bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2025–05–04
nine papers selected by
Henry Lamb, Queensland University of Technology
  1. Heuristic energy-based cyclic peptide design.
  2. Novel 177Lu-Labeled [Thz14]Bombesin(6-14) Derivatives with Low Pancreas Accumulation for Targeting Gastrin-Releasing Peptide Receptor-Expressing Cancer.
  3. Helicity-Dependent Enzymatic Peptide Cyclization.
  4. An optimized integrin α6-targeted peptide capable of delivering toxins for melanoma treatment.
  5. Palindromic peptide foldamers: a strategy for structural stability and cellular uptake.
  6. A novel peptide targeting PD-1: implications for protein-protein interaction studies and immunotherapy.
  7. Antimicrobial Activity of Short Analogues of the Marine Peptide EeCentrocin 1: Synthesis of Lipopeptides and Head-to-Tail Cyclic Peptides and Mechanism of Action Studies.
  8. Advances in cell-penetrating peptide-based nose-to-brain drug delivery systems.
  9. Engineered Peptide Coacervates Enable Efficient Intracellular Delivery of the MYC Inhibitor omoMYC.
  1. PLoS Comput Biol. 2025 Apr;21(4): e1012290
    Heuristic energy-based cyclic peptide design.
    Qiyao Zhu, Vikram Khipple Mulligan, Dennis Shasha.
      Rational computational design is crucial to the pursuit of novel drugs and therapeutic agents. Meso-scale cyclic peptides, which consist of 7-40 amino acid residues, are of particular interest due to their conformational rigidity, binding specificity, degradation resistance, and potential cell permeability. Because there are few natural cyclic peptides, de novo design involving non-canonical amino acids is a potentially useful goal. Here, we develop an efficient pipeline (CyclicChamp) for cyclic peptide design. After converting the cyclic constraint into an error function, we employ a variant of simulated annealing to search for low-energy peptide backbones while maintaining peptide closure. Compared to the previous random sampling approach, which was capable of sampling conformations of cyclic peptides of up to 14 residues, our method both greatly accelerates the computation speed for sampling conformations of small macrocycles (ca. 7 residues), and addresses the high-dimensionality challenge that large macrocycle designs often encounter. As a result, CyclicChamp makes conformational sampling tractable for 15- to 24-residue cyclic peptides, thus permitting the design of macrocycles in this size range. Microsecond-length molecular dynamics simulations on the resulting 15, 20, and 24 amino acid cyclic designs identify designs with kinetic stability. To test their thermodynamic stability, we perform additional replica exchange molecular dynamics simulations and generate free energy surfaces. Three 15-residue designs, one 20-residue and one 24-residue design emerge as promising candidates.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012290
  2. Pharmaceuticals (Basel). 2025 Mar 23. pii: 449. [Epub ahead of print]18(4):
    Novel 177Lu-Labeled [Thz14]Bombesin(6-14) Derivatives with Low Pancreas Accumulation for Targeting Gastrin-Releasing Peptide Receptor-Expressing Cancer.
    Lei Wang, Devon E Chapple, Hsiou-Ting Kuo, Sara Kurkowska, Ryan P Wilson, Wing Sum Lau, Pauline Ng, Carlos Uribe, François Bénard, Kuo-Shyan Lin.
