scholarly journals Experimental study and computational modelling of cruzain cysteine protease inhibition by dipeptidyl nitriles

2018 ◽  
Vol 20 (37) ◽  
pp. 24317-24328 ◽  
Author(s):  
Alberto Monteiro Dos Santos ◽  
Lorenzo Cianni ◽  
Daniela De Vita ◽  
Fabiana Rosini ◽  
Andrei Leitão ◽  
...  
Keyword(s):  
Experimental Study ◽  
Cysteine Protease ◽  
Computational Modelling ◽  
Inhibition Mechanism ◽  
Protease Inhibition ◽  
Reaction Inhibition

A combined computational and experimental study aimed to gain insights into the reaction inhibition mechanism of cruzain by dipeptidyl nitriles.

scholarly journals Equilibrium Between Tri- and Tetra-Coordinate Chalcogenuranes Is Critical for Cysteine Protease Inhibition

2020 ◽  
Author(s):  
Gabriela Dias SIlva ◽  
Rodrigo L O R Cunha ◽  
Mauricio Domingues Coutinho Neto
Keyword(s):  
Cysteine Protease ◽  
Density Functional ◽  
Active Form ◽  
Sulfhydryl Group ◽  
Cysteine Proteases ◽  
Inhibition Mechanism ◽  
Direct Reaction ◽  
Exchange Reactions ◽  
Protease Inhibition ◽  
Biological Media

<div>There have been significant advances in the biological use of hypervalent selenium and tellurium compounds as cysteine protease inhibitors over the recent past. However, the full understanding of their reaction mechanisms in aqueous medium and the mechanism of cysteine proteases inhibition is still elusive. Kinetic studies suggest an irreversible inhibition mechanism, which was explained by forming a covalent bond between the enzyme sulfhydryl group and the chalcogen atom at its hypervalent state (+4). However, it is still unclear the active form of the inhibitor present in the aqueous biological media. To uncover this question, we performed a theoretical investigation using density functional theory (DFT). This study investigated chloride ligand exchange reactions by oxygen and sulfur nucleophiles on hypervalent selenium and tellurium compounds. All tetra- and tri-coordinate chalcogen compounds and distinct protonation states of the nucleophiles were considered, totaling 34 unique species, 7</div><div>nucleophiles and 155 free energies rections. We discovered that chloride is easily replaced by a nonprotonated nucleophile (SH<sup>–</sup> or OH<sup>– </sup>) in R<sub>2</sub>SeCl<sub>2</sub> . We also found that</div><div>tri-coordinate species are more stable than their tetra-coordinate counterparts, with selenoxide (R<sub>2</sub>SeO) protonation being strongly exergonic in acid pH. These results suggest that the protonated selenoxide (R<sub>2</sub>SeOH<sup>+</sup>) is the most probable active chemical species in biological media. The computed energetic profiles paint a possible picture for the selenurane activity, with successive exergonic steps leading to a covalent inhibition of thiol dependent enzymes, like cysteine proteases. A second less exergonic pathway has also been uncovered, with a direct reaction to chalcogenonium cation (R<sub>2</sub>SeCl<sup>+</sup>) as the inhibition step. The trends observed for the telluranes were similar, albeit with</div><div>more exergonic reactions and a stronger trend to form bonds with oxygen species then selenuranes.</div><div><br></div>

scholarly journals Equilibrium Between Tri- and Tetra-Coordinate Chalcogenuranes Is Critical for Cysteine Protease Inhibition

2020 ◽  
Author(s):  
Gabriela Dias SIlva ◽  
Rodrigo L O R Cunha ◽  
Mauricio Domingues Coutinho Neto
Keyword(s):  
Cysteine Protease ◽  
Density Functional ◽  
Active Form ◽  
Sulfhydryl Group ◽  
Cysteine Proteases ◽  
Inhibition Mechanism ◽  
Direct Reaction ◽  
Exchange Reactions ◽  
Protease Inhibition ◽  
Biological Media

