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Journal of Natural Products Nov 2020Plant peptide protease inhibitors are important molecules in seed storage metabolism and to fight insect pests. Commonly they contain multiple disulfide bonds and are...
Plant peptide protease inhibitors are important molecules in seed storage metabolism and to fight insect pests. Commonly they contain multiple disulfide bonds and are exceptionally stable molecules. In this study, a novel peptide protease inhibitor from beetroot () termed bevuTI-I was isolated, and its primary structure was determined via mass spectrometry-based amino acid sequencing. By sequence homology analysis a few peptides with high similarity to bevuTI-I, also known as the trypsin inhibitor subfamily of knottin-type protease inhibitors, were discovered. Hence, we assessed bevuTI-I for inhibitory activity toward trypsin (IC = 471 nM) and human prolyl oligopeptidase (IC = 11 μM), which is an emerging drug target for neurodegenerative and inflammatory disorders. Interestingly, using a customized bioinformatics approach, bevuTI-I was found to be the missing link to annotate 243 novel sequences of trypsin inhibitor-like peptides. According to their phylogenetic distribution they appear to be common in several plant families. Therefore, the presented approach and our results may help to discover and classify other plant-derived cystine knot peptides, a class of plant molecules that play important functions in plant physiology and are currently being explored as lead molecules and scaffolds in drug development.
Topics: Amino Acid Sequence; Beta vulgaris; Cystine; Drug Discovery; Peptides; Phylogeny; Plant Proteins; Protease Inhibitors; Proteolysis; Sequence Homology, Amino Acid; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 33118348
DOI: 10.1021/acs.jnatprod.0c00648 -
Journal of Medicinal Chemistry Jun 2022SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral... (Review)
Review
SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral polymerase inhibitors remdesivir and molnupiravir and the viral main protease inhibitor nirmatrelvir/ritonavir have been approved by the U.S. FDA. However, the emergence of variants of concern/interest calls for additional antivirals with novel mechanisms of action. The SARS-CoV-2 papain-like protease (PL) mediates the cleavage of viral polyprotein and modulates the host's innate immune response upon viral infection, rendering it a promising antiviral drug target. This Perspective highlights major achievements in structure-based design and high-throughput screening of SARS-CoV-2 PL inhibitors since the beginning of the pandemic. Encouraging progress includes the design of non-covalent PL inhibitors with favorable pharmacokinetic properties and the first-in-class covalent PL inhibitors. In addition, we offer our opinion on the knowledge gaps that need to be filled to advance PL inhibitors to the clinic.
Topics: Antiviral Agents; Coronavirus Papain-Like Proteases; Humans; Pandemics; Protease Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35620927
DOI: 10.1021/acs.jmedchem.2c00303 -
Molecules (Basel, Switzerland) Apr 2022Since the outbreak of COVID-19, one of the strategies used to search for new drugs has been to find inhibitors of the main protease (Mpro) of the virus SARS-CoV-2.... (Review)
Review
Since the outbreak of COVID-19, one of the strategies used to search for new drugs has been to find inhibitors of the main protease (Mpro) of the virus SARS-CoV-2. Initially, previously reported inhibitors of related proteases such as the main proteases of SARS-CoV and MERS-CoV were tested. A huge effort was then carried out by the scientific community to design, synthesize and test new small molecules acting as inactivators of SARS-CoV-2 Mpro. From the chemical structure view, these compounds can be classified into two main groups: one corresponds to modified peptides displaying an adequate sequence for high affinity and a reactive warhead; and the second is a diverse group including chemical compounds that do not have a peptide framework. Although a drug including a SARS-CoV-2 main protease inhibitor has already been commercialized, denoting the importance of this field, more compounds have been demonstrated to be promising potent inhibitors as potential antiviral drugs.
