bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2025–01–19
seventeen papers selected by
Henry Lamb, Queensland University of Technology
  1. Cancer-Targeting Applications of Cell-Penetrating Peptides.
  2. Peptide-Bismuth Tricycles: Maximizing Stability by Constraint.
  3. Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection.
  4. Transformation-Guided Genome Mining Provides Access to Brominated Lanthipeptides.
  5. Macrocyclic peptides as a new class of targeted protein degraders.
  6. Discovery of a highly potent, selective, and stable d-amino acid-containing peptide inhibitor of CDK9/cyclin T1 interaction for the treatment of prostate cancer.
  7. Peptide design to control protein-protein interactions.
  8. To conjugate or not to conjugate? evaluating the potential use of cell-penetrating peptides for conjugation or complexation with oligonucleotides by surface plasmon resonance.
  9. Directed Evolution of Multicyclic Peptides Using Yeast Display for Sensitive and Selective Fluorescent Analysis of CD28 on the Cell Surface.
  10. Re-evaluation of Cyclic Peptide Binding to Neurotensin Receptor 1 by Shifting the Peptide Register during Synthesis.
  11. Exploring the Chemical Features and Biomedical Relevance of Cell-Penetrating Peptides.
  12. Protocol for the Generation and 3D Culture of Fluorescently Labeled Multicellular Spheroids.
  13. Computational Insights into Membrane Disruption by Cell-Penetrating Peptides.
  14. Discovery of Brain-Penetrative Negative Allosteric Modulators of NMDA Receptors Using FEP-Guided Structure Optimization and Membrane Permeability Prediction.
  15. Peptide-based PET/CT imaging visualizes PD-L1-driven radioresistance in glioblastoma.
  16. A versatile entry to unnatural, disulfide-linked amino acids and peptides through the disulfuration of azlactones.
  17. A Conjugate of an EGFR-Binding Peptide and Doxorubicin Shows Selective Toxicity to Triple-Negative Breast Cancer Cells.
  1. Int J Mol Sci. 2024 Dec 24. pii: 2. [Epub ahead of print]26(1):
    Cancer-Targeting Applications of Cell-Penetrating Peptides.
    Liliana Marisol Moreno-Vargas, Diego Prada-Gracia.
      Cell-penetrating peptides (CPPs) offer a unique and efficient mechanism for delivering therapeutic agents directly into cancer cells. These peptides can traverse cellular membranes, overcoming one of the critical barriers in drug delivery systems. In this review, we explore recent advancements in the application of CPPs for cancer treatment, focusing on mechanisms, delivery strategies, and clinical potential. The review highlights the use of CPP-drug conjugates, CPP-based vaccines, and their role in targeting and inhibiting tumor growth.
    Keywords:  apoptosis inductors; cancer; cancer immunotherapy; cell-penetrating peptides; fluorescent peptide dye; multi resistance; peptide receptor radionuclide therapy; selective membrane disruption; targeted cancer therapeutic peptides; targeted drug delivery
    DOI:  https://doi.org/10.3390/ijms26010002
  2. Chemistry. 2025 Jan 13. e202500064
    Peptide-Bismuth Tricycles: Maximizing Stability by Constraint.
    Lani J Davies, Pritha Ghosh, Sauhta Siryer, Sven Ullrich, Christoph Nitsche.
      Constrained peptides possess excellent properties for identifying lead compounds in drug discovery. While it has become increasingly straightforward to discover selective high-affinity peptide ligands, especially through genetically encoded libraries, their stability and bioavailability remain significant challenges. By integrating macrocyclization chemistry with bismuth binding, we generated series of linear, cyclic, bicyclic, and tricyclic peptides with identical sequences. Utilizing bismuth to rigidify the peptide structure allows for a better comparison of different constraint levels, reducing confounding effects of interactions often seen with hydrophobic stapling reagents. Our study facilitated the identification of a peptide-bismuth tricycle that fully withstands cellular levels of glutathione, acts as a nanomolar protease inhibitor without being proteolytically digested by its target, and is fully stable in human plasma. Importantly, this multicyclic peptide does not possess any non-canonical amino acid modifications. Using oxime ligation, we conjugated an analogue of this tricycle to the N-terminus of two nanobodies to demonstrate potential applications in targeted therapy.
    Keywords:  bismuth; macrocyclization; multicycles; nanobodies; peptides
    DOI:  https://doi.org/10.1002/chem.202500064
  3. Nat Chem Biol. 2025 Jan 13.
    Rapid discovery of cyclic peptide protein aggregation inhibitors by continuous selection.
    Linwei Yang, Jingwei Zhang, James S Andon, Lingjun Li, Tina Wang.
