-
International Journal of Molecular... May 2023Biomarker development, improvement, and clinical implementation in the context of kidney disease have been a central focus of biomedical research for decades. To this... (Review)
Review
Biomarker development, improvement, and clinical implementation in the context of kidney disease have been a central focus of biomedical research for decades. To this point, only serum creatinine and urinary albumin excretion are well-accepted biomarkers in kidney disease. With their known blind spot in the early stages of kidney impairment and their diagnostic limitations, there is a need for better and more specific biomarkers. With the rise in large-scale analyses of the thousands of peptides in serum or urine samples using mass spectrometry techniques, hopes for biomarker development are high. Advances in proteomic research have led to the discovery of an increasing amount of potential proteomic biomarkers and the identification of candidate biomarkers for clinical implementation in the context of kidney disease management. In this review that strictly follows the PRISMA guidelines, we focus on urinary peptide and especially peptidomic biomarkers emerging from recent research and underline the role of those with the highest potential for clinical implementation. The Web of Science database (all databases) was searched on 17 October 2022, using the search terms "marker *" OR biomarker * AND "renal disease" OR "kidney disease" AND "proteome *" OR "peptid *" AND "urin *". English, full-text, original articles on humans published within the last 5 years were included, which had been cited at least five times per year. Studies based on animal models, renal transplant studies, metabolite studies, studies on miRNA, and studies on exosomal vesicles were excluded, focusing on urinary peptide biomarkers. The described search led to the identification of 3668 articles and the application of inclusion and exclusion criteria, as well as abstract and consecutive full-text analyses of three independent authors to reach a final number of 62 studies for this manuscript. The 62 manuscripts encompassed eight established single peptide biomarkers and several proteomic classifiers, including CKD273 and IgAN237. This review provides a summary of the recent evidence on single peptide urinary biomarkers in CKD, while emphasizing the increasing role of proteomic biomarker research with new research on established and new proteomic biomarkers. Lessons learned from the last 5 years in this review might encourage future studies, hopefully resulting in the routine clinical applicability of new biomarkers.
Topics: Humans; Proteomics; Renal Insufficiency, Chronic; Kidney; Peptides; Biomarkers
PubMed: 37298105
DOI: 10.3390/ijms24119156 -
Archives of Microbiology Mar 2019Peptides and proteins are important bioorganic compounds in nature, among which a special place is occupied by antimicrobial substances. There are more than 2000... (Review)
Review
Peptides and proteins are important bioorganic compounds in nature, among which a special place is occupied by antimicrobial substances. There are more than 2000 different antimicrobial peptides (AMPs) produced by a variety of living organisms. Bacteriocins produced by bacteria are the minor group, whose chemical structures are most complicated among all AMPs. The review summarized the main points related to antimicrobial action of the bacteriocins including steps of peptide's interaction with bacterial membranes and details of membrane damaging. The membrane-disordered bacteriocins were described in accordance with structural-functional relationships.
Topics: Bacteria; Bacteriocins; Cell Membrane; Peptides; Structure-Activity Relationship
PubMed: 30554292
DOI: 10.1007/s00203-018-1610-3 -
Journal of Molecular Biology Oct 2022Sec secretory proteins are distinguished from cytoplasmic ones by N-terminal signal peptides with multiple roles during post-translational translocation. They contribute...
Sec secretory proteins are distinguished from cytoplasmic ones by N-terminal signal peptides with multiple roles during post-translational translocation. They contribute to preprotein targeting to the translocase by slowing down folding, binding receptors and triggering secretion. While signal peptides get cleaved after translocation, mature domains traffic further and/or fold into functional states. How signal peptides delay folding temporarily, to keep mature domains translocation-competent, remains unclear. We previously reported that the foldon landscape of the periplasmic prolyl-peptidyl isomerase is altered by its signal peptide and mature domain features. Here, we reveal that the dynamics of signal peptides and mature domains crosstalk. This involves the signal peptide's hydrophobic helical core, the short unstructured connector to the mature domain and the flexible rheostat at the mature domain N-terminus. Through this cis mechanism the signal peptide delays the formation of early initial foldons thus altering their hierarchy and delaying mature domain folding. We propose that sequence elements outside a protein's native core exploit their structural dynamics to influence the folding landscape.
Topics: Isomerases; Protein Domains; Protein Folding; Protein Sorting Signals; SEC Translocation Channels
PubMed: 35970402
DOI: 10.1016/j.jmb.2022.167790 -
ACS Chemical Biology Sep 2022The three-dimensional structure of natural products is critical for their biological activities and, as such, enzymes have evolved that specifically generate active...