<div>There have been significant advances in the biological use of hypervalent selenium and tellurium compounds as cysteine protease inhibitors over the recent past. However, the full understanding of their reaction mechanisms in aqueous medium and the mechanism of cysteine proteases inhibition is still elusive. Kinetic studies suggest an irreversible inhibition mechanism, which was explained by forming a covalent bond between the enzyme sulfhydryl group and the chalcogen atom at its hypervalent state (+4). However, it is still unclear the active form of the inhibitor present in the aqueous biological media. To uncover this question, we performed a theoretical investigation using density functional theory (DFT). This study investigated chloride ligand exchange reactions by oxygen and sulfur nucleophiles on hypervalent selenium and tellurium compounds. All tetra- and tri-coordinate chalcogen compounds and distinct protonation states of the nucleophiles were considered, totaling 34 unique species, 7</div><div>nucleophiles and 155 free energies rections. We discovered that chloride is easily replaced by a nonprotonated nucleophile (SH<sup>–</sup> or OH<sup>– </sup>) in R<sub>2</sub>SeCl<sub>2</sub> . We also found that</div><div>tri-coordinate species are more stable than their tetra-coordinate counterparts, with selenoxide (R<sub>2</sub>SeO) protonation being strongly exergonic in acid pH. These results suggest that the protonated selenoxide (R<sub>2</sub>SeOH<sup>+</sup>) is the most probable active chemical species in biological media. The computed energetic profiles paint a possible picture for the selenurane activity, with successive exergonic steps leading to a covalent inhibition of thiol dependent enzymes, like cysteine proteases. A second less exergonic pathway has also been uncovered, with a direct reaction to chalcogenonium cation (R<sub>2</sub>SeCl<sup>+</sup>) as the inhibition step. The trends observed for the telluranes were similar, albeit with</div><div>more exergonic reactions and a stronger trend to form bonds with oxygen species then selenuranes.</div><div><br></div>

The Experimental Study on the Inhibition Effect of Fusarium oxyspomm with Bio-Slurry Based on Material Properties

2013 ◽  
Vol 675 ◽  
pp. 317-321
Author(s):  
Meng Ying Fang ◽  
Li Chun Liu ◽  
Fang Yin ◽  
Wu Di Zhang ◽  
Shi Qing Liu ◽  
...  
Keyword(s):  
Experimental Study ◽  
Material Properties ◽  
Water Soluble ◽  
Inhibition Mechanism ◽  
Main Subject ◽  
Soluble Substance ◽  
Inhibition Effect ◽  
Water Soluble Substance ◽  
Main Component ◽  
Better Than

Using petroleum ether to extract the fermentative fluid (bio-slurry), then to get the inhibition mechanism of it, and infer which is the main component in inhibition mechanism of biogas. The conclusion found by the experiment is that fat soluble substance is better than water soluble substance in inhibition mechanism, and fat soluble substance is close to 75% biogas fermentation fluid, while water soluble substance is worst. That is to say, the main subject in inhibition mechanism is hided in the fat soluble substance.

Lipofuscin-Like Substances Accumulate Rapidly in Brain, Retina and Internal Organs with Cysteine Protease Inhibition

1990 ◽  
pp. 31-47 ◽  
Author(s):  
G. O. Ivy ◽  
S. Kanai ◽  
M. Ohta ◽  
G. Smith ◽  
Y. Sato ◽  
...  
Keyword(s):  
Cysteine Protease ◽  
Protease Inhibition ◽  
Internal Organs

scholarly journals Studies of Inhibitory Mechanisms of Propeptide-Like Cysteine Protease Inhibitors

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Bui T. T. Nga ◽  
Yuki Takeshita ◽  
Misa Yamamoto ◽  
Yoshimi Yamamoto
Keyword(s):  
Protease Inhibitors ◽  
Cysteine Protease ◽  
Cathepsin L ◽  
Cysteine Residue ◽  
Cysteine Protease Inhibitor ◽  
Inhibition Mechanism ◽  
Cysteine Protease Inhibitors ◽  
Inhibitory Potency ◽  
Inhibitory Mechanisms

Mouse cytotoxic T-lymphocyte antigen-2α (CTLA-2α), Drosophila CTLA-2-like protein (crammer), and Bombyx cysteine protease inhibitor (BCPI) belong to a novel family of cysteine protease inhibitors (I29). Their inhibitory mechanisms were studied comparatively. CTLA-2α contains a cysteine residue (C75), which is essential for its inhibitory potency. The CTLA-2α monomer was converted to a disulfide-bonded dimer in vitro and in vivo. The dimer was fully inhibitory, but the monomer, which possessed a free thiol residue, was not. A disulfide-bonded CTLA-2α/cathepsin L complex was isolated, and a cathepsin L subunit with a molecular weight of 24,000 was identified as the interactive enzyme protein. Crammer also contains a cysteine residue (C72). Both dimeric and monomeric forms of crammer were inhibitory. A crammer mutant with Cys72 to alanine (C72A) was fully inhibitory, while the replacement of Gly73 with alanine (G73A) caused a significant loss in inhibitory potency, which suggests a different inhibition mechanism from CTLA-2α. BCPI does not contain cysteine residue. C-terminal region (L77-R80) of BCPI was essential for its inhibitory potency. CTLA-2α was inhibitory in the acidic pH condition but stabilized cathepsin L under neutral pH conditions. The different inhibition mechanisms and functional considerations of these inhibitors are discussed.

