scholarly journals Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1044
Author(s):  
Qingxin Li ◽  
Congbao Kang
Keyword(s):  
Small Molecule ◽  
Conformational Changes ◽  
Zika Virus ◽  
Cleavage Site ◽  
Inhibitor Design ◽  
Allosteric Inhibitors ◽  
Protease Cleavage ◽  
Enzyme Cleavage ◽  
Enzyme Cleavage Site ◽  
Inhibit Protease Activity

Zika virus (ZIKV)—a member of the Flaviviridae family—is an important human pathogen. Its genome encodes a polyprotein that can be further processed into structural and non-structural proteins. ZIKV protease is an important target for antiviral development due to its role in cleaving the polyprotein to release functional viral proteins. The viral protease is a two-component protein complex formed by NS2B and NS3. Structural studies using different approaches demonstrate that conformational changes exist in the protease. The structures and dynamics of this protease in the absence and presence of inhibitors were explored to provide insights into the inhibitor design. The dynamic nature of residues binding to the enzyme cleavage site might be important for the function of the protease. Due to the charges at the protease cleavage site, it is challenging to develop small-molecule compounds acting as substrate competitors. Developing small-molecule compounds to inhibit protease activity through an allosteric mechanism is a feasible strategy because conformational changes are observed in the protease. Herein, structures and dynamics of ZIKV protease are summarized. The conformational changes of ZIKV protease and other proteases in the same family are discussed. The progress in developing allosteric inhibitors is also described. Understanding the structures and dynamics of the proteases are important for designing potent inhibitors.

Insertion of a Lysosomal Enzyme Cleavage Site into the Sequence of a Radiolabeled Neuropeptide Influences Cell Trafficking In Vitro and In Vivo

2010 ◽  
Vol 25 (1) ◽  
pp. 89-95 ◽  
Author(s):  
Syed Ali Raza Naqvi ◽  
Torkjel Matzow ◽  
Ciara Finucane ◽  
Saeed A. Nagra ◽  
Malik M. Ishfaq ◽  
...  
Keyword(s):  
Lysosomal Enzyme ◽  
Cleavage Site ◽  
Cell Trafficking ◽  
Enzyme Cleavage ◽  
Enzyme Cleavage Site

Trivalent metal complex geometry of the substrate governs cathepsin B enzymatic cleavage rate

2020 ◽  
Vol 56 (53) ◽  
pp. 7289-7292 ◽  
Author(s):  
Shin Hye Ahn ◽  
James N. Iuliano ◽  
Eszter Boros
Keyword(s):  
Metal Complex ◽  
Cathepsin B ◽  
Cleavage Site ◽  
Metal Ion ◽  
Complex Geometry ◽  
Enzymatic Cleavage ◽  
Trivalent Metal ◽  
Cleavage Rate ◽  
Enzyme Cleavage ◽  
Enzyme Cleavage Site

The identity of the trivalent metal ion controls the rate of the enzymatic cleavage of a series of metal-complexed cathepsin B substrates. Increasing the distance between the metal complex and the enzyme cleavage site diminishes this effect.

scholarly journals A New Escherichia coli Entry Vector Series (pIIS18) for Seamless Gene Cloning Using Type IIS Restriction Enzymes

2019 ◽  
Vol 8 (41) ◽  
Author(s):  
Hend Altaib ◽  
Yuka Ozaki ◽  
Tomoya Kozakai ◽  
Yassien Badr ◽  
Izumi Nomura ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Gene Cloning ◽  
Cleavage Site ◽  
Restriction Enzymes ◽  
Cleavage Sites ◽  
Content Type ◽  
Entry Vector ◽  
Enzyme Cleavage ◽  
Multiple Cloning Sites ◽  
Enzyme Cleavage Site

A series of new Escherichia coli entry vectors (pIIS18-SapI, pIIS18-BsmBI, pIIS18-BsaI, pIIS18-BfuAI-1, and pIIS18-BfuAI-2) was constructed based on a modified pUC18 backbone, which carried newly designed multiple cloning sites, consisting of two facing type IIS enzyme cleavage sites and one blunt-end enzyme cleavage site. These vectors are useful for seamless gene cloning.

scholarly journals Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

2020 ◽  
Vol 21 (9) ◽  
pp. 3099 ◽  
Author(s):  
Maria Bzówka ◽  
Karolina Mitusińska ◽  
Agata Raczyńska ◽  
Aleksandra Samol ◽  
Jack A. Tuszyński ◽  
...  
Keyword(s):  
Drug Design ◽  
Small Molecule ◽  
Conformational Changes ◽  
Active Sites ◽  
Rational Design ◽  
De Novo ◽  
Sequence Similarity ◽  
Effective Vaccine ◽  
Evolutionary Analysis ◽  
Inhibitor Design

The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mixed-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar severe acute respiratory syndrome (SARS) Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins showed major differences in both shape and size, indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site’s conformational changes during the simulation time indicated its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicated that the virus’ mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.

scholarly journals An aggrecan-degrading activity associated with chondrocyte membranes

1998 ◽  
Vol 336 (1) ◽  
pp. 207-212 ◽  
Author(s):  
Caron J. BILLINGTON ◽  
Ian M. CLARK ◽  
Tim E. CAWSTON
Keyword(s):  
Matrix Metalloproteinase ◽  
Cleavage Site ◽  
Mmp Inhibitors ◽  
Membrane Activity ◽  
Alanine Residue ◽  
Naturally Occurring ◽  
Enzyme Cleavage ◽  
N Terminus ◽  
Enzyme Cleavage Site

The breakdown of aggrecan in cartilage is, in part, mediated by an enzyme named aggrecanase that cleaves within the interglobular domain of the molecule between a glutamic residue and an alanine residue. Although the enzyme cleavage site has been identified, the identity, characteristics and localization of this enzyme remain unclear. We have demonstrated that membranes isolated from stimulated chondrocytes are able to generate aggrecan fragments that are labelled by an antibody that recognizes the new N-terminus formed by aggrecanase activity. It was further shown that the membrane activity was a metalloproteinase but was not inhibited by the naturally occurring matrix metalloproteinase (MMP) inhibitors, TIMPs 1 and 2. These results show that an aggrecanase activity is associated with the membranes of the chondrocytes and is a metalloproteinase, but might not be a member of the MMP family.

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