Topics: Antiviral Agents; Coronavirus 3C Proteases; Humans; Molecular Docking Simulation; Peptide Hydrolases; Protease Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35458721
DOI: 10.3390/molecules27082523 -
Eye & Contact Lens Mar 2020Tears are highly concentrated in proteins relative to other biofluids, and a notable fraction of tear proteins are proteases and protease inhibitors. These components... (Review)
Review
Tears are highly concentrated in proteins relative to other biofluids, and a notable fraction of tear proteins are proteases and protease inhibitors. These components are present in a delicate equilibrium that maintains ocular surface homeostasis in response to physiological and temporal cues. Dysregulation of the activity of protease and protease inhibitors in tears occurs in ocular surface diseases including dry eye and infection, and ocular surface conditions including wound healing after refractive surgery and contact lens (CL) wear. Measurement of these changes can provide general information regarding ocular surface health and, increasingly, has the potential to give specific clues regarding disease diagnosis and guidance for treatment. Here, we review three major categories of tear proteases (matrix metalloproteinases, cathepsins, and plasminogen activators [PAs]) and their endogenous inhibitors (tissue inhibitors of metalloproteinases, cystatins, and PA inhibitors), and the changes in these factors associated with dry eye, infection and allergy, refractive surgery, and CLs. We highlight suggestions for development of these and other protease/protease inhibitor biomarkers in this promising field.
Topics: Biomarkers; Dry Eye Syndromes; Eye Proteins; Humans; Peptide Hydrolases; Protease Inhibitors; Tears
PubMed: 31369467
DOI: 10.1097/ICL.0000000000000641 -
The European Respiratory Journal Feb 2017Proteases were traditionally viewed as mere protein-degrading enzymes with a very restricted spectrum of substrates. A major expansion in protease research has uncovered... (Review)
Review
Proteases were traditionally viewed as mere protein-degrading enzymes with a very restricted spectrum of substrates. A major expansion in protease research has uncovered a variety of novel substrates, and it is now evident that proteases are critical pleiotropic actors orchestrating pathophysiological processes. Recent findings evidenced that the net proteolytic activity also relies upon interconnections between different protease and protease inhibitor families in the protease web.In this review, we provide an overview of these novel concepts with a particular focus on pulmonary pathophysiology. We describe the emerging roles of several protease families including cysteine and serine proteases.The complexity of the protease web is exemplified in the light of multidimensional regulation of serine protease activity by matrix metalloproteases through cognate serine protease inhibitor processing. Finally, we will highlight how deregulated protease activity during pulmonary pathogenesis may be exploited for diagnosis/prognosis purposes, and utilised as a therapeutic tool using nanotechnologies.Considering proteases as part of an integrative biology perspective may pave the way for the development of new therapeutic targets to treat pulmonary diseases related to intrinsic protease deregulation.
Topics: Animals; Humans; Lung; Lung Diseases; Matrix Metalloproteinases; Mice; Protease Inhibitors; Proteolysis
PubMed: 28179435
DOI: 10.1183/13993003.01200-2015 -
Toxins Apr 2022The Bowman-Birk protease inhibitor (BBI) family is a prototype group found mainly in plants, particularly grasses and legumes, which have been subjected to decades of...
The Bowman-Birk protease inhibitor (BBI) family is a prototype group found mainly in plants, particularly grasses and legumes, which have been subjected to decades of study. Recently, the discovery of attenuated peptides containing the canonical Bowman-Birk protease inhibitory motif has been detected in the skin secretions of amphibians, mainly from Ranidae family members. The roles of these peptides in amphibian defense have been proposed to work cooperatively with antimicrobial peptides and reduce peptide degradation. A novel trypsin inhibitory peptide, named livisin, was found in the skin secretion of the green cascade frog, . The cDNA encoding the precursor of livisin was cloned, and the predicted mature peptide was characterized. The mature peptide was found to act as a potent inhibitor against several serine proteases. A comparative activity study among the native peptide and its engineered analogs was performed, and the influence of the P and P positions, as well as the C-terminal amidation on the structure-activity relationship for livisin, was illustrated. The findings demonstrated that livisin might serve as a potential drug discovery/development tool.
