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Chembiochem : a European Journal of... Oct 2022Emerging variants of SARS-CoV-2 and potential novel epidemic coronaviruses underline the importance of investigating various viral proteins as potential drug targets.... (Review)
Review
Emerging variants of SARS-CoV-2 and potential novel epidemic coronaviruses underline the importance of investigating various viral proteins as potential drug targets. The papain-like protease of coronaviruses has been less explored than other viral proteins; however, its substantive role in viral replication and impact on the host immune response make it a suitable target to study. This review article focuses on the structure and function of the papain-like protease (PL ) of SARS-CoV-2, including variants of concern, and compares it to those of other coronaviruses, such as SARS-CoV-1 and MERS-CoV. The protease's recognition motif is mirrored in ubiquitin and ISG15, which are involved in the antiviral immune response. Inhibitors, including GRL0617 derivatives, and their prospects as potential future antiviral agents are also discussed.
Topics: Aniline Compounds; Antiviral Agents; Benzamides; Coronavirus Papain-Like Proteases; Humans; Naphthalenes; Papain; Peptide Hydrolases; Protease Inhibitors; SARS-CoV-2; Ubiquitin; Viral Proteins; COVID-19 Drug Treatment
PubMed: 35993805
DOI: 10.1002/cbic.202200327 -
The New Phytologist Dec 2016902 I. 902 II. 903 III. 903 IV. 903 V. 905 VI. 905 VII. 905 906 References 906 SUMMARY: Plants deploy a sophisticated immune system to cope with different microbial... (Review)
Review
902 I. 902 II. 903 III. 903 IV. 903 V. 905 VI. 905 VII. 905 906 References 906 SUMMARY: Plants deploy a sophisticated immune system to cope with different microbial pathogens and other invaders. Recent research provides an increasing body of evidence for papain-like cysteine proteases (PLCPs) being central hubs in plant immunity. PLCPs are required for full resistance of plants to various pathogens. At the same time, PLCPs are targeted by secreted pathogen effectors to suppress immune responses. Consequently, they are subject to a co-evolutionary host-pathogen arms race. When activated, PLCPs induce a broad spectrum of defense responses including plant cell death. While the important role of PLCPs in plant immunity has become more evident, it remains largely elusive how these enzymes are activated and which signaling pathways are triggered to orchestrate different downstream responses.
Topics: Adaptation, Physiological; Cell Death; Host-Pathogen Interactions; Papain; Plant Immunity; Receptors, Cell Surface
PubMed: 27488095
DOI: 10.1111/nph.14117 -
Advances in Experimental Medicine and... 2011Staphylococcus aureus remains one of the major humanpathogens, causing a number of diverse infections. the growing antibiotic resistance, including vancomycin and... (Review)
Review
Staphylococcus aureus remains one of the major humanpathogens, causing a number of diverse infections. the growing antibiotic resistance, including vancomycin and methicilin-resistant strains raises the special interest in virulence mechanism of this pathogen. among a number of extracellular virulence factors, S. aureus secretes several proteases of three catalytic classes-metallo, serine and papain-like cysteine proteases. the expression of proteolytic enzymes is strictly controlled by global regulators of virulence factors expression agr and sar and proteases take a role in a phenotype change in postlogarithmic phase of growth. the staphylococcal proteases are secreted as proenzymes and undergo activation in a cascade manner. Staphopains, two cysteine, papain-like proteases of S. aureus are both approximately 20 kDa proteins that have almost identical three-dimensional structures, despite sharing limited primary sequence identity. although staphopain a displays activity similar to cathepsins, recognising hydrophobic residues at P2 position and large charged residues at P1, staphopain B differs significantly, showing significant preference towards β-branched residues at P2 and accepting only small, neutral residues at the P1 position. there is limited data available on the virulence potential of staphopains in in vivo models. However, in vitro experiments have demonstrated a very broad activity of these enzymes, including destruction of connective tissue, disturbance of clotting and kinin systems and direct interaction with host immune cells. Staphopain genes in various staphylococci species are regularly followed by a gene encoding an extremely specific inhibitor of the respective staphopain. This pattern is conserved across species and it is believed that inhibitors (staphostatins) protect the cytoplasm of the cell from premature activation of staphopains during protein folding. Notably, production and activity of staphopains is controlled on each level, from gene expression, through presence of specific inhibitors in cytoplasm, to the cascade-like activation in extracellular environment. Since these systems are highly conserved, this points to the importance of these proteases in the survival and/or pathogenicity of S. aureus.