scholarly journals Mechanistic Insights into the Enhancement of Adeno-Associated Virus Transduction by Proteasome Inhibitors

2013 ◽  
Vol 87 (23) ◽  
pp. 13035-13041 ◽  
Author(s):  
Angela M. Mitchell ◽  
R. Jude Samulski
Keyword(s):  
Cysteine Protease ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Proteasome Activity ◽  
Protease Inhibition ◽  
Adeno Associated Virus

Proteasome inhibitors (e.g., bortezomib, MG132) are known to enhance adeno-associated virus (AAV) transduction; however, whether this results from pleotropic proteasome inhibition or off-target serine and/or cysteine protease inhibition remains unresolved. Here, we examined recombinant AAV (rAAV) effects of a new proteasome inhibitor, carfilzomib, which specifically inhibits chymotrypsin-like proteasome activity and no other proteases. We determined that proteasome inhibitors act on rAAV through proteasome inhibition and not serine or cysteine protease inhibition, likely through positive changes late in transduction.

scholarly journals Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release

2005 ◽  
Vol 12 (11) ◽  
pp. 1445-1448 ◽  
Author(s):  
V J Yuste ◽  
R S Moubarak ◽  
C Delettre ◽  
M Bras ◽  
P Sancho ◽  
...  
Keyword(s):  
Cysteine Protease ◽  
Mitochondrial Apoptosis ◽  
Protease Inhibition ◽  
Apoptosis Inducing Factor

P3-344: Cathepsin B gene deletion and cysteine protease inhibition are effective in a traumatic brain injury model

2012 ◽  
Vol 8 (4S_Part_16) ◽  
pp. P577-P577
Author(s):  
Mark Kindy ◽  
Jin Yu ◽  
Michael Pierschbacher ◽  
Nancy Sipes ◽  
Greg Hook
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cysteine Protease ◽  
Cathepsin B ◽  
Gene Deletion ◽  
Protease Inhibition ◽  
Traumatic Brain Injury Model ◽  
Injury Model

scholarly journals Computational Evaluation of the COVID-19 3c-like Protease Inhibition Mechanism, and Drug Repurposing Screening

2020 ◽  
Author(s):  
Hao Liu ◽  
Tao Jiang ◽  
Wenlang Liu ◽  
Zheng Zheng
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Energy Method ◽  
Drug Repurposing ◽  
Inhibition Mechanism ◽  
Binding Affinities ◽  
Protease Inhibition ◽  
Drug Candidates ◽  
Experimental Drugs ◽  
Drugbank Database

<p>The rapid spread of the COVID-19 outbreak is now a global threat with over a million diagnosed cases and more than 70 thousand deaths. Specific treatments and effective drugs regarding such disease are in urgent need. To contribute to the drug discovery against COVID-19, we performed computational study to understand the inhibition mechanism of the COVID-19 3c-like protease, and search for possible drug candidates from approved or experimental drugs through drug repurposing screening against the DrugBank database. Two novel computational methods were applied in this study. We applied the “Consecutive Histogram Monte Carlo” (CHMC) sampling method for understanding the inhibition mechanism from studying the 2-D binding free energy landscape. We also applied the “Movable Type” (MT) free energy method for the lead compound screening by evaluating the binding free energies of the COVID-19 3c-like protease – inhibitor complexes. Lead compounds from the DrugBank database were first filtered using ligand similarity comparison to 19 published SARS 3c-like protease inhibitors. 70 selected compounds were then evaluated for protein-ligand binding affinities using the MT free energy method. 4 drug candidates with strong binding affinities and reasonable protein-ligand binding modes were selected from this study, <i>i.e.</i> Enalkiren (DB03395), Rupintrivir (DB05102), Saralasin (DB06763) and TRV-120027 (DB12199). </p>

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