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Chemical Biology & Drug Design Mar 2023Peptides are increasingly present in all branches of medicine as innovative drugs, imaging agents, theragnostic, and constituent moieties of other sophisticated drugs... (Review)
Review
Peptides are increasingly present in all branches of medicine as innovative drugs, imaging agents, theragnostic, and constituent moieties of other sophisticated drugs such as peptide-drug conjugates. Due to new developments in chemical synthesis strategies, computational biology, recombinant technology, and chemical biology, peptide drug development has made a great progress in the last decade. Numerous natural peptides and peptide mimics have been obtained and studied, covering multiple therapeutic areas. Even though peptides have been investigated across the wide therapeutic spectrum, oncology, metabolism, and endocrinology are the most frequent medical indications of them. This review summarizes the current use of and the emerging new opportunities of peptides for diagnosis and treatment of various diseases.
Topics: Peptides
PubMed: 36366980
DOI: 10.1111/cbdd.14180 -
Molecules (Basel, Switzerland) Feb 2020To penetrate solid tumors, low molecular weight (Mw < 10 KDa) compounds have an edge over antibodies: their higher penetration because of their small size. Because of... (Review)
Review
To penetrate solid tumors, low molecular weight (Mw < 10 KDa) compounds have an edge over antibodies: their higher penetration because of their small size. Because of the dense stroma and high interstitial fluid pressure of solid tumors, the penetration of higher Mw compounds is unfavored and being small thus becomes an advantage. This review covers a wide range of peptidic ligands-linear, cyclic, macrocyclic and cyclotidic peptides-to target tumors: We describe the main tools to identify peptides experimentally, such as phage display, and the possible chemical modifications to enhance the properties of the identified peptides. We also review in silico identification of peptides and the most salient non-peptidic ligands in clinical stages. We later focus the attention on the current validated ligands available to target different tumor compartments: blood vessels, extracelullar matrix, and tumor associated macrophages. The clinical advances and failures of these ligands and their therapeutic conjugates will be discussed. We aim to present the reader with the state-of-the-art in targeting tumors, by using low Mw molecules, and the tools to identify new ligands.
Topics: Animals; Cell Surface Display Techniques; Extracellular Matrix; Humans; Macrophages; Neoplasms; Peptides
PubMed: 32069856
DOI: 10.3390/molecules25040808 -
Current Protein & Peptide Science 2020Ghrelin is a 28-amino acid octanoylated peptide hormone that is implicated in many physiological and pathophysiological processes. Specific visualization of ghrelin and... (Review)
Review
Ghrelin is a 28-amino acid octanoylated peptide hormone that is implicated in many physiological and pathophysiological processes. Specific visualization of ghrelin and its cognate receptor using traceable ligands is crucial in elucidating the localization, functions, and expression pattern of the peptide's signaling pathway. Here 12 representative radio- and fluorescently-labeled peptide-based ligands are reviewed for in vitro and in vivo imaging studies. In particular, the focus is on their structural features, pharmacological properties, and applications in further biochemical research.
Topics: Amino Acid Sequence; Animals; Fluorescent Dyes; Gene Expression Regulation; Ghrelin; Humans; Ligands; Microscopy, Fluorescence; Molecular Structure; Peptides; Receptors, Ghrelin; Signal Transduction; Staining and Labeling
PubMed: 32614744
DOI: 10.2174/1389203721666200702131457 -
Advances in Experimental Medicine and... 2020Peptides, as a large group of molecules, are composed of amino acid residues and can be divided into linear or cyclic peptides according to the structure. Over 13,000... (Review)
Review
Peptides, as a large group of molecules, are composed of amino acid residues and can be divided into linear or cyclic peptides according to the structure. Over 13,000 molecules of natural peptides have been found and many of them have been well studied. In artificial peptide libraries, the number of peptide diversity could be up to 1 × 10. Peptides have more complex structures and higher affinity to target proteins comparing with small molecular compounds. Recently, the development of targeting cancer immune checkpoint (CIP) inhibitors is having a very important role in tumor therapy. Peptides targeting ligands or receptors in CIP have been designed based on three-dimensional structures of target proteins or directly selected by random peptide libraries in biological display systems. Most of these targeting peptides work as inhibitors of protein-protein interaction and improve CD8+ cytotoxic T-lymphocyte (CTL) activation in the tumor microenvironment, for example, PKHB1, Ar5Y4 and TPP1. Peptides could be designed to regulate CIP protein degradation in vivo, such as PD-LYSO and PD-PALM. Besides its use in developing therapeutic drugs for targeting CIP, targeting peptides could be used in drug's targeted delivery and diagnosis in tumor immune therapy.
