bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2024–12–08
ten papers selected by
Henry Lamb, Queensland University of Technology
  1. Discovery of Selective Cyclic d-Sulfopeptide Ligands of the Chemokine CCL22 via Mirror-Image mRNA Display with Genetic Reprogramming.
  2. pH Controlled transient cyclization of peptides for increased stability towards oral delivery.
  3. Engineered Cyclotide Blocks Neuronal Excitotoxicity.
  4. High-Affinity Peptides for Target Protein Screened in Ultralarge Virtual Libraries.
  5. Constrained TACC3 peptidomimetics for a non-canonical protein-protein interface elucidate allosteric communication in Aurora-A kinase.
  6. Discovery of peptides for ligand-mediated delivery of mRNA lipid nanoparticles to cystic fibrosis lung epithelia.
  7. Chemoselective, regioselective, and positionally selective fluorogenic stapling of unprotected peptides for cellular uptake and direct cell imaging.
  8. Selection of LRP1 ligand phage-displayed single domain antibody that transmigrates BBB.
  9. Selective delivery of G-quadruplex ligand in glioma cell lines: the power of cyclic-RGD peptide.
  10. Fatty acid chain modification enhances the serum stability of antimicrobial peptide B1 and activities against Staphylococcus aureus and Klebsiella pneumoniae.
  1. J Am Chem Soc. 2024 Dec 04.
    Discovery of Selective Cyclic d-Sulfopeptide Ligands of the Chemokine CCL22 via Mirror-Image mRNA Display with Genetic Reprogramming.
    Belinda B Zhang, Katriona Harrison, Yichen Zhong, Joshua W C Maxwell, Daniel J Ford, Liam P Calvey, Sean S So, Francis C Peterson, Brian F Volkman, Martin J Stone, Ram Prasad Bhusal, Sameer S Kulkarni, Richard J Payne.
      Chemokines are small proteins involved in recruiting leukocytes to sites of inflammation via interactions with specific cell surface receptors. CCL22 is a chemokine known to play a critical role in inflammatory diseases such as atopic dermatitis and asthma; inhibition of this chemokine therefore represents an attractive therapeutic strategy. Herein, we describe the discovery of cyclic d-sulfopeptide inhibitors of CCL22 identified through mirror-image mRNA display with genetic reprogramming. Chemical synthesis of mirror-image d-CCL22 enabled screening of a cyclic peptide library comprised of all l-amino acids, with reprogramming of l-sulfotyrosine to mimic the presence of this post-translational modification on native chemokine receptors. Enriched macrocyclic peptides were prepared in their mirror-image d-form and assessed for binding against native l-CCL22. The most potent ligand, a plasma-stable d-cyclic peptide bearing four d-sulfotyrosine residues, exhibited nanomolar affinity for CCL22, high selectivity over other chemokines, and nanomolar inhibition of CCL22 signaling through CCR4. This work highlights the vast potential of mirror-image mRNA display technology for discovering proteolytically stable d-peptide inhibitors of protein-protein interactions relevant across a range of therapeutic indications.
    DOI:  https://doi.org/10.1021/jacs.4c12057
  2. Chemistry. 2024 Dec 04. e202403503
    pH Controlled transient cyclization of peptides for increased stability towards oral delivery.
    Maciej Paprocki, Kasper Kildegaard Sørensen, Knud J Jensen.
      Peptides are highly efficient for treatment of many diseases, especially in oncology and diabetes. Oral delivery of peptides is desirable, but is challenged by low bioavailability and new chemical methods to enable oral delivery are needed. Here, we developed pH responsive linearization as a strategy for transient protection of peptides to extend their half-life in model systems. Peptides were cyclized to increase their stability at the low pH in the stomach, while they linearize at neutral pH to form the active peptide. We developed ester based responsive linkers with a protonable amine for O-to-N acyl shift, which allowed linearization strategies based on pyroglutamoyl (pGlu) or diketopiperazine (DKP) formation. After coupling of the linker, peptides were cyclized by CuAAC. We studied the stability against simulated gastric fluid (SGF) at different pH and the ability of cyclic peptides to linearize. This led to PYY3-36 analogues with pH responsive linearization for increased stability.