The three-dimensional structure of natural products is critical for their biological activities and, as such, enzymes have evolved that specifically generate active stereoisomers. Lanthipeptides are post-translationally modified peptidic natural products that contain macrocyclic thioethers featuring lanthionine (Lan) and/or methyllanthionine (MeLan) residues with defined stereochemistry. In this report, we compare two class I lanthipeptide biosynthetic gene clusters (BGCs), and , that represent two families of lanthipeptide gene clusters found in Actinobacteria. The precursor peptides and BGCs are quite similar with genes encoding a dehydratase, cyclase, and methyltransferase (MT). We illustrate that the precursor peptide CoiA1 is converted by these enzymes into a polymacrocyclic product, mCoiA1, that contains an analogous ring pattern to the previously characterized post-translationally modified OlvA peptide (mOlvA). However, a clear distinction between the two BGCs is an additional Thr-glutamyl lyase (GL) domain that is fused to the MT, CoiS, which results in divergence of the product stereochemistry for the BGC. Two out of three MeLan rings of mCoiA1 contain different stereochemistry than the corresponding residues in mOlvA, with the most notable difference being a rare d--l-MeLan residue, the formation of which is guided by CoiS. This study illustrates how nature utilizes a distinct GL to control natural product stereochemistry in lanthipeptide biosynthesis.
Topics: Biological Products; Hydro-Lyases; Lyases; Methyltransferases; Peptides; Sulfides
PubMed: 36001880
DOI: 10.1021/acschembio.2c00492 -
Expert Opinion on Therapeutic Patents Jan 2018Although many caspase inhibitors have been patented, caspase inhibitors have not entered the market due to their toxicity and poor pharmacokinetic profile. (Review)
Review
INTRODUCTION
Although many caspase inhibitors have been patented, caspase inhibitors have not entered the market due to their toxicity and poor pharmacokinetic profile.
AREAS COVERED
In this article, we review patents (2013-2015) for peptide and non-peptide caspase inhibitors and their compositions.
EXPERT OPINION
Noteworthy patents include a peptidic caspase-2 inhibitor for nasal administration and a peptidomimetic caspase-6 inhibitor that can be administered via several routes for the treatment of neurodegenerative diseases. Furthermore, caspase-1 inhibitors for contact dermatitis and inflammation, cardiovascular diseases, and liver diseases and a caspase-3 inhibitor for cerebral stroke have been patented. Of particular interest is the novel use of tyrosine kinase inhibitors (sunitinib and its derivatives) for the prevention and treatment of age-related ocular diseases via inhibition of the caspase-3, dual-leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) pathways. However, for effective clinical application of caspase inhibitors, novel peptidic and nonpeptidic caspase inhibitors with lower toxicity and improved efficacy should be developed via structural modifications, and further animal studies and preclinical and clinical trials are needed. In addition, the poor pharmacokinetic properties of classic caspase inhibitors may be improved by using advanced drug delivery systems that employ liposomes, polymers, and nanoparticles through effective administration routes.
Topics: Animals; Caspase Inhibitors; Caspases; Drug Delivery Systems; Drug Design; Humans; Patents as Topic; Peptides
PubMed: 28885866
DOI: 10.1080/13543776.2017.1378426 -
ACS Chemical Biology Oct 2019Peptides constitute an important class of drugs for the treatment of multiple metabolic, oncological, and neurodegenerative diseases, and several hundred novel...
Peptides constitute an important class of drugs for the treatment of multiple metabolic, oncological, and neurodegenerative diseases, and several hundred novel therapeutic peptides are currently in the preclinical and clinical stages of development. However, many leads fail to advance clinically because of poor cellular membrane and tissue permeability. Therefore, assessment of the ability of a peptide to cross cellular membranes is critical when developing novel peptide-based therapeutics. Current methods to assess peptide cellular permeability are limited by multiple factors, such as the need to introduce rather large modifications (e.g., fluorescent dyes) that require complex chemical reactions as well as an inability to provide kinetic information on the internalization of a compound or distinguish between internalized and membrane-bound compounds. In addition, many of these methods are based on end point assays and require multiple sample manipulation steps. Herein, we report a novel "Split Luciferin Peptide" (SLP) assay that enables the real-time noninvasive imaging and quantification of peptide uptake both and using a very sensitive bioluminescence readout. This method is based on a straightforward, stable chemical modification of the peptide of interest with a d-cysteine tag that preserves the overall peptidic character of the original molecule. This method can be easily adapted for screening peptide libraries and can thus become an important tool for preclinical peptide drug development.
