scholarly journals Crystal Structure of Feline Infectious Peritonitis Virus Main Protease in Complex with Synergetic Dual Inhibitors

2015 ◽  
Vol 90 (4) ◽  
pp. 1910-1917 ◽  
Author(s):  
Fenghua Wang ◽  
Cheng Chen ◽  
Xuemeng Liu ◽  
Kailin Yang ◽  
Xiaoling Xu ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Zinc Ion ◽  
Inhibition Mechanism ◽  
Granulomatous Disease ◽  
Feline Infectious Peritonitis Virus ◽  
Feline Infectious Peritonitis ◽  
Main Protease ◽  
Michael Acceptor ◽  
Dual Inhibitors ◽  
Dual Inhibition

ABSTRACTCoronaviruses (CoVs) can cause highly prevalent diseases in humans and animals. Feline infectious peritonitis virus (FIPV) belongs to the genusAlphacoronavirus, resulting in a lethal systemic granulomatous disease called feline infectious peritonitis (FIP), which is one of the most important fatal infectious diseases of cats worldwide. No specific vaccines or drugs have been approved to treat FIP. CoV main proteases (Mpros) play a pivotal role in viral transcription and replication, making them an ideal target for drug development. Here, we report the crystal structure of FIPV Mproin complex with dual inhibitors, a zinc ion and a Michael acceptor. The complex structure elaborates a unique mechanism of two distinct inhibitors synergizing to inactivate the protease, providing a structural basis to design novel antivirals and suggesting the potential to take advantage of zinc as an adjunct therapy against CoV-associated diseases.IMPORTANCECoronaviruses (CoVs) have the largest genome size among all RNA viruses. CoV infection causes various diseases in humans and animals, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). No approved specific drugs or vaccinations are available to treat their infections. Here, we report a novel dual inhibition mechanism targeting CoV main protease (Mpro) from feline infectious peritonitis virus (FIPV), which leads to lethal systemic granulomatous disease in cats. Mpro, conserved across all CoV genomes, is essential for viral replication and transcription. We demonstrated that zinc ion and a Michael acceptor-based peptidomimetic inhibitor synergistically inactivate FIPV Mpro. We also solved the structure of FIPV Mprocomplexed with two inhibitors, delineating the structural view of a dual inhibition mechanism. Our study provides new insight into the pharmaceutical strategy against CoV Mprothrough using zinc as an adjuvant therapy to enhance the efficacy of an irreversible peptidomimetic inhibitor.

scholarly journals In silico Repositioning for Dual Inhibitor Discovery of SARS-CoV-2 (COVID-19) 3C-like Protease and Papain-like Peptidase

2020 ◽  
Author(s):  
Kowsar Bagherzadeh ◽  
Kourosh Daneshvarnejad ◽  
Mohammad Abbasinazari ◽  
homa azizian
Keyword(s):  
Active Sites ◽  
Reproduction Number ◽  
Antiviral Agents ◽  
Binding Energies ◽  
Dual Inhibitor ◽  
Main Protease ◽  
Inhibitor Discovery ◽  
Dual Inhibitors ◽  
Dual Inhibition ◽  
Novel Coronavirus

Aims: In late December 2019, early reports predicted the onset of a potential Coronavirus outbreak in china, given the estimate of a reproduction number for the 2019 Novel Coronavirus (COVID-19). Because of high ability of transmission and widespread prevalence, the mortality of COVID-19 infection is growing fast worldwide. Absent of an anti-COVID-19 has put scientists on the urge to repurpose already approved therapeutics or to find new active compounds against coronavirus. Here in this study, a set of computational approaches were performed in order to repurpose antivirals for dual inhibition of the frontier proteases involved in virus replication, papain-like protease (PLpro; corresponding to nsp3) and a main protease (Mpro), 3C‑like protease (3CLpro; corresponding to nsp5). Materials and Methods: In this regard, a rational virtual screening procedure including exhaustive docking techniques was performed for a database of 160 antiviral agents over 3CLpro and PLpro active sites of SARS-CoV-2. The compounds binding energies and interaction modes over 3CLpro and PLpro active sites were analyzed and ranked with the aid of free Gibbs binding energy. The most potent compounds, based on our filtering process, are then proposed as dual inhibitors of SARSC-CoV-2 proteases. Key findings: Accordingly, seven antiviral agents including two FDA approved (Nelfinavir, Valaganciclovir) and five investigational compounds (Merimepodib, Inarigivir, Remdesivir, Taribavirine and TAS106-106) are proposed as potential dual inhibitors of the enzymes necessary for RNA replication in which Remdesivir as well as Inagrivir have the highest binding affinity for both of the active sites. Significance: The mentioned drug proposed to inhibit both PLpro and 3CLpro enzymes with the aim of finding dual inhibitors of SARSC-CoV-2 proteases.

