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Bioorganic & Medicinal Chemistry Jun 2018The development of solid phase peptide synthesis has released tremendous opportunities for using synthetic peptides in medicinal applications. In the last decades,... (Review)
Review
The development of solid phase peptide synthesis has released tremendous opportunities for using synthetic peptides in medicinal applications. In the last decades, peptide therapeutics became an emerging market in pharmaceutical industry. The need for synthetic strategies in order to improve peptidic properties, such as longer half-life, higher bioavailability, increased potency and efficiency is accordingly rising. In this mini-review, we present a toolbox of modifications in peptide chemistry for overcoming the main drawbacks during the transition from natural peptides to peptide therapeutics. Modifications at the level of the peptide backbone, amino acid side chains and higher orders of structures are described. Furthermore, we are discussing the future of peptide therapeutics development and their impact on the pharmaceutical market.
Topics: Animals; Chemistry Techniques, Synthetic; Drug Discovery; Humans; Lipids; Models, Molecular; Peptides; Polyethylene Glycols; Polymers; Solid-Phase Synthesis Techniques
PubMed: 29395804
DOI: 10.1016/j.bmc.2018.01.012 -
Chimia Jun 2021The new Energypolis campus brings together the skills of EPFL Valais-Wallis, HES-SO Valais-Wallis, and the Ark Foundation's services. Together these partners respond to... (Review)
Review
The new Energypolis campus brings together the skills of EPFL Valais-Wallis, HES-SO Valais-Wallis, and the Ark Foundation's services. Together these partners respond to today's major concerns in the domains of energy, health, and the environment cutting-edge technology. The spirit of this new campus is to foster innovation in these disciplines and emulate the creation of start-up companies. The HES-SO hosts the School of Engineering (HEI) at this campus, which includes the following degree programmes: Life Technologies, Systems Engineering and Energy and Environmental Engineering, as well as their corresponding applied research institutes. Peptide technologies belong to the many activities that are carrying out in the Institute of Life Technologies. The present review summarizes the peptide technologies that are currently under development, that is, the regioselective labeling of therapeutic antibodies for cancer imaging, the development of peptide antivirals and antimicrobials for the treatment of infectious diseases, targeting of drugs conjugated to peptidic scaffolds as well as engineering of biomaterials.
Topics: Anti-Infective Agents; Peptides; Technology
PubMed: 34233821
DOI: 10.2533/chimia.2021.539 -
Journal of the American Chemical Society Aug 2023Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets....
Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including log can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide's main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski's rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.
Topics: Humans; Proto-Oncogene Proteins p21(ras); Caco-2 Cells; Peptides; Peptides, Cyclic; Molecular Conformation
PubMed: 37463267
DOI: 10.1021/jacs.3c03886 -
Chemical Society Reviews Mar 2021Coacervates are condensed liquid-like droplets formed by liquid-liquid phase separation of molecules through multiple weak associative interactions. In recent years it... (Review)
Review
Coacervates are condensed liquid-like droplets formed by liquid-liquid phase separation of molecules through multiple weak associative interactions. In recent years it has emerged that not only long polymers, but also short peptides are capable of forming simple and complex coacervates. The coacervate droplets they form act as compartments that sequester and concentrate a wide range of solutes, and their spontaneous formation make coacervates attractive protocell models. The main advantage of peptides as building blocks lies in the functional diversity of the amino acid residues, which allows for tailoring of the peptide's phase separation propensity, their selectivity in guest molecule uptake and the physicochemical and catalytic properties of the compartments. The aim of this tutorial review is to illustrate the recent developments in the field of peptide-based coacervates in a systematic way and to deduce the basic requirements for both simple and complex coacervation of peptides. We review a selection of peptide coacervates that illustrates the essentials of phase separation, the limitations, and the properties that make peptide coacervates biomimetic protocells. Finally, we provide some perspectives of this novel research field in the direction of active droplets, moving away from thermodynamic equilibrium.
Topics: Artificial Cells; Biomimetics; Catalysis; Nucleotides; Peptides; Polyethylene Glycols
PubMed: 33616129
DOI: 10.1039/d0cs00307g -
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 -
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