-
Chemical Reviews Nov 2019Dendrimers have attracted immense interest in science and technology due to their unique chemical structure that offers a myriad of opportunities for researchers.... (Review)
Review
Dendrimers have attracted immense interest in science and technology due to their unique chemical structure that offers a myriad of opportunities for researchers. Dendritic design allows us to present peptides in a branched three-dimensional fashion that eventually leads to a globular shape, thus mimicking globular proteins. Peptide dendrimers, unlike other classes of dendrimers, have immense applications in biomedical research due to their biological origin. The diversity of potential building blocks and innumerable possibilities for design, along with the fact that the area is relatively underexplored, make peptide dendrimers sought-after candidates for various applications. This review summarizes the stepwise evolution of peptidic dendrimers along with their multifaceted applications in various fields. Further, the introduction of biomacromolecules such as proteins to a dendritic scaffold, resulting in complex macromolecules with discrete molecular weights, is an altogether new addition to the area of organic chemistry. The synthesis of highly complex and fully folded biomacromolecules on a dendritic scaffold requires expertise in synthetic organic chemistry and biology. Presently, there are only a handful of examples of protein dendrimers; we believe that these limited examples will fuel further research in this area.
Topics: Amino Acid Sequence; Animals; Antiviral Agents; Cross-Sectional Studies; Dendrimers; Drug Carriers; Humans; Peptides; Proteins
PubMed: 31556597
DOI: 10.1021/acs.chemrev.9b00153 -
Foodborne Pathogens and Disease Jun 2022As host defense peptides, peptide antibiotics exist in almost all organisms. Many of their activities come from their inactivation of bacteria, yeast, fungi, and even... (Review)
Review
As host defense peptides, peptide antibiotics exist in almost all organisms. Many of their activities come from their inactivation of bacteria, yeast, fungi, and even cancer cells. However, natural peptide antibiotics are relatively poor in stability and penetration, and have high hemolytic properties, which makes them difficult to directly apply. Therefore, natural peptide antibiotics can be modified to enhance their activity and biocompatibility. Based on the characteristics of amino acids, amino acid substitutions can be performed to study the effect of amino acid types on the activity of peptide antibiotics. The design of ultrashort peptides, cyclic peptides, and self-assembling peptides is also a way to improve the activity of peptide antibiotics. In addition, antibacterial peptides can also be conjugated with antibiotics, lipids, or metal ions to prepare antibacterial peptides with special activities. This review introduces several methods for modifying peptide antibiotics and their specific applications, providing a theoretical basis for the further application of peptide antibiotics.
Topics: Anti-Bacterial Agents; Bacteria; Fungi; Hemolysis; Humans; Peptides
PubMed: 35713924
DOI: 10.1089/fpd.2021.0112 -
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 -
Molecules (Basel, Switzerland) Oct 2019Peptide-based drugs, despite being relegated as niche pharmaceuticals for years, are now capturing more and more attention from the scientific community. The main... (Review)
Review
Peptide-based drugs, despite being relegated as niche pharmaceuticals for years, are now capturing more and more attention from the scientific community. The main problem for these kinds of pharmacological compounds was the low degree of cellular uptake, which relegates the application of peptide-drugs to extracellular targets. In recent years, many new techniques have been developed in order to bypass the intrinsic problem of this kind of pharmaceuticals. One of these features is the use of . consist of peptide chains that bring an external brace that force the peptide structure into an α -helical one. The cross-link is obtained by the linkage of the side chains of opportune-modified amino acids posed at the right distance inside the peptide chain. In this account, we report the main stapling methodologies currently employed or under development and the synthetic pathways involved in the amino acid modifications. Moreover, we report the results of two comparative studies upon different kinds of stapled-peptides, evaluating the properties given from each typology of staple to the target peptide and discussing the best choices for the use of this feature in peptide-drug synthesis.
Topics: Drug Design; Peptides; Protein Conformation, alpha-Helical
PubMed: 31658723
DOI: 10.3390/molecules24203654 -
Viruses Apr 2024Phage display is a versatile method often used in the discovery of peptides that targets disease-related biomarkers. A major advantage of this technology is the ease and... (Review)
Review
Phage display is a versatile method often used in the discovery of peptides that targets disease-related biomarkers. A major advantage of this technology is the ease and cost efficiency of affinity selection, also known as biopanning, to identify novel peptides. While it is relatively straightforward to identify peptides with optimal binding affinity, the pharmacokinetics of the selected peptides often prove to be suboptimal. Therefore, careful consideration of the experimental conditions, including the choice of using in vitro, in situ, or in vivo affinity selections, is essential in generating peptides with high affinity and specificity that also demonstrate desirable pharmacokinetics. Specifically, in vivo biopanning, or the combination of in vitro, in situ, and in vivo affinity selections, has been proven to influence the biodistribution and clearance of peptides and peptide-conjugated nanoparticles. Additionally, the marked difference in properties between peptides and nanoparticles must be considered. While peptide biodistribution depends primarily on physiochemical properties and can be modified by amino acid modifications, the size and shape of nanoparticles also affect both absorption and distribution. Thus, optimization of the desired pharmacokinetic properties should be an important consideration in biopanning strategies to enable the selection of peptides and peptide-conjugated nanoparticles that effectively target biomarkers in vivo.