      Background/Objectives: Gastrin-releasing peptide receptor is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake of reported GRPR-targeted radioligands limits their clinical applications. Our group previously reported one 68Ga-labeled GRPR antagonist, [68Ga]Ga-TacsBOMB5 (68Ga-DOTA-Pip-[D-Phe6,NMe-Gly11,Leu13ψThz14]Bombesin(6-14)), and two agonists, [68Ga]Ga-LW01110 (68Ga-DOTA-Pip-[D-Phe6,Tle10,NMe-His12,Thz14]Bombesin(6-14)) and [68Ga]Ga-LW01142 (68Ga-DOTA-Pip-[D-Phe6,His7,Tle10,NMe-His12,Thz14]Bombesin(6-14)) showing minimal pancreas uptake. Thus, in this study, we prepared their 177Lu-labeled analogs, evaluated their therapeutic potentials, and compared them with the clinically evaluated [177Lu]Lu-AMBA. Methods: GRPR binding affinities were determined by in vitro competition binding assay using PC-3 prostate cancer cells. Longitudinal SPECT/CT imaging and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice. Dosimetry data were calculated from the biodistribution results. Results: The Ki(GRPR) values of Lu-TacsBOMB5, Lu-LW01110, Lu-LW01142, and Lu-AMBA were 12.6 ± 1.02, 3.07 ± 0.15, 2.37 ± 0.28, and 0.33 ± 0.16 nM, respectively. SPECT/CT images and biodistribution results demonstrated good tumor accumulation of [177Lu]Lu-TacsBOMB5, [177Lu]Lu-LW01110, and [177Lu]Lu-LW01142 at early time points with rapid clearance over time. The pancreas uptake of all three [Thz14]Bombesin(6-14)-derived ligands was significantly lower than that of [177Lu]Lu-AMBA at all time points. The calculated absorbed doses of [177Lu]Lu-TacsBOMB5, [177Lu]Lu-LW01110, and [177Lu]Lu-LW01142 in PC-3 tumor xenografts were 87.1, 312, and 312 mGy/MBq, respectively, higher than that of [177Lu]Lu-AMBA (79.1 mGy/MBq), but lower than that of the previously reported [177Lu]Lu-RM2 (429 mGy/MBq). Conclusions: Our data suggest that [177Lu]Lu-TacsBOMB5 and [177Lu]Lu-LW01142 reduce radiation exposure to the pancreas. However, further optimizations are needed for both radioligands to prolong their tumor retention and enhance treatment efficacy.
    Keywords:  dosimetry; gastrin-releasing peptide receptor; lutetium-177; radioligand therapy; single-photon emission computed tomography
    DOI:  https://doi.org/10.3390/ph18040449
  3. J Pept Sci. 2025 Jun;31(6): e70024
    Helicity-Dependent Enzymatic Peptide Cyclization.
    Canan Durukan, Jannik Faierson, Isabel van der Wal, Juan Lizandra Pérez, Sven Hennig, Tom N Grossmann.
      The secondary structure plays a crucial role in the biological activity of peptides. Various strategies have been developed to stabilize particular peptide conformations, including sequence modifications and macrocyclization approaches. Often, the interplay between conformational constraint and flexibility is central to bioactivity. Here, we investigate how peptide α-helicity influences enzymatic head-to-tail cyclization using an engineered Sortase. We show that peptides with low helicity readily undergo intramolecular cyclization, while more rigid, helical peptides exhibit complex cyclization behaviors including cyclic dimer formation. These findings reveal that increased peptide rigidity can redirect enzymatic reactions from intramolecular to intermolecular processes, and demonstrates how changes in molecular rigidity can guide chemical reactivity. These insights can advance the design of peptide-derived materials, hydrogels, and stimuli-responsive probes.
    Keywords:  Sortase; helix; macrocyclization; peptidomimetic; stapled peptide
    DOI:  https://doi.org/10.1002/psc.70024
  4. J Transl Med. 2025 Apr 30. 23(1): 495
    An optimized integrin α6-targeted peptide capable of delivering toxins for melanoma treatment.
    Zheng Zhao, Zi-Qian Li, Ying-Bin Huang, Meng-Meng Liu, Fei Cao, Guo-Long Bu, Peng-Fei Xu, Qi Fang, Zhu-Long Hu, Di Wu, Guo-Kai Feng, Xue-Kui Liu.
       BACKGROUND: Peptide-based therapeutics for melanoma have received increasing attention in medical research. However, the local delivery of such therapeutics poses unique challenges. Cell-penetrating peptides (CPPs) with the ability to selectively enter cancer cells, with sufficient stability and increased endosomal escape mechanisms, can provide a new and improved delivery strategy for therapeutic agents for treating cancer.