Topics: Antineoplastic Agents; Cell Cycle Checkpoints; Drug Delivery Systems; Humans; Ligands; Molecular Targeted Therapy; Neoplasms; Peptide Library; Peptides; Tripeptidyl-Peptidase 1
PubMed: 32185724
DOI: 10.1007/978-981-15-3266-5_21 -
Chemical Reviews Sep 2019Cyclization is an important post-translational modification of peptides and proteins that confers key advantages such as protection from proteolytic degradation, altered... (Review)
Review
Cyclization is an important post-translational modification of peptides and proteins that confers key advantages such as protection from proteolytic degradation, altered solubility, membrane permeability, bioavailability, and especially restricted conformational freedom in water that allows the peptide backbone to adopt the major secondary structure elements found in proteins. Non-ribosomal synthesis in bacteria, fungi, and plants or synthetic chemistry can introduce unnatural amino acids and non-peptidic constraints that modify peptide backbones and side chains to fine-tune cyclic peptide structure. Structures can be potentially altered further upon binding to a protein in biological environments. Here we analyze three-dimensional crystal structures for 211 bioactive cyclic peptides bound to 65 different proteins. The protein-bound cyclic peptides were examined for similarities and differences in bonding modes, for main-chain and side-chain structure, and for the importance of polarity, hydrogen bonds, hydrophobic effects, and water molecules in interactions with proteins. Many protein-bound cyclic peptides show backbone structures like those (strands, sheets, turns, helices, loops, or distorted variations) found at protein-protein binding interfaces. However, the notion of macrocycles simply as privileged scaffolds that primarily project side-chain substituents for complementary interactions with proteins is dispelled here. Unlike small-molecule drugs, the cyclic peptides do not rely mainly upon hydrophobic and van der Waals interactions for protein binding; they also use their main chain and side chains to form polar contacts and hydrogen bonds with proteins. Compared to small-molecule ligands, cyclic peptides can bind across larger, polar, and water-exposed protein surface areas, making many more contacts that can increase affinity, selectivity, biological activity, and ligand-receptor residence time. Cyclic peptides have a greater capacity than small-molecule drugs to modulate protein-protein interfaces that involve large, shallow, dynamic, polar, and water-exposed protein surfaces.
Topics: Animals; Bacteria; Catalytic Domain; Crystallography, X-Ray; Humans; Hydrogen Bonding; Peptides, Cyclic; Protein Binding; Proteins; Static Electricity
PubMed: 31046237
DOI: 10.1021/acs.chemrev.8b00807 -
Journal of Peptide Science : An... Jan 2023Protein-protein interactions (PPI) are involved in all cellular processes and many represent attractive therapeutic targets. However, the frequently rather flat and... (Review)
Review
Protein-protein interactions (PPI) are involved in all cellular processes and many represent attractive therapeutic targets. However, the frequently rather flat and large interaction areas render the identification of small molecular PPI inhibitors very challenging. As an alternative, peptide interaction motifs derived from a PPI interface can serve as starting points for the development of inhibitors. However, certain proteins remain challenging targets when applying inhibitors with a competitive mode of action. For that reason, peptide-based ligands with an irreversible binding mode have gained attention in recent years. This review summarizes examples of covalent inhibitors that employ peptidic binders and have been tested in a biological context.
Topics: Peptides
PubMed: 36239115
DOI: 10.1002/psc.3457 -
Journal of Peptide Science : An... Aug 2023Membrane-active peptides play an essential role in many living organisms and their immune systems and counter many infectious diseases. Many have dual or multiple... (Review)
Review
Membrane-active peptides play an essential role in many living organisms and their immune systems and counter many infectious diseases. Many have dual or multiple mechanisms and can synergize with other molecules, like peptides, proteins, and small molecules. Although membrane-active peptides have been intensively studied in the past decades and more than 3500 sequences have been identified, only a few received approvals from the US Food and Drug Administration. In this review, we investigated all the peptide therapeutics that have entered the market or were subjected to preclinical and clinical studies to understand how they succeeded. With technological advancement (e.g., chemical modifications and pharmaceutical formulations) and a better understanding of the mechanism of action and the potential targets, we found at least five membrane-active peptide drugs that have entered preclinical/clinical phases and show promising results for cancer treatment. We summarized our findings in this review and provided insights into membrane-active anticancer peptide therapeutics.
Topics: United States; Peptides; Proteins; Pharmaceutical Preparations; Drug Delivery Systems; Drug Compounding
PubMed: 36739581
DOI: 10.1002/psc.3482 -
Molecules (Basel, Switzerland) Jan 2023The dramatic rise in cancer incidence, alongside treatment deficiencies, has elevated cancer to the second-leading cause of death globally. The increasing morbidity and... (Review)
Review
The dramatic rise in cancer incidence, alongside treatment deficiencies, has elevated cancer to the second-leading cause of death globally. The increasing morbidity and mortality of this disease can be traced back to a number of causes, including treatment-related side effects, drug resistance, inadequate curative treatment and tumor relapse. Recently, anti-cancer bioactive peptides (ACPs) have emerged as a potential therapeutic choice within the pharmaceutical arsenal due to their high penetration, specificity and fewer side effects. In this contribution, we present a general overview of the literature concerning the conformational structures, modes of action and membrane interaction mechanisms of ACPs, as well as provide recent examples of their successful employment as targeting ligands in cancer treatment. The use of ACPs as a diagnostic tool is summarized, and their advantages in these applications are highlighted. This review expounds on the main approaches for peptide synthesis along with their reconstruction and modification needed to enhance their therapeutic effect. Computational approaches that could predict therapeutic efficacy and suggest ACP candidates for experimental studies are discussed. Future research prospects in this rapidly expanding area are also offered.