    Keywords:  Peptide medicinal chemistry Cyclic peptides Oral delivery
    DOI:  https://doi.org/10.1002/chem.202403503
  3. J Med Chem. 2024 Dec 04.
    Engineered Cyclotide Blocks Neuronal Excitotoxicity.
    Daryl Ariawan, Julia van der Hoven, Nicolle Morey, Kanishka Pushpitha, Sian Genoud, Holly Stefen, Sanne Veltman, Magdalena Przybyla, Yuanyuan Deng, Thomas Fath, Ole Tietz, Janet van Eersel, Lars Matthias Ittner.
      Cyclotides are naturally occurring cyclic peptides with three disulfide bonds, offering remarkable stability. In neurological disorders, the formation of a complex between postsynaptic density protein 95 and NMDA receptors (NMDARs) can lead to neuronal cell death. In this study, we modified the MCoTI-II cyclotide backbone with polyarginines for enhanced intracellular delivery and grafted a 9-amino acid PSD-95-NMDAR inhibitor sequence, NR2B9c, into loop 6. We found that incorporating polyarginines into the cyclotide backbone significantly improved uptake into neuronal cells. Primary neurons treated with the NR2B9c cyclotide (c5R-NR2B9c) prevented cell death in response to high concentrations of N-methyl-d-aspartate (NMDA), demonstrating protection from excitotoxicity. Administration of c5R-NR2B9c in a chemically induced seizure model in mice resulted in increased survival and reduced seizure severity. Overall, we show that modifying cyclotides with a polyarginine backbone can enhance the delivery of therapeutic peptides into neuronal cells, which can be utilized to administer therapeutic peptides for the protection of neuronal cells from excitotoxicity.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c01710
  4. ACS Cent Sci. 2024 Nov 27. 10(11): 2111-2118
    High-Affinity Peptides for Target Protein Screened in Ultralarge Virtual Libraries.
    Boyuan Xue, Ruixue Li, Zhao Cheng, Xiaohong Zhou.
      High-throughput virtual screening (HTVS) has emerged as a pivotal strategy for identifying high-affinity peptides targeting functional proteins, which are crucial for diagnostic and therapeutic applications. In the HTVS of peptides, expanding the library capacity to enhance peptide sequence diversity, thereby screening out excellent affinity peptide candidates, remains a significant challenge. This study presents a de novo design strategy that leverages directed mutation driven HTVS to evolve vast virtual libraries and screen peptides with ultrahigh affinities for various target proteins. Utilizing a computer-generated library of 104 random 15-mer peptide scaffolds, we employed a self-developed algorithm for parallelized HTVS with Autodock Vina. The top 1% of designs underwent random mutations at a rate of 20% for six generations, theoretically expanding the library to 1014 members. This approach was applied to various protein targets, including a tumor marker (alpha fetoprotein, AFP) and virus surface proteins (SARS-CoV-2 RBD and norovirus P-domain). Starting from the same 104 random 15-mer peptide library, peptides with high affinities in the nanomolar range for three protein targets were successfully identified. The energy-saving and high-efficient design strategy presents new opportunities for the cost-effective development of more effective high-affinity peptides for various environmental and health applications.
    DOI:  https://doi.org/10.1021/acscentsci.4c01385
  5. Chem Sci. 2024 Nov 28.
    Constrained TACC3 peptidomimetics for a non-canonical protein-protein interface elucidate allosteric communication in Aurora-A kinase.
    Diana Gimenez, Martin Walko, Jennifer A Miles, Richard Bayliss, Megan H Wright, Andrew J Wilson.
      Peptidomimetic design for non-canonical interfaces is less well established than for α-helix and β-strand mediated protein-protein interactions. Using the TACC3/Aurora-A kinase interaction as a model, we developed a series of constrained TACC3 peptide variants with 10-fold increased binding potencies (K d) towards Aurora-A in comparison to the parent peptide. High-affinity is achieved in part by restricting the accessible conformational ensemble of the peptide leading to a more favourable entropy of binding. In addition to acting as potent orthosteric TACC3/Aurora-A inhibitors, these peptidomimetics were shown to activate the kinase and inhibit the N-Myc/Aurora-A interaction at a distal site. Thus, the potency of these tools uniquely allowed us to unveil new insight into the role of allosteric communication in the kinase.
