamane ◽  
Satsuki Onitsuka ◽  
Suyong Re ◽  
Hikaru Isogai ◽  
Rui Hamada ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Antiviral Agents ◽  
Optical Resolution ◽  
Covalent Modification ◽  
Causative Pathogen ◽  
Protein Target ◽  
Main Protease ◽  
Covalent Inhibitors ◽  
Rapid Generation ◽  
Derivatives Of

The pandemic of COVID-2019 has urged the development of antiviral agents against its causative pathogen SARS-CoV-2. The main protease (Mpro), a cysteine protease essential for viral replication, is a promising protein target. Here we report an irreversible SARS-CoV-2 Mpro inhibitor possessing chlorofluoroacetamide (CFA) as the warhead for covalent modification of Mpro. Ugi multi-component reaction employing chlorofluoroacetic acid allowed rapid generation of CFA derivatives, of which diastereomers displayed significantly different inhibitory activity against Mpro. We established a practical protocol for the optical resolution of chlorofluoroacetic acid, which enable the isolation of the stereoisomers of the best CFA compound. Kinetic analysis revealed that (R)-CFA is crucial for both binding affinity and the rate of irreversible inactivation of Mpro. Our findings highlight the prominent influence of the CFA chirality on the covalent modification of cysteine, and provide the basis for improving the potency and selectivity in the development of novel CFA-based covalent inhibitors.

scholarly journals Peptide Derivatives of the Zonulin Inhibitor Larazotide (AT1001) as Potential Anti SARS CoV-2: Molecular Modelling, Synthesis and Bioactivity Evaluation

2021 ◽  
Vol 22 (17) ◽  
pp. 9427
Author(s):  
Simone Di Micco ◽  
Simona Musella ◽  
Marina Sala ◽  
Maria C. Scala ◽  
Graciela Andrei ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Fast Response ◽  
Main Protease ◽  
Promising Target ◽  
Peptide Derivatives ◽  
Novel Coronavirus ◽  
Derivatives Of

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been identified as the pathogen responsible for the outbreak of a severe, rapidly developing pneumonia (Coronavirus disease 2019, COVID-19). The virus enzyme, called 3CLpro or main protease (Mpro), is essential for viral replication, making it a most promising target for antiviral drug development. Recently, we adopted the drug repurposing as appropriate strategy to give fast response to global COVID-19 epidemic, by demonstrating that the zonulin octapeptide inhibitor AT1001 (Larazotide acetate) binds Mpro catalytic domain. Thus, in the present study we tried to investigate the antiviral activity of AT1001, along with five derivatives, by cell-based assays. Our results provide with the identification of AT1001 peptide molecular framework for lead optimization step to develop new generations of antiviral agents of SARS-CoV-2 with an improved biological activity, expanding the chance for success in clinical trials.

Synthesis and investigation of viral-inhibitory activity of nitrogen-containing derivatives of adamantane

1991 ◽  
Vol 25 (7) ◽  
pp. 485-488 ◽  
Author(s):  
Yu. N. Klimochkin ◽  
I. K. Moiseev ◽  
G. V. Vladyko ◽  
L. V. Korobchenko ◽  
E. I. Boreko
Keyword(s):  
Inhibitory Activity ◽  
Derivatives Of

Synthesis and antibacterial evaluation of novel Schiff's base derivatives of nitroimidazole nuclei as potent E. coli FabH inhibitors

RSC Advances ◽  
2014 ◽  
Vol 4 (97) ◽  
pp. 54217-54225 ◽  
Author(s):  
Xin Zhang ◽  
Chetan B. Sangani ◽  
Li-Xin Jia ◽  
Pi-Xian Gong ◽  
Fang Wang ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Schiff’S Base ◽  
E Coli ◽  
Derivatives Of ◽  
Antibacterial Evaluation ◽  
Potent Inhibitory Activity

Series of novel Schiff's base derivatives have been synthesized. Compound 10q showed the most potent inhibitory activity (IC50 = 2.6883 μM).