Topics: Amino Acid Sequence; Animals; Anti-Infective Agents; Peptides; Protease Inhibitors; Ranidae; Skin
PubMed: 35448882
DOI: 10.3390/toxins14040273 -
Biopolymers Nov 2016Proteases play crucial roles in various biological processes, and their activities are essential for all living organisms-from viruses to humans. Since their functions... (Review)
Review
Proteases play crucial roles in various biological processes, and their activities are essential for all living organisms-from viruses to humans. Since their functions are closely associated with many pathogenic mechanisms, their inhibitors or activators are important molecular targets for developing treatments for various diseases. Here, we describe drugs/drug candidates that target proteases, such as malarial plasmepsins, β-secretase, virus proteases, and dipeptidyl peptidase-4. Previously, we reported inhibitors of aspartic proteases, such as renin, human immunodeficiency virus type 1 protease, human T-lymphotropic virus type I protease, plasmepsins, and β-secretase, as drug candidates for hypertension, adult T-cell leukaemia, human T-lymphotropic virus type I-associated myelopathy, malaria, and Alzheimer's disease. Our inhibitors are also described in this review article as examples of drugs that target proteases. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 563-579, 2016.
Topics: Animals; Drug Discovery; Humans; Peptide Hydrolases; Plasmodium; Protease Inhibitors; Protozoan Proteins; Viral Proteins; Viruses
PubMed: 26584340
DOI: 10.1002/bip.22780 -
MEDICC Review Oct 2022In inflammatory respiratory diseases, the imbalance between proteases and endogenous protease inhibitors leads to an exacerbated activity of human neutrophil elastase (a...
INTRODUCTION
In inflammatory respiratory diseases, the imbalance between proteases and endogenous protease inhibitors leads to an exacerbated activity of human neutrophil elastase (a protease that destroys the extracellular matrix and stimulates proinflammatory cytokine release). Elastase is considered a target in the search for therapeutic treatments for inflammatory respiratory diseases. Pulmonary surfactant is a promising product for this purpose, because in addition to its biophysical function, it has anti-inflammatory properties.
OBJECTIVE
Evaluate effect of the Cuban porcine pulmonary surfactant (Surfacen), the rCmPI-II elastase inhibitor, and the Surfacen/rCmPI-II combination on activated neutrophil elastase activity in vitro, and determine if Surfacen's interface property changes in the presence of the inhibitor.
METHODS
The anti-elastase effect of Surfacen, rCmPI-II and the Surfacen/rCmPI-II combination was evaluated in an in vitro model of activated neutrophils, previously purified from the blood of healthy subjects. The cells were stimulated with LPS/fMLP and were incubated with different concentrations of Surfacen, rCmPI-II and the Surfacen/rCmPI-II combination. Elastase activity was measured. The interface property was determined on a Langmuir surface balance. The new index, called the abdominal adipose deposit index, was obtained by multiplying the subcutaneous fat thickness by visceral fat thickness, both measured by ultrasound. A cutoff point was established that facilitated discernment of an unhealthy phenotype: normal weight but metabolically obese, a cardiometabolic risk factor.
RESULTS
Surfacen at 10 mg/mL inhibited 71% of stimulated neutrophil elastase activity. rCmPI-II at 0.1 μM reduced 20% of elastase activity; at 200 μM-the maximum concentration evaluated-inhibition was 68%. Both products had a dose-dependent effect. The Surfacen/inhibitor combination (0.5 mg/mL/80 µM) did not affect the surfactant interface property or the inhibitory activity of rCmPI-II against human neutrophil elastase.
CONCLUSIONS
Surfacen and the rCmPI-II inhibitor have an anti-elastase effect on an activated neutrophil model. rCmPI-II does not affect Surfacen's interface property and, therefore, both can be evaluated for combined use in treating inflammatory lung diseases.