Topics: Bacterial Proteins; Enzyme Activation; Papain; Staphylococcus aureus; Virulence
PubMed: 21660655
DOI: 10.1007/978-1-4419-8414-2_1 -
Advances in Protein Chemistry 1971
Review
Topics: Acylation; Amino Acid Sequence; Binding Sites; Catalysis; Crystallization; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Mercury; Models, Structural; Papain; Protein Binding; Protein Conformation; Tryptophan; Tyrosine; X-Ray Diffraction
PubMed: 4946704
DOI: 10.1016/s0065-3233(08)60279-x -
Postepy Biochemii 1972
Topics: Amino Acid Sequence; Chemical Phenomena; Chemistry; Enzyme Activation; Hydrogen-Ion Concentration; Hydrolysis; Models, Structural; Molecular Conformation; Molecular Weight; Papain
PubMed: 4680436
DOI: No ID Found -
The Journal of Biological Chemistry Jun 2023Papain-like cysteine peptidases form a big and highly diverse superfamily of proteins involved in many important biological functions, such as protein turnover,...
Papain-like cysteine peptidases form a big and highly diverse superfamily of proteins involved in many important biological functions, such as protein turnover, deubiquitination, tissue remodeling, blood clotting, virulence, defense, and cell wall remodeling. High sequence and structure diversity observed within these proteins hinders their comprehensive classification as well as the identification of new representatives. Moreover, in general protein databases, many families already classified as papain like lack details regarding their mechanism of action or biological function. Here, we use transitive remote homology searches and 3D modeling to newly classify 21 families to the papain-like cysteine peptidase superfamily. We attempt to predict their biological function and provide structural characterization of 89 protein clusters defined based on sequence similarity altogether spanning 106 papain-like families. Moreover, we systematically discuss observed diversity in sequences, structures, and catalytic sites. Eventually, we expand the list of human papain-related proteins by seven representatives, including dopamine receptor-interacting protein 1 as potential deubiquitinase, and centriole duplication regulating CEP76 as retaining catalytically active peptidase-like domain. The presented results not only provide structure-based rationales to already existing peptidase databases but also may inspire further experimental research focused on peptidase-related biological processes.
Topics: Humans; Catalytic Domain; Centrioles; Cysteine Proteases; Deubiquitinating Enzymes; Models, Molecular; Papain; Databases, Protein
PubMed: 37164157
DOI: 10.1016/j.jbc.2023.104801 -
The Journal of Physical Chemistry. B Nov 2019The effect of papain adsorption on the surface charge properties and aggregation mechanism of sulfate-functionalized polystyrene latex particles was studied. The...
The effect of papain adsorption on the surface charge properties and aggregation mechanism of sulfate-functionalized polystyrene latex particles was studied. The positively charged enzyme possessed a high affinity to the oppositely charged particles, giving rise to charge neutralization and charge reversal at appropriate papain concentrations. The tendency in the particle aggregation rates at different enzyme doses revealed that the colloidal stability of the samples is governed by interparticle forces of electrostatic origin. The aggregation mechanism was qualitatively described within the classical DLVO theory, and unstable dispersions were detected near the charge neutralization point, while particle aggregation was not observed at low and elevated papain concentrations. The relatively high dispersion stability of the bare latex particles was maintained upon the formation of an enzyme layer on the surface, and the obtained latex-papain composite showed notable resistance against salt-induced aggregation. Remarkable hydrolytic and antioxidant activities of the immobilized enzyme were observed in probe reactions; therefore, the obtained hybrid can be considered as a multifunctional biocatalytic system with great promise in applications in industrial manufacturing processes.