Derivatives of 3′-and 5′-Deoxyadenosine: Their Inhibitory Activity against DNA Viruses

Chemotherapy ◽  
1980 ◽  
Vol 26 (5) ◽  
pp. 316-322 ◽  
Author(s):  
Barbara Grytzmann ◽  
M. Morr ◽  
R. Wigand
Keyword(s):  
Inhibitory Activity ◽  
Dna Viruses ◽  
Derivatives Of

scholarly journals Mechanism of Covalent Binding of Ibrutinib to Bruton’s Tyrosine Kinase revealed by QM/MM Calculations

2020 ◽  
Author(s):  
Angus Voice ◽  
Gary Tresadern ◽  
Rebecca Twidale ◽  
Herman Van Vlijmen ◽  
Adrian Mulholland
Keyword(s):  
Tyrosine Kinase ◽  
Covalent Binding ◽  
Bond Formation ◽  
Covalent Bond ◽  
Covalent Modification ◽  
Mechanistic Study ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Covalent Inhibitors ◽  
Covalent Bond Formation

<p>Ibrutinib is the first covalent inhibitor of Bruton’s tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition is crucial for the design of safer and more selective covalent inhibitors that target BTK. There are questions surrounding the precise mechanism of covalent bond formation in BTK as there is no appropriate active site residue that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. To address this, we have investigated several mechanistic pathways of covalent modification of C481 in BTK by ibrutinib using QM/MM reaction simulations. The lowest energy pathway we identified involves a direct proton transfer from C481 to the acrylamide warhead in ibrutinib, followed by covalent bond formation to form an enol intermediate. There is a subsequent rate-limiting keto-enol tautomerisation step (DG<sup>‡</sup>=10.5 kcal mol<sup>-1</sup>) to reach the inactivated BTK/ibrutinib complex. Our results represent the first mechanistic study of BTK inactivation by ibrutinib to consider multiple mechanistic pathways. These findings should aid in the design of covalent drugs that target BTK and related proteins. </p>

scholarly journals Crystal structure of SARS-CoV-2 main protease in complex with a Chinese herb inhibitor shikonin

2020 ◽  
Author(s):  
Jian Li ◽  
Xuelan Zhou ◽  
Yan Zhang ◽  
Fanglin Zhong ◽  
Cheng Lin ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Conformational Changes ◽  
Drug Targets ◽  
Chinese Herb ◽  
Binding Modes ◽  
High Potency ◽  
Main Protease ◽  
Covalent Inhibitors ◽  
Catalytic Dyad ◽  
Important Drug

AbstractMain protease (Mpro, also known as 3CLpro) has a major role in the replication of coronavirus life cycle and is one of the most important drug targets for anticoronavirus agents. Here we report the crystal structure of main protease of SARS-CoV-2 bound to a previously identified Chinese herb inhibitor shikonin at 2.45 angstrom resolution. Although the structure revealed here shares similar overall structure with other published structures, there are several key differences which highlight potential features that could be exploited. The catalytic dyad His41-Cys145 undergoes dramatic conformational changes, and the structure reveals an unusual arrangement of oxyanion loop stabilized by the substrate. Binding to shikonin and binding of covalent inhibitors show different binding modes, suggesting a diversity in inhibitor binding. As we learn more about different binding modes and their structure-function relationships, it is probable that we can design more effective and specific drugs with high potency that can serve as effect SARS-CoV-2 anti-viral agents.

scholarly journals Potential anti-COVID-19 activity of Egyptian propolis using computational modeling

2021 ◽  
Author(s):  
Bassma H Elwakil ◽  
Marwa M Shaaban ◽  
Adnan A Bekhit ◽  
Moustafa Y El-Naggar ◽  
Zakia A Olama
Keyword(s):  
Mass Spectrometry ◽  
Gas Chromatography ◽  
Computational Modeling ◽  
Antiviral Agents ◽  
Mass Spectrometry Analysis ◽  
Gas Chromatography Mass Spectrometry ◽  
Promising Candidate ◽  
Spectrometry Analysis ◽  
Chromatography Mass Spectrometry ◽  
Main Protease

Aim: To investigate the prospective anti COVID-19 activity of Egyptian propolis. Material & methods: Propolis samples were collected from different Egyptian geographical areas and characterized using standardized methods, scanning electron microscope and gas chromatography/mass spectrometry along with computational modeling to predict the anti-COVID-19 activity. Results & conclusion: Gas chromatography/mass spectrometry analysis of Menoufia propolis proved the presence of Octatriacontyl pentafluoropropionate (4.2%). Docking analyses declared that Octatriacontyl pentafluoropropionate is well oriented inside the enzyme pockets, in addition to excellent binding manner with the active site of the target macromolecules (RNA-dependent RNA polymerase, Spike protein S1 and main protease) in relation to some broad-spectrum antiviral agents. Menoufia propolis could be a promising candidate in the combat against the pandemic COVID-19.

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