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

2020 ◽  
Author(s):  
Kai S. Yang ◽  
Xinyu R. Ma ◽  
Yuying Ma ◽  
Yugendar R. Alugubelli ◽  
Danielle A. Scott ◽  
...  
Keyword(s):  
Chemical Space ◽  
A549 Cells ◽  
Covalent Bond ◽  
Structural Rearrangement ◽  
High Potency ◽  
Active Site Cysteine ◽  
Virus Inhibition ◽  
Main Protease ◽  
Reversible Covalent ◽  
Cytopathogenic Effect

ABSTRACTThe COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2MPro) to digest two of its translated polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replication in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1MPro), we have designed and synthesized a series of SC2MPro inhibitors that contain β-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2MPro active site cysteine C145. All inhibitors display high potency with IC50 values at or below 100 nM. The most potent compound MPI3 has as an IC50 value as 8.5 nM. Crystallographic analyses of SC2MPro bound to 7 inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549 cells. Two inhibitors MP5 and MPI8 completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5-5 μM and A549 cells at 0.16-0.31 μM. Their virus inhibition potency is much higher than some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2MPro inhibitors with extreme potency. Due to the urgent matter of the COVID-19 pandemic, MPI5 and MPI8 may be quickly advanced to preclinical and clinical tests for COVID-19.

scholarly journals Bepridil is potent against SARS-CoV-2 In Vitro

2020 ◽  
Author(s):  
Erol C. Vatansever ◽  
Kai Yang ◽  
Kaci C. Kratch ◽  
Aleksandra Drelich ◽  
Chia-Chuan Cho ◽  
...  
Keyword(s):  
Small Molecule ◽  
A549 Cells ◽  
Live Virus ◽  
Docking Analysis ◽  
Computational Docking ◽  
Main Protease ◽  
Infected Cells ◽  
Endosomal Ph ◽  
Cytopathogenic Effect

ABSTRACTGuided by a computational docking analysis, about 30 FDA/EMA-approved small molecule medicines were characterized on their inhibition of the SARS-CoV-2 main protease (MPro). Of these tested small molecule medicines, six displayed an IC50 value in inhibiting MPro below 100 μM. Three medicines pimozide, ebastine, and bepridil are basic small molecules. Their uses in COVID-19 patients potentiate dual functions by both raising endosomal pH to slow SARS-CoV-2 entry into the human cell host and inhibiting MPro in infected cells. A live virus-based microneutralization assay showed that bepridil inhibited cytopathogenic effect induced by SARS-CoV-2 in Vero E6 cells completely at and dose-dependently below 5 μM and in A549 cells completely at and dose-dependently below 6.25 μM. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.

scholarly journals MPI8 is Potent Against SARS-CoV-2 by Inhibiting Dually and Selectively the SARS-CoV-2 Main Protease and the Host Cathepsin L

2021 ◽  
Author(s):  
Xinyu R Ma ◽  
Yugendar R Alugubelli ◽  
Yuying Ma ◽  
Erol Can Vatansever ◽  
Danielle A Scott ◽  
...  
Keyword(s):  
Active Site ◽  
Cathepsin L ◽  
Critical Role ◽  
Cathepsin K ◽  
Host Cells ◽  
High Potency ◽  
Active Site Cysteine ◽  
Cellular Analysis ◽  
Main Protease ◽  
Ic50 Values

A number of inhibitors have been developed for the SARS-CoV-2 main protease (MPro) as potential COVID-19 medications but little is known about their selectivity. Using enzymatic assays, we characterized inhibition of TMPRSS2, furin, and cathepsins B/K/L by more than a dozen of previously developed MPro inhibitors including MPI1-9, GC376, 11a, 10-1, 10-2, and 10-3. MPI1-9, GC376 and 11a all contain an aldehyde for the formation of a reversible covalent hemiacetal adduct with the MPro active site cysteine and 10-1, 10-2 and 10-3 contain a labile ester to exchange with the MPro active site cysteine for the formation of a thioester. Our data revealed that all these inhibitors are inert toward TMPRSS2 and furin. Diaryl esters also showed low inhibition of cathepsins. However, all aldehyde inhibitors displayed high potency in inhibiting three cathepsins. Their determined IC50 values vary from 4.1 to 380 nM for cathepsin B, 0.079 to 2.3 nM for cathepsin L, and 0.35 to 180 nM for cathepsin K. All aldehyde inhibitors showed similar inhibition levels toward cathepsin L. A cellular analysis indicated high potency of MPI5 and MPI8 in inhibiting lysosomal activity, which is probably attributed to their inhibition of cathepsins. Among all aldehyde inhibitors, MPI8 shows the best selectivity toward cathepsin L. With respect to cathepsins B and K, the selective indices are 192 and 150, respectively. MPI8 is the most potent compound among all aldehyde inhibitors in cellular MPro inhibition potency and anti-SARS-CoV-2 activity in Vero E6 cells. Cathepsin L has been demonstrated to play a critical role in the SARS-CoV-2 cell entry. By selectively inhibiting both SARS-CoV-2 MPro and the host cathepsin L, MPI8 potentiates dual inhibition effects to synergize its overall antiviral potency and efficacy. Due to its high selectivity toward cathepsin L that reduces potential toxicity toward host cells and high cellular and antiviral potency, we urge serious consideration of MPI8 for preclinical and clinical investigations for treating COVID-19.