Topics: Adsorption; Antioxidants; Biocatalysis; Dynamic Light Scattering; Enzymes, Immobilized; Latex; Papain; Salts
PubMed: 31670963
DOI: 10.1021/acs.jpcb.9b08799 -
Neurotoxicity Research Oct 2022Since the appearance of SARS-CoV-2 and the COVID-19 pandemic, the search for new approaches to treat this disease took place in the scientific community. The in silico... (Review)
Review
Since the appearance of SARS-CoV-2 and the COVID-19 pandemic, the search for new approaches to treat this disease took place in the scientific community. The in silico approach has gained importance at this moment, once the methodologies used in this kind of study allow for the identification of specific protein-ligand interactions, which may serve as a filter step for molecules that can act as specific inhibitors. In addition, it is a low-cost and high-speed technology. Molecular docking has been widely used to find potential viral protein inhibitors for structural and non-structural proteins of the SARS-CoV-2, aiming to block the infection and the virus multiplication. The papain-like protease (PLpro) participates in the proteolytic processing of SARS-CoV-2 and composes one of the main targets studied for pharmacological intervention by in silico methodologies. Based on that, we performed a systematic review about PLpro inhibitors from the perspective of in silico research, including possible therapeutic molecules in relation to this viral protein. The neurological problems triggered by COVID-19 were also briefly discussed, especially relative to the similarities of neuroinflammation present in Alzheimer's disease. In this context, we focused on two molecules, curcumin and glycyrrhizinic acid, given their PLpro inhibitory actions and neuroprotective properties and potential therapeutic effects on COVID-19.
Topics: Curcumin; Glycyrrhizic Acid; Humans; Ligands; Molecular Docking Simulation; Pandemics; Papain; Peptide Hydrolases; SARS-CoV-2; Viral Proteins; COVID-19 Drug Treatment
PubMed: 35917086
DOI: 10.1007/s12640-022-00542-2 -
Colloids and Surfaces. B, Biointerfaces Oct 2020Wound dressings based on natural polymers are of considerable interest in the pharmaceutical industry owing to their improved performance in the human body when compared...
Wound dressings based on natural polymers are of considerable interest in the pharmaceutical industry owing to their improved performance in the human body when compared to synthetic polymers. Alginate, a polysaccharide from brown algae, is commonly studied as a wound dressing owing to its biocompatibility and biodegradability. To improve its therapeutic features and thereby increase wound healing, papain (a proteolytic enzyme from Carica papaya latex) was proposed to be incorporated. Papain is capable of promoting the debridement of devitalized or necrotic tissues. The development of dressing based on alginate and papain aggregates the healing properties of both materials. In addition, the adsorption on a support can stabilize the enzyme structure and permits its release in a controlled manner. The optimal conditions for immobilization were evaluated (initial concentration, temperature, and pH), and the amount immobilized was measured by Bradford assay. The enzyme activity stability over 28 days was measured. The release profile was determined using Franz cell. In vitro cytotoxicity assays were performed using fibroblasts and keratinocytes. Optimal immobilization conditions were identified in a neutral medium at a papain concentration of 20 mg/mL and temperature of 25 °C. The enzyme remained active after immobilization (80 % of its initial activity), and the matrix protected the enzyme from deactivation (70 % reduction on the matrix compared to 94 % in a buffer solution). Franz cell displayed a release profile of 64.1 % of the enzyme after 24 h. The biological assays indicated a bioactive material with proteolytic properties.
Topics: Alginates; Bandages; Enzyme Stability; Enzymes, Immobilized; Papain; Wound Healing
PubMed: 32610228
DOI: 10.1016/j.colsurfb.2020.111222 -
Proceedings of the National Academy of... Apr 2019Cyclotides are plant defense peptides that have been extensively investigated for pharmaceutical and agricultural applications, but key details of their...
Cyclotides are plant defense peptides that have been extensively investigated for pharmaceutical and agricultural applications, but key details of their posttranslational biosynthesis have remained elusive. Asparaginyl endopeptidases are crucial in the final stage of the head-to-tail cyclization reaction, but the enzyme(s) involved in the prerequisite steps of N-terminal proteolytic release were unknown until now. Here we use activity-guided fractionation to identify specific members of papain-like cysteine proteases involved in the N-terminal cleavage of cyclotide precursors. Through both characterization of recombinantly produced enzymes and peptide cyclization assays, we define the molecular basis of the substrate requirements of these enzymes, including the prototypic member, here termed kalatase A. The findings reported here will pave the way for improving the efficiency of plant biofactory approaches for heterologous production of cyclotide analogs of therapeutic or agricultural value.
Topics: Cyclotides; Cysteine Proteases; Defensins; Models, Molecular; Papain; Plant Proteins
PubMed: 30944220
DOI: 10.1073/pnas.1901807116