Topics: Animals; Biological Assay; Cell Line, Tumor; Cysteine; Female; Firefly Luciferin; Humans; Luciferases, Firefly; Luminescent Measurements; Mice; Nitriles; Peptides; Protein Transport
PubMed: 31498986
DOI: 10.1021/acschembio.9b00439 -
International Journal of Molecular... Jul 2023Thyrotropin-releasing hormone (TRH) is a tripeptide that regulates the neuroendocrine thyroid axis. Moreover, its widespread brain distribution has indicated that it is... (Review)
Review
Thyrotropin-releasing hormone (TRH) is a tripeptide that regulates the neuroendocrine thyroid axis. Moreover, its widespread brain distribution has indicated that it is a relevant neuromodulator of behaviors such as feeding, arousal, anxiety, and locomotion. Importantly, it is also a neurotrophic peptide, and thus may halt the development of neurodegenerative diseases and improve mood-related disorders. Its neuroprotective actions on those pathologies and behaviors have been limited due to its poor intestinal and blood-brain barrier permeability, and because it is rapidly degraded by a serum enzyme. As new strategies such as TRH intranasal delivery emerge, a renewed interest in the peptide has arisen. TRH analogs have proven to be safe in animals and humans, while not inducing alterations in thyroid hormones' levels. In this review, we integrate research from different approaches, aiming to demonstrate the therapeutic effects of TRH, and to summarize new efforts to prolong and facilitate the peptide's actions to improve symptoms and the progression of several pathologies.
Topics: Animals; Humans; Thyrotropin-Releasing Hormone; Brain; Thyroid Gland; Peptides; Thyroid Hormones
PubMed: 37446225
DOI: 10.3390/ijms241311047 -
Methods in Molecular Biology (Clifton,... 2023Mutant Peptide eXtractor and Informer (MuPeXI), by Bjerregaard et al. (Cancer Immunol Immunother CII 66:1123-1130, 2017), is a program which identifies tumor-specific...
Mutant Peptide eXtractor and Informer (MuPeXI), by Bjerregaard et al. (Cancer Immunol Immunother CII 66:1123-1130, 2017), is a program which identifies tumor-specific peptides and assesses their potential to be neoepitopes. MuPeXI takes as input a VCF file and a list of human leukocyte antigen (HLA) types and optionally a gene expression profile to assess a peptide's potential to be a neoepitope. MuPeXI can be downloaded and run both locally and on a web server. Here, we describe a pipeline for processing the input data so that it can be used for MuPeXI and how to run MuPeXI both locally and as a web server.
Topics: Humans; Neoplasms; Antigens, Neoplasm; Peptides; Immunotherapy
PubMed: 36346610
DOI: 10.1007/978-1-0716-2609-2_27 -
Molecules (Basel, Switzerland) May 2019In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy... (Review)
Review
In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed.
Topics: Animals; Body Weight; Cardiovascular System; Cyclic AMP; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Kinetics; Ligands; Peptides; Primates; Protein Binding; Protein Transport; Receptor, Melanocortin, Type 4; Rodentia; Signal Transduction; alpha-MSH
PubMed: 31100979
DOI: 10.3390/molecules24101892 -
Peptides Feb 2018Dipeptidyl peptidase-4 (DPP-4) inhibitors are now a widely used, safe and efficacious class of antidiabetic drugs, which were developed prospectively using a rational... (Review)
Review
Dipeptidyl peptidase-4 (DPP-4) inhibitors are now a widely used, safe and efficacious class of antidiabetic drugs, which were developed prospectively using a rational drug design approach based on a thorough understanding of the endocrinology and degradation of glucagon-like peptide-1 (GLP-1). GLP-1 is an intestinal hormone with potent insulinotropic and glucagonostatic effects and can normalise blood glucose levels in patients with type 2 diabetes, but the native peptide is not therapeutically useful because of its inherent metabolic instability. Using the GLP-1/DPP-4 system and type 2 diabetes as an example, this review summarises how knowledge of a peptide's biological effects coupled with an understanding of the pathways involved in its metabolic clearance can be exploited in a rational, step-by-step manner to develop a therapeutic agent, which is effective and well tolerated, and any side effects are minor and largely predictable. Other peptides with metabolic effects which can also be degraded by DPP-4 will be reviewed, and their potential role as additional mediators of the effects of DPP-4 inhibitors will be assessed.
Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Peptides; Proteolysis
PubMed: 29412814
DOI: 10.1016/j.peptides.2017.10.011