    METHODS: We developed a new combination strategy for the synthesis of penetrating peptides functionalized with targeting of integrin α6. The linear peptide S5 was multimerized with 4 copies in linear sequential order spaced by GSG between each copy to yield the 4S5 peptide. The multimerized 4S5 peptide coupled with an intracellular delivery peptide (N) and endosomal escape peptide (G) was separated by a GGS spacer. This optimized peptide was called 4S5NG. The 4S5NG, EGFP or PE24 peptide-protein conjugates were purified via a C-terminal His-tag. The uptake efficacy, intracellular distribution and integrin α6-targeting ability of these 4S5NG peptides were systematically characterized via IncuCyte, flow cytometry and in vivo imaging using 4S5NG-Cy5 or 4S5NG-EGFP. Moreover, 4S5NG-incorporated Pseudomonas aeruginosa (PE24) exotoxin A generated therapeutic peptides. The antitumor efficacy and underlying mechanism were studied in cell lines and a mouse model. In addition, the effect of 4S5NG-PE24 on antitumor immunity of a healthy immune system was investigated via a mouse model.
    RESULTS: Images of living cells and mice indicated that 4S5NG accumulated at tumor sites in vitro and in vivo and was much more effective than the S5 and 4S5 peptides. 4S5NG-PE24 induced cell pyroptosis in integrin α6-expressing melanoma through the caspase 3/gasdermin E (GSDME) signaling pathway in the absence of histological alterations in other organs. 4S5NG-PE24 also promoted the response rate of programmed cell death protein-1 (PD-1) checkpoint blockade to increase antitumor efficacy.
    CONCLUSIONS: Collectively, these results highlight the potential use of 4S5NG to deliver the toxin PE24 to selectively eliminate integrin α6+ cells in melanoma, which may represent a novel treatment approach for melanoma patients.
    Keywords:  4S5NG CPP; Antitumor immunity; Integrin α6; Melanoma; Pyroptosis
    DOI:  https://doi.org/10.1186/s12967-025-06511-5
  5. Org Biomol Chem. 2025 May 02.
    Palindromic peptide foldamers: a strategy for structural stability and cellular uptake.
    Minami Fujita, Takahito Ito, Akihiko Inokuma, Kosuke Saito, Motoharu Hirano, Hidetomo Yokoo, Yosuke Demizu.
      Mid-sized peptide therapeutics have gained significant attention for their potential to overcome the limitations of small molecules and biologics. However, their clinical application is often hindered by poor stability and low cellular permeability. In this study, we designed a palindromic peptide foldamer composed of L-leucine and L-arginine residues to investigate its structural and functional properties. CD spectroscopy confirmed that the designed peptide adopts a stable α-helical conformation, even under denaturing conditions. Cellular uptake studies using LC-MS/MS and flow cytometry indicated efficient intracellular delivery, suggesting that the peptide's amphiphilic structure enhances membrane permeability. These findings provide valuable insights into the rational design of structurally stable and functionally enhanced peptide therapeutics.
    DOI:  https://doi.org/10.1039/d5ob00430f
  6. Chem Commun (Camb). 2025 Apr 30.
    A novel peptide targeting PD-1: implications for protein-protein interaction studies and immunotherapy.
    Satya Prakash Arya, Hari Timilsina, Siddhartha Kalpa Samadhi Thennakoon, Rick Mason Postema, Raunak Jahan, Andrew Michael Reynolds, Xiaohong Tan.
      Chemical ligand binding to PD-1 is a powerful approach for studying protein-protein interactions and advancing immunotherapy. In this study, we introduce a novel II peptide with strong binding affinity for PD-1. Molecular docking analysis reveals key interactions between the II peptide and PD-1, supporting inhibition ELISA data and indicating that the II peptide overlaps with the PD-1/PD-L1 interaction interface.
    DOI:  https://doi.org/10.1039/d5cc01198a
  7. J Pept Sci. 2025 Jun;31(6): e70025
    Antimicrobial Activity of Short Analogues of the Marine Peptide EeCentrocin 1: Synthesis of Lipopeptides and Head-to-Tail Cyclic Peptides and Mechanism of Action Studies.
    Danijela Simonovic, Hymonti Dey, Natascha Johansen, Trude Anderssen, Ida K Ø Hansen, Hege Devold, Terje Vasskog, Hans-Matti Blencke, Frode Jacobsen Øyen, Elizabeth G Aarag Fredheim, Tor Haug, Morten B Strøm.