scholarly journals Combinatorial Therapeutic Effect of Inhibitors of Aldehyde Dehydrogenase and Mitochondrial Complex I, and the Chemotherapeutic Drug, Temozolomide against Glioblastoma Tumorspheres

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 282
Author(s):  
Hun Ho Park ◽  
Junseong Park ◽  
Hye Joung Cho ◽  
Jin-Kyoung Shim ◽  
Ju Hyung Moon ◽  
...  
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Cell Metabolism ◽  
Dual Therapy ◽  
Mechanisms Of Action ◽  
Therapeutic Effects ◽  
Chemotherapeutic Drug ◽  
Mitochondrial Complex ◽  
Dual Inhibitors ◽  
Dual Inhibition ◽  
Tumor Bioenergetics

Resident cancer cells with stem cell-like features induce drug tolerance, facilitating survival of glioblastoma (GBM). We previously showed that strategies targeting tumor bioenergetics present a novel emerging avenue for treatment of GBM. The objective of this study was to enhance the therapeutic effects of dual inhibition of tumor bioenergetics by combination of gossypol, an aldehyde dehydrogenase inhibitor, and phenformin, a biguanide compound that depletes oxidative phosphorylation, with the chemotherapeutic drug, temozolomide (TMZ), to block proliferation, stemness, and invasiveness of GBM tumorspheres (TSs). Combination therapy with gossypol, phenformin, and TMZ induced a significant reduction in ATP levels, cell viability, stemness, and invasiveness compared to TMZ monotherapy and dual therapy with gossypol and phenformin. Analysis of differentially expressed genes revealed up-regulation of genes involved in programmed cell death, autophagy, and protein metabolism and down-regulation of those associated with cell metabolism, cycle, and adhesion. Combination of TMZ with dual inhibitors of tumor bioenergetics may, therefore, present an effective strategy against GBM by enhancing therapeutic effects through multiple mechanisms of action.

The first crystal structure of the peptidase domain of the U32 peptidase family

2015 ◽  
Vol 71 (12) ◽  
pp. 2505-2512 ◽  
Author(s):  
Magdalena Schacherl ◽  
Angelika A. M. Montada ◽  
Elena Brunstein ◽  
Ulrich Baumann
Keyword(s):  
Crystal Structure ◽  
Catalytic Mechanism ◽  
Quaternary Structure ◽  
Catalytic Domain ◽  
Three Dimensional ◽  
Zinc Ion ◽  
Crystal Structure Analysis ◽  
Dimensional Structure ◽  
Sequence Motifs ◽  
Conserved Sequence

The U32 family is a collection of over 2500 annotated peptidases in the MEROPS database with unknown catalytic mechanism. They mainly occur in bacteria and archaea, but a few representatives have also been identified in eukarya. Many of the U32 members have been linked to pathogenicity, such as proteins fromHelicobacterandSalmonella. The first crystal structure analysis of a U32 catalytic domain fromMethanopyrus kandleri(genemk0906) reveals a modified (βα)8TIM-barrel fold with some unique features. The connecting segment between strands β7 and β8 is extended and helix α7 is located on top of the C-terminal end of the barrel body. The protein exhibits a dimeric quaternary structure in which a zinc ion is symmetrically bound by histidine and cysteine side chains from both monomers. These residues reside in conserved sequence motifs. No typical proteolytic motifs are discernible in the three-dimensional structure, and biochemical assays failed to demonstrate proteolytic activity. A tunnel in which an acetate ion is bound is located in the C-terminal part of the β-barrel. Two hydrophobic grooves lead to a tunnel at the C-terminal end of the barrel in which an acetate ion is bound. One of the grooves binds to aStrep-Tag II of another dimer in the crystal lattice. Thus, these grooves may be binding sites for hydrophobic peptides or other ligands.