scholarly journals A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shin-ichiro Hattori ◽  
Nobuyo Higashi-Kuwata ◽  
Hironori Hayashi ◽  
Srinivasa Rao Allu ◽  
Jakka Raghavaiah ◽  
...  
Keyword(s):  
Small Molecule ◽  
Covalent Bond ◽  
Amino Acid Residues ◽  
X Ray ◽  
Viral Breakthrough ◽  
Main Protease ◽  
Small Molecule Compound ◽  
Polar Interactions ◽  
High Concentrations

AbstractExcept remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.

scholarly journals Molecular recognition of organic ammonium ions in solution using synthetic receptors

2010 ◽  
Vol 6 ◽  
Author(s):  
Andreas Späth ◽  
Burkhard König
Keyword(s):  
Molecular Recognition ◽  
Hydrophobic Interactions ◽  
Covalent Bond ◽  
Ammonium Ion ◽  
Synthetic Receptors ◽  
Ammonium Ions ◽  
Wide Range ◽  
Covalent Bond Formation ◽  
Reversible Covalent ◽  
Ion Receptors

Ammonium ions are ubiquitous in chemistry and molecular biology. Considerable efforts have been undertaken to develop synthetic receptors for their selective molecular recognition. The type of host compounds for organic ammonium ion binding span a wide range from crown ethers to calixarenes to metal complexes. Typical intermolecular interactions are hydrogen bonds, electrostatic and cation–π interactions, hydrophobic interactions or reversible covalent bond formation. In this review we discuss the different classes of synthetic receptors for organic ammonium ion recognition and illustrate the scope and limitations of each class with selected examples from the recent literature. The molecular recognition of ammonium ions in amino acids is included and the enantioselective binding of chiral ammonium ions by synthetic receptors is also covered. In our conclusion we compare the strengths and weaknesses of the different types of ammonium ion receptors which may help to select the best approach for specific applications.

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.

Hypervalent Iodine Based Reversible Covalent Bond in Rotaxane Synthesis

2019 ◽  
Vol 131 (50) ◽  
pp. 18350-18353
Author(s):  
Markéta Kandrnálová ◽  
Zoran Kokan ◽  
Václav Havel ◽  
Marek Nečas ◽  
Vladimír Šindelář
Keyword(s):  
Covalent Bond ◽  
Hypervalent Iodine ◽  
Reversible Covalent

scholarly journals Structural Basis and Binding Kinetics of Vaborbactam in Class A β-Lactamase Inhibition

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Orville A. Pemberton ◽  
Ruslan Tsivkovski ◽  
Maxim Totrov ◽  
Olga Lomovskaya ◽  
Yu Chen
Keyword(s):  
Crystal Structure ◽  
Covalent Bond ◽  
Binding Mode ◽  
Binding Kinetics ◽  
Structural Basis ◽  
Inhibition Mechanism ◽  
Class A ◽  
Reversible Covalent ◽  
The Stability ◽  
M 14

ABSTRACT Class A β-lactamases are a major cause of β-lactam resistance in Gram-negative bacteria. The recently FDA-approved cyclic boronate vaborbactam is a reversible covalent inhibitor of class A β-lactamases, including CTX-M extended-spectrum β-lactamase and KPC carbapenemase, both frequently observed in the clinic. Intriguingly, vaborbactam displayed different binding kinetics and cell-based activity for these two enzymes, despite their similarity. A 1.0-Å crystal structure of CTX-M-14 demonstrated that two catalytic residues, K73 and E166, are positively charged and neutral, respectively. Meanwhile, a 1.25-Å crystal structure of KPC-2 revealed a more compact binding mode of vaborbactam versus CTX-M-14, as well as alternative conformations of W105. Together with kinetic analysis of W105 mutants, the structures demonstrate the influence of this residue and the unusual conformation of the β3 strand on the inactivation rate, as well as the stability of the reversible covalent bond with S70. Furthermore, studies of KPC-2 S130G mutant shed light on the different impacts of S130 in the binding of vaborbactam versus avibactam, another recently approved β-lactamase inhibitor. Taken together, these new data provide valuable insights into the inhibition mechanism of vaborbactam and future development of cyclic boronate inhibitors.

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