Topics: Animals; Humans; Antiviral Agents; Leukocyte Elastase; Neutrophils; Protease Inhibitors; Pulmonary Surfactants; Swine
PubMed: 36417334
DOI: 10.37757/MR2022.V24.N3-4.7 -
Ginekologia Polska 2022Investigating the expression levels of plasma protein Z (PZ) and protein Z-dependent protease inhibitor (ZPI) in fetal growth restriction (FGR) and to explore their...
OBJECTIVES
Investigating the expression levels of plasma protein Z (PZ) and protein Z-dependent protease inhibitor (ZPI) in fetal growth restriction (FGR) and to explore their diagnostic value in FGR.
MATERIAL AND METHODS
In this study, the number of pregnant women with FGR, healthy pregnant women (Healthy Control, HC), and childbearing-age women without pregnancy (Blank Control, BC) is 79, 79, and 60, respectively; their plasma PZ and ZPI levels in each group are determined by ELISAs. Then, the correlations between these indices and FGR were assessed using Spearman analysis. Moreover, these indices' diagnostic values for FGR are evaluated using the receiver operating characteristics (ROC) curves.
RESULTS
The plasma levels of PZ and ZPI are significantly decreased in the HC and FGR groups compared against the BC group (P < 0.001), whilst the levels of PZ and ZPI in the FGR groups are lower than those in the HC group (P < 0.01) notably. PZ plasma concentration has positive relationship with ZPI concentrations in the HC and FGR groups. The combination of PZ and ZPI, with the Area under the Curve (AUC) 0.92 (95% CI = 0.88-0.96), the sensitivity 0.82, and the specificity 0.88, outperforms everyone.
CONCLUSIONS
Plasma PZ and ZPI are significantly decreased in pregnant women with FGR, which can be used for pregnant women's FGR screening.
Topics: Female; Humans; Pregnancy; Blood Proteins; Fetal Growth Retardation; Protease Inhibitors; Serpins
PubMed: 35072242
DOI: 10.5603/GP.a2021.0205 -
World Journal of Gastroenterology Mar 2017The gastrointestinal barrier is - with approximately 400 m - the human body's largest surface separating the external environment from the internal milieu. This barrier... (Review)
Review
The gastrointestinal barrier is - with approximately 400 m - the human body's largest surface separating the external environment from the internal milieu. This barrier serves a dual function: permitting the absorption of nutrients, water and electrolytes on the one hand, while limiting host contact with noxious luminal antigens on the other hand. To maintain this selective barrier, junction protein complexes seal the intercellular space between adjacent epithelial cells and regulate the paracellular transport. Increased intestinal permeability is associated with and suggested as a player in the pathophysiology of various gastrointestinal and extra-intestinal diseases such as inflammatory bowel disease, celiac disease and type 1 diabetes. The gastrointestinal tract is exposed to high levels of endogenous and exogenous proteases, both in the lumen and in the mucosa. There is increasing evidence to suggest that a dysregulation of the protease/antiprotease balance in the gut contributes to epithelial damage and increased permeability. Excessive proteolysis leads to direct cleavage of intercellular junction proteins, or to opening of the junction proteins activation of protease activated receptors. In addition, proteases regulate the activity and availability of cytokines and growth factors, which are also known modulators of intestinal permeability. This review aims at outlining the mechanisms by which proteases alter the intestinal permeability. More knowledge on the role of proteases in mucosal homeostasis and gastrointestinal barrier function will definitely contribute to the identification of new therapeutic targets for permeability-related diseases.
Topics: Animals; Diabetes Mellitus, Type 1; Electrolytes; Epithelial Cells; Humans; Inflammation; Inflammatory Bowel Diseases; Intestines; Matrix Metalloproteinase Inhibitors; Mice; Peptide Hydrolases; Permeability; Protease Inhibitors; Serine Proteinase Inhibitors; Tight Junctions; Treatment Outcome
PubMed: 28405139
DOI: 10.3748/wjg.v23.i12.2106