Topics: Humans; Antineoplastic Agents; Neoplasms; Peptides
PubMed: 36770815
DOI: 10.3390/molecules28031148 -
ACS Biomaterials Science & Engineering Aug 2021Bolaamphiphile, which is a class of amphiphilic molecules, has a unique structure of two hydrophilic head groups at the ends of the hydrophobic center. Peptidic... (Review)
Review
Bolaamphiphile, which is a class of amphiphilic molecules, has a unique structure of two hydrophilic head groups at the ends of the hydrophobic center. Peptidic bolaamphiphiles that employ peptides or amino acids as their hydrophilic groups exhibit unique biochemical activities when they self-organize into supramolecular structures, which are not observed in a single molecule. The self-assembled peptidic bolaamphiphiles hold considerable promise for imitating proteins with biochemical activities, such as specific affinity toward heterogeneous substances, a catalytic activity similar to a metalloenzyme, physicochemical activity from harmonized amino acid segments, and the capability to encapsulate genes like a viral vector. These diverse activities give rise to large research interest in biomaterials engineering, along with the synthesis and characterization of the assembled structures. This review aims to address the recent progress in the applications of peptidic bolaamphiphile assemblies whose densely packed peptide motifs on their surface and their stacked hydrophobic centers exhibit unique protein-like activity and designer functionality, respectively.
Topics: Biomimetics; Furans; Peptides; Proteins; Pyridones
PubMed: 34309378
DOI: 10.1021/acsbiomaterials.1c00576 -
Accounts of Chemical Research May 2022Biologically active peptides are a major growing class of drugs, but their therapeutic potential is constrained by several limitations including bioavailability and poor... (Review)
Review
Biologically active peptides are a major growing class of drugs, but their therapeutic potential is constrained by several limitations including bioavailability and poor pharmacokinetics. The attachment of functional groups like lipids has proven to be a robust and effective strategy for improving their therapeutic potential. Biochemical and bioactivity-guided screening efforts have identified the cyanobactins as a large class of ribosomally synthesized and post-translationally modified peptides (RiPPs) that are modified with lipids. These lipids are attached by the F superfamily of peptide prenyltransferase enzymes that utilize 5-carbon (prenylation) or 10-carbon (geranylation) donors. The chemical structures of various cyanobactins initially showed isoprenoid attachments on Ser, Thr, or Tyr. Biochemical characterization of the F prenyltransferases from the corresponding clusters shows that the different enzymes have different acceptor residue specificities but are otherwise remarkably sequence tolerant. Hence, these enzymes are well suited for biotechnological applications. The crystal structure of the Tyr -prenyltransferase PagF reveals that the F enzyme shares a domain architecture reminiscent of a canonical ABBA prenyltransferase fold but lacks secondary structural elements necessary to form an enclosed active site. Binding of either cyclic or linear peptides is sufficient to close the active site to allow for productive catalysis, explaining why these enzymes cannot use isolated amino acids as substrates.Almost all characterized isoprenylated cyanobactins are modified with 5-carbon isoprenoids. However, chemical characterization demonstrates that the piricyclamides are modified with a 10-carbon geranyl moiety, and in vitro reconstitution of the corresponding PirF shows that the enzyme is a geranyltransferase. Structural analysis of PirF shows an active site nearly identical with that of the PagF prenyltransferase but with a single amino acid substitution. Of note, mutation at this residue in PagF or PirF can completely switch the isoprenoid donor specificity of these enzymes. Recent efforts have resulted in significant expansion of the F family with enzymes identified that can carry out -prenylations of Trp, -prenylations of Trp, and bis--prenylations of Arg. Additional genome-guided efforts based on the sequence of F enzymes identify linear cyanobactins that are α--prenylated and α--methylated by a bifunctional prenyltransferase/methyltransferase fusion and a bis-α-- and α--prenylated linear peptide. The discovery of these different classes of prenyltransferases with diverse acceptor residue specificities expands the biosynthetic toolkit for enzymatic prenylation of peptide substrates.In this Account, we review the current knowledge scope of the F family of peptide prenyltransferases, focusing on the biochemical, structure-function, and chemical characterization studies that have been carried out in our laboratories. These enzymes are easily amenable for diversity-oriented synthetic efforts as they can accommodate substrate peptides of diverse sequences and are thus attractive catalysts for use in synthetic biology approaches to generate high-value peptidic therapeutics.
Topics: Carbon; Catalysis; Dimethylallyltranstransferase; Lipids; Peptides; Terpenes
PubMed: 35442036
DOI: 10.1021/acs.accounts.2c00108