    DOI:  https://doi.org/10.1039/d4sc06100d
  6. Mol Ther Nucleic Acids. 2024 Dec 10. 35(4): 102375
    Discovery of peptides for ligand-mediated delivery of mRNA lipid nanoparticles to cystic fibrosis lung epithelia.
    Melissa R Soto, Mae M Lewis, Jasmim Leal, Yuting Pan, Rashmi P Mohanty, Arian Veyssi, Esther Y Maier, Brittany J Heiser, Debadyuti Ghosh.
      For cystic fibrosis patients, a lung-targeted gene therapy would significantly alleviate pulmonary complications associated with morbidity and mortality. However, mucus in the airways and cell entry pose huge delivery barriers for local gene therapy. Here, we used phage display technology to select for and identify mucus- and cell-penetrating peptides against primary human bronchial epithelial cells from cystic fibrosis patients cultured at the air-liquid interface. At the air-liquid interface, primary human bronchial epithelial cells produce mucus and reflect cystic fibrosis disease pathology, making it a clinically relevant model. Using this model, we discovered a lead candidate peptide and incorporated it into lipid nanoparticles to deliver mRNA to primary human bronchial epithelia in vitro and mouse lungs in vivo. Compared to lipid nanoparticles without our peptide, peptide-lipid nanoparticles demonstrated up to 7.8-fold and 3.4-fold higher reporter luciferase bioactivity in vitro and in vivo, respectively. Importantly, these peptides facilitated higher specific uptake of nanoparticles into lung epithelia relative to other cell types. Since gene delivery to primary human bronchial epithelia is a significant challenge, we are encouraged by these results and anticipate that our peptide could be used to successfully deliver cystic fibrosis gene therapies in future work.
    Keywords:  MT: Delivery Strategies; cystic fibrosis; lipid nanoparticles; mRNA; nucleic acid delivery; peptides; phage display; pulmonary delivery
    DOI:  https://doi.org/10.1016/j.omtn.2024.102375
  7. Chem Sci. 2024 Nov 05.
    Chemoselective, regioselective, and positionally selective fluorogenic stapling of unprotected peptides for cellular uptake and direct cell imaging.
    Naysilla L Dayanara, Juliette Froelich, Pascale Roome, David M Perrin.
      Peptide stapling reactions represent powerful methods for structuring native α-helices to improve their bioactivity in targeting protein-protein interactions (PPIs). In light of a growing need for regio- and positionally selective stapling methods involving natural amino acid residues in their unprotected states, we report a rapid, mild, and highly chemoselective three-component stapling reation using a class of molecular linchpins based on 2-arylketobenzaldehydes (ArKBCHOs) that create a fluorescent staple, hereafter referred to as a Fluorescent Isoindole Crosslink (FlICk). This methodology offers positional selectivity favouring i, i + 4 helical staples comprising a lysine and cysteine, in the presence of competing nucleophiles on unprotected peptides. In our efforts to further validate this chemistry, we have successfully shown in vitro cytotoxicity of a FlICk-ed peptide (IC50 = 5.10 ± 1.27 μM), equipotent to an olefin-stapled congener. In harnessing the innate fluorescence of the thiol-isoindole, we report new blue-green fluorophores, which arise as a consequence of stapling, with appreciable quantum yields that enable direct cellular imaging in the assessment of cell permeability, thus bridging therapeutic potential with cytological probe development.
    DOI:  https://doi.org/10.1039/d4sc04839c
  8. J Drug Target. 2024 Dec 02. 1-10
    Selection of LRP1 ligand phage-displayed single domain antibody that transmigrates BBB.
    Viana Manrique-Suárez, Bryan A Mangui Catota, Frank Camacho Casanova, Nery A Jara Mendoza, Maria A Contreras Vera, Rafael Maura Pérez, Fátima Reyes López, Roberto Toledo Alonso, Pablo Ignacio Castro Henriquez, Oliberto Sánchez Ramos.