      We have synthesised a series of 12-residue analogues of a previously reported lead peptide (P6) developed from the heavy chain of the marine peptide EeCentrocin 1, isolated from the sea urchin Echinus esculentus. We optimised the lead peptide by increasing its net positive charge, its lipophilicity through N-terminal fatty acid acylation or incorporation of a Trp residue, and by synthesising head-to-tail cyclic peptides under pseudo-high-dilution conditions. All peptides were screened for antimicrobial and antifungal activity, and toxicity was determined against human red blood cells. The two most potent peptide analogues were the linear peptide P6-W6R8 and its head-to-tail cyclic analogue cP6-W6R8 displaying minimum inhibitory concentrations of 0.4-6.6 μM against Gram-positive and Gram-negative bacteria and 6.2-13 μM against fungi. All peptides showed low haemolytic activity except for two of the lipopeptides, in which haemolytic activity correlated with increasing acyl chain length. Mode of action studies using bacterial biosensor strains revealed a membrane disruptive effect of both the linear and the cyclic peptide. Overall, the results of our study demonstrated that relatively simple structural modifications could be successfully employed in the development of potent antimicrobial lead peptides derived from marine natural products.
    Keywords:  antifungal peptides; antimicrobial peptides; bacterial biosensors; head‐to‐tail cyclisation; lipopeptides; mechanism of action; pseudodilution cyclisation
    DOI:  https://doi.org/10.1002/psc.70025
  8. Int J Pharm. 2025 Apr 27. pii: S0378-5173(25)00435-1. [Epub ahead of print] 125598
    Advances in cell-penetrating peptide-based nose-to-brain drug delivery systems.
    Shuai Hong, Jinyou Piao, Junsheng Hu, Xinyu Liu, Jing Xu, Heying Mao, Jingshu Piao, Ming Guan Piao.
      The incidence of brain disorders has gained worldwide attention and the presence of the blood-brain barrier prevents numerous drugs from reaching the targeted brain. The specific physiology of the nasal cavity and the brain provides the feasibility of direct nose-brain delivery, a system that bypasses the blood-brain barrier in a non-invasive manner for brain-targeted drug delivery via intracellular and extracellular mechanisms. The use of CPPs provides further feasibility for naso-brain drug delivery studies, and liposomes, nanopolymer particles, and gels modified with CPPs have demonstrated significant brain-targeting capabilities after nasal delivery. In this paper, the physiology of the nasal cavity and brain, the pathways of naso-brain delivery and the influencing factors are discussed in detail. At the same time, the introduction, classification, mechanism of action and application of CPPs in the nasal-brain delivery system are discussed in detail to provide a theoretical basis for the in-depth study of the application of CPPs in the nasal-brain delivery system.
    Keywords:  Cell-penetrating peptide; Gel; Lipid nanocarrier; Mechanism; Nasal-brain delivery system
    DOI:  https://doi.org/10.1016/j.ijpharm.2025.125598
  9. Mol Pharm. 2025 Apr 30.
    Engineered Peptide Coacervates Enable Efficient Intracellular Delivery of the MYC Inhibitor omoMYC.
    Carmine P Cerrato, Martin Krkoška, Yue Sun, Judit Liaño-Pons, Qi Ying Neo, Thibault Vosselman, Mohammad Alzrigat, Borek Vojtěšek, David P Lane, Marie Arsenian Henriksson, Ali Miserez, Michael Landreh.
      Intracellular delivery is a bottleneck in the development of therapeutic peptides and proteins. Here, we demonstrate the efficient delivery of omoMYC, the first MYC inhibitor in clinical trials, using HBpep-SP, an engineered peptide forming liquid-liquid phase-separated coacervates. HBpep-SP coacervates facilitate efficient cellular uptake and intracellular delivery of the omoMYC peptide at concentrations lower than those required for spontaneous uptake. Strikingly, omoMYC coacervates result in reduced proliferation and apoptosis induction in the low c-MYC expressing cell lines HEK293 and SH-SY5Y cells, but not in HeLa and SK-N-BE(2) cells with high c-MYC/MYCN expression, respectively, suggesting that endogenous MYC/N levels may impact the effects of omoMYC. Importantly, our approach bypasses the need for cell penetration-enhancing chemical modifications, offering a novel strategy for the investigation of peptide drug mechanisms in therapeutic development.
    Keywords:  drug delivery; liquid−liquid phase separation; protein engineering
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c00468
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