scholarly journals Structural Basis for Dual-Inhibition Mechanism of a Non-Classical Kazal-Type Serine Protease Inhibitor from Horseshoe Crab in Complex with Subtilisin

PLoS ONE ◽  
2011 ◽  
Vol 6 (4) ◽  
pp. e18838 ◽  
Author(s):  
Rajesh T. Shenoy ◽  
Saravanan Thangamani ◽  
Adrian Velazquez-Campoy ◽  
Bow Ho ◽  
Jeak Ling Ding ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Serine Protease ◽  
Horseshoe Crab ◽  
Serine Protease Inhibitor ◽  
Structural Basis ◽  
Inhibition Mechanism ◽  
Dual Inhibition

Effect of Ion Migration of Multiple Copper-Zinc Alloy on the Crystal Structure of Calcium Carbonate Scale

2010 ◽  
Vol 96 ◽  
pp. 35-40 ◽  
Author(s):  
Yan Ding ◽  
Jun Ping Meng ◽  
Xu Hong Zhang ◽  
Li Juan Wang ◽  
Qing Guo Tang
Keyword(s):  
Crystal Structure ◽  
Calcium Carbonate ◽  
Zinc Ion ◽  
Ion Concentration ◽  
Zinc Alloy ◽  
Heating Process ◽  
Ion Migration ◽  
Heat Transfer Efficiency ◽  
Copper Zinc ◽  
Calcium Carbonate Scale

Multiple copper-zinc alloy was used to treat water in order to restrict the formation of hard scale during heating process. Trace amounts of metal ions were dissolved from the alloy under the action of tiny battery corrosion, which took part in the crystallization of calcium carbonate crystal. The ion migration rules and its effect on the crystal structure of water scale were studied. The ICP test results show that after immersion in the water for 20 min, the zinc ion concentration increased to 0.35 mg•L-1 compared with contrast group. The simulating experiment of the scale crystal growth demonstrated that the calcium carbonate scale after treated with the alloy showed a transformation from calcite to aragonite, and the ratio of calcite to aragonite changed from 1:0.125 to 1:2.30. Meanwhile, the heat transfer efficiency was increased to 2.19%.

scholarly journals Virucidal Efficacy of Blue LED and Far-UVC Light Disinfection against Feline Infectious Peritonitis Virus as a Model for SARS-CoV-2

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1436
Author(s):  
Amanda Gardner ◽  
Sayani Ghosh ◽  
Magdalena Dunowska ◽  
Gale Brightwell
Keyword(s):  
Artificial Saliva ◽  
Individual Action ◽  
Feline Infectious Peritonitis Virus ◽  
Feline Infectious Peritonitis ◽  
Blue Led ◽  
Log Reduction ◽  
Dual Action ◽  
Almost All ◽  
Respiratory Droplets ◽  
Virucidal Efficacy

Transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs through respiratory droplets passed directly from person to person or indirectly through fomites, such as common use surfaces or objects. The aim of this study was to determine the virucidal efficacy of blue LED (405 nm) and far-UVC (222 nm) light in comparison to standard UVC (254 nm) irradiation for the inactivation of feline infectious peritonitis virus (FIPV) on different matrices as a model for SARS-CoV-2. Wet or dried FIPV on stainless steel, plastic, or paper discs, in the presence or absence of artificial saliva, were exposed to various wavelengths of light for different time periods (1–90 min). Dual activity of blue LED and far-UVC lights were virucidal for most wet and dried FIPV within 4 to 16 min on all matrices. Individual action of blue LED and far-UVC lights were virucidal for wet FIPV but required longer irradiation times (8–90 min) to reach a 4-log reduction. In comparison, LED (265 nm) and germicidal UVC (254 nm) were virucidal on almost all matrices for both wet and dried FIPV within 1 min exposure. UVC was more effective for the disinfection of surfaces as compared to blue LED and far-UVC individually or together. However, dual action of blue LED and far-UVC was virucidal. This combination of lights could be used as a safer alternative to traditional UVC.

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