      Effective drug delivery to the central nervous system (CNS) remains a challenge due to the blood-brain barrier (BBB). Macromolecules such as proteins and peptides are unable to cross BBB and have poor therapeutic efficacy due to little or no drug distribution. A promising alternative is the conjugation of a drug to a shuttle molecule that can reach the CNS via receptor-mediated transcytosis (RMT). Several receptors have been described for RMT, such as low-density lipoprotein receptor-related protein 1 (LRP1). We used phage display technology combined with an in vitro BBB model to identify LRP1 ligands. A single domain antibody (dAb) library was used to enrich for species that selectively bind to immobilised LRP1 ligand. We obtained a novel nanobody, dAb D11, that selectively binds to LRP1 receptor and mediates in vitro internalisation of phage particles in brain endothelial cells, with a dissociation constant Kd of 183.1 ± 85.8 nM. The high permeability of D11 was demonstrated by an in vivo biodistribution assay in mice. We discovered D11, the first LRP1 binding dAb with BBB permeability. Our findings will contribute to the development of RMT-based drugs for the treatment of CNS diseases.
    Keywords:  Blood–brain barrier (BBB); central nervous system (CNS); human domain antibody (dAb); low-density lipoprotein receptor-related protein 1 (LRP1); phage display; receptor-mediated transcytosis (RMT)
    DOI:  https://doi.org/10.1080/1061186X.2024.2434908
  9. Sci Rep. 2024 12 04. 14(1): 30180
    Selective delivery of G-quadruplex ligand in glioma cell lines: the power of cyclic-RGD peptide.
    Valentina Pirota, Giovanni Bisbano, Amanda Oldani, Eric Bernardi, Massimo Serra, Mayra Paolillo, Filippo Doria.
      Compounds targeting non-canonical secondary structures of nucleic acids, known as G-quadruplexes, are highly cytotoxic, both for cancer and healthy cells, because of their action mechanism's lack of appropriate selectivity. The targeted delivery of cytotoxic molecules to cancer cells is a valuable strategy to expand the repertoire of potential drugs, especially for cancer types for which new therapeutic tools are urgently needed, like glioblastoma. In this work, we conjugated a cyclic arginyl-glycyl-aspartic acid peptide to a naphthalene diimide, previously described as a highly performing stabilizing ligand for DNA G-quadruplexes, to specifically target glioma cells overexpressing RGD-binding integrin receptors. Our results, including confocal microscopy and cell toxicity assays, demonstrated improved efficacy and selective cellular absorption of the new conjugate without affecting the NDI's ability to interact with the G4 target.
    DOI:  https://doi.org/10.1038/s41598-024-81513-9
  10. Bioorg Chem. 2024 Nov 28. pii: S0045-2068(24)00920-9. [Epub ahead of print]154 108015
    Fatty acid chain modification enhances the serum stability of antimicrobial peptide B1 and activities against Staphylococcus aureus and Klebsiella pneumoniae.
    Zhouyuji Liao, Yong Wu, Meng Liu, Junjie Zhang, Yunfei Cui, Dongting Zhangsun, Sulan Luo.
      Antimicrobial peptides (AMPs) possess broad-spectrum antibacterial properties and low resistance development, making them promising candidates for new antibacterial drugs. Incorporating fatty acid chains into AMPs can increase their hydrophobicity, strengthen membrane affinity, and improve their antibacterial effectiveness and stability. This study introduces fatty acid chains of varying lengths into the naturally derived antimicrobial peptide B1. These modified peptides were evaluated for their antibacterial activity, stability, and biocompatibility to identify the optimal chain length for analogues. The analogues B1-C6 and B1-C8 exhibited significantly enhanced antimicrobial activities against Staphylococcus aureus (S. aureus) and Klebsiella pneumoniae (K. pneumonia), demonstrating better stability and biocompatibility. Following acute toxicity and skin irritation tests on mice, further in vivo tests using a mouse skin inflammation model showed that these peptides significantly restrain bacterial growth and promote wound healing. The skin healing rate in the high-concentration group reached 95.92%, 97.35% 98.42% and 98.17%, respectively. These findings indicated that optimizing the hydrophobic-hydrophilic balance in AMPs is crucial for maximizing their therapeutic potential. This research offers a promising approach for designing effective AMPs to treat infections caused by S. aureus and K. pneumoniae.
    Keywords:  Antibacterial peptide modification; Fatty acid chains; K. pneumoniae; S. aureus
    DOI:  https://doi.org/10.1016/j.bioorg.2024.108015
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