Topics: Peptides; Animals; Cell Surface Display Techniques; Humans; Tissue Distribution; Nanoparticles; Peptide Library
PubMed: 38675913
DOI: 10.3390/v16040570 -
Journal of Medicinal Chemistry Feb 2024Building on recent advances in peptide science, medicinal chemists have developed a hybrid class of bioconjugates, called peptide-drug conjugates, that demonstrate... (Review)
Review
Building on recent advances in peptide science, medicinal chemists have developed a hybrid class of bioconjugates, called peptide-drug conjugates, that demonstrate improved efficacy compared to peptides and small molecules independently. In this Perspective, we discuss how the conjugation of synergistic peptides and small molecules can be used to overcome complex disease states and resistance mechanisms that have eluded contemporary therapies because of their multi-component activity. We highlight how peptide-drug conjugates display a multi-factor therapeutic mechanism similar to that of antibody-drug conjugates but also demonstrate improved therapeutic properties such as less-severe off-target effects and conjugation strategies with greater site-specificity. The many considerations that go into peptide-drug conjugate design and optimization, such as peptide/small-molecule pairing and chemo-selective chemistries, are discussed. We also examine several peptide-drug conjugate series that demonstrate notable activity toward complex disease states such as neurodegenerative disorders and inflammation, as well as viral and bacterial targets with established resistance mechanisms.
Topics: Immunoconjugates; Antigens; Peptides; Drug Design
PubMed: 38277480
DOI: 10.1021/acs.jmedchem.3c01835 -
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 -
Biochemical Pharmacology Jul 2020Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone with physiological roles in adipose tissue, the central nervous system and bone metabolism. While...
Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone with physiological roles in adipose tissue, the central nervous system and bone metabolism. While selective ligands for GIP receptor (GIPR) have not been advanced for disease treatment, dual and triple agonists of GIPR, in conjunction with that of glucagon-like peptide-1 (GLP-1) and glucagon receptors, are currently in clinical trials, with an expectation of enhanced efficacy beyond that of GLP-1 receptor (GLP-1R) agonist monotherapy for diabetic patients. Consequently, it is important to understand the pharmacological behavior of such drugs. In this study, we have explored signaling pathway specificity and the potential for biased agonism of mono-, dual- and tri-agonists of GIPR using human embryonic kidney 293 (HEK293) cells recombinantly expressing human GIPR or GLP-1R. Compared to GIP(1-42), the GIPR mono-agonists Pro3GIP and Lys3GIP are biased towards ERK1/2 phosphorylation (pERK1/2) relative to cAMP accumulation at GIPR, whereas the triple agonist at GLP-1R/GCGR/GIPR is biased towards pERK1/2 relative to β-arrestin2 recruitment. Moreover, the dual GIPR/GLP-1R agonist, LY3298176, is biased towards pERK1/2 relative to cAMP accumulation at both GIPR and GLP-1R compared to their respective endogenous ligands. These data reveal novel pharmacological properties of potential therapeutic agents that may impact on diversity in clinical responses.
Topics: Chromogranins; Cyclic AMP; GTP-Binding Protein alpha Subunits, Gs; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; HEK293 Cells; Humans; Iodine Radioisotopes; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Peptide Fragments; Peptides; Phosphorylation; Receptors, Gastrointestinal Hormone; beta-Arrestins
PubMed: 32360365
DOI: 10.1016/j.bcp.2020.114001 -
Biomolecules Jul 2023Myofibroblasts are the principal effector cells driving fibrosis, and their accumulation in tissues is a fundamental feature of fibrosis. Essential pathways have been... (Review)
Review
Myofibroblasts are the principal effector cells driving fibrosis, and their accumulation in tissues is a fundamental feature of fibrosis. Essential pathways have been identified as being central to promoting myofibroblast differentiation, revealing multiple targets for intervention. Compared with large proteins and antibodies, peptide-based therapies have transpired to serve as biocompatible and cost-effective solutions to exert biomimicry, agonistic, and antagonistic activities with a high degree of targeting specificity and selectivity. In this review, we summarize emergent antifibrotic peptides and their utilization for the targeted prevention of myofibroblasts. We then highlight recent studies on peptide inhibitors of upstream pathogenic processes that drive the formation of profibrotic cell phenotypes. We also briefly discuss peptides from non-mammalian origins that show promise as antifibrotic therapeutics. Finally, we discuss the future perspectives of peptide design and development in targeting myofibroblasts to mitigate fibrosis.
Topics: Myofibroblasts; Peptides; Antibodies; Cell Differentiation
PubMed: 37627244
DOI: 10.3390/biom13081179