      Protein aggregates are associated with numerous diseases. Here we report a platform for the rapid phenotypic selection of protein aggregation inhibitors from genetically encoded cyclic peptide libraries in Escherichia coli based on phage-assisted continuous evolution (PACE). We developed a new PACE-compatible selection for protein aggregation inhibition and used it to identify cyclic peptides that suppress amyloid-β42 and human islet amyloid polypeptide aggregation. Additionally, we integrated a negative selection that removes false positives and off-target hits, greatly improving cyclic peptide selectivity. We show that selected inhibitors are active when chemically resynthesized in in vitro assays. Our platform provides a powerful approach for the rapid discovery of cyclic peptide inhibitors of protein aggregation and may serve as the basis for the future evolution of cyclic peptides with a broad spectrum of inhibitory activities.
    DOI:  https://doi.org/10.1038/s41589-024-01823-x
  4. Org Lett. 2025 Jan 17.
    Transformation-Guided Genome Mining Provides Access to Brominated Lanthipeptides.
    Nirmal Saha, F N U Vidya, Youran Luo, Wilfred A van der Donk, Vinayak Agarwal.
      Natural product biosynthesis is nature's tinkering ground for developing new enzymes that can achieve chemical transformations that are outside the purview of traditional chemical catalysis. Herein we describe a genome mining approach that leads to the discovery of a halogenase that regioselectively brominates a tryptophan side chain indole for a macrocyclic peptide substrate, enabling downstream chemical arylation by Suzuki-Miyaura coupling. The halogenase was found to prefer a macrocyclic peptide substrate over a linear peptide. The brominase presents a starting point for biocatalytic access to macrocyclic peptides bearing a chemically versatile aryl-bromide reactive handle.
    DOI:  https://doi.org/10.1021/acs.orglett.4c04529
  5. RSC Chem Biol. 2025 Jan 15.
    Macrocyclic peptides as a new class of targeted protein degraders.
    Xuefei Jing, Joel P Mackay, Toby Passioura.
      Targeted protein degraders, in the form of proteolysis targeting chimaeras (PROTACs) and molecular glues, leverage the ubiquitin-proteasome system to catalytically degrade specific target proteins of interest. Because such molecules can be extremely potent, they have attracted considerable attention as a therapeutic modality in recent years. However, while targeted degraders have great potential, they are likely to face many of the same challenges as more traditional small molecules when it comes to their development as therapeutics. In particular, existing targeted degrader design is largely only applicable to the same set of protein targets as traditional small molecules (i.e., ∼15% of the human proteome). Here, we consider the potential of macrocyclic peptides to overcome this limitation. Such molecules possess several features that make them well-suited for the role, including the ability to induce the formation of ternary protein complexes that can involve relatively flat surfaces and their structural commonality with E3 ligase-recruiting peptide degrons. For these reasons, macrocyclic peptides provide the opportunity both to broaden the number of targets accessible to degrader activity and to broaden the number of E3 ligases that can be harnessed to mediate that activity.
    DOI:  https://doi.org/10.1039/d4cb00199k
  6. Eur J Med Chem. 2025 Jan 06. pii: S0223-5234(25)00013-3. [Epub ahead of print]285 117248
    Discovery of a highly potent, selective, and stable d-amino acid-containing peptide inhibitor of CDK9/cyclin T1 interaction for the treatment of prostate cancer.
    Zhen Xu, Yifei Geng, Lixia Guan, Miao-Miao Niu, Cen Xu, Li Yang, Sudong Liang.
      Cyclin-dependent kinase 9 (CDK9) plays a pivotal role in promoting oncogenic transcriptional pathways, significantly contributing to the development and progression of cancer. Given the unique biostability of d-amino acid, the development of d-amino acid-containing peptides (DAACPs) is a promising strategy for cancer treatment. Currently, no DAACPs inhibitor targeting CDK9-cyclin T1 have been reported. Here, we reported the identification of a novel, highly potent, selective and stable DAACPs inhibitor (peptide-5) targeting CDK9-cyclin T1 interaction. Peptide-5 showed nanomolar inhibitory effect against CDK9-cyclin T1 (IC50 = 4.16 ± 0.11 nM). Molecular dynamics (MD) simulation exhibited that peptide-5 stably bound to CDK9. Peptide-5 showed good inhibitory activity against multiple types of prostate cancer cells and demonstrated good biostability in mouse serum. Moreover, peptide-5 suppresses the tumor growth in DU145 cell-derived xenografts nude mice. These data suggest that peptide-5 is a potent antitumor candidate for further research.
    Keywords:  CDK9-Cyclin T1; Prostate cancer (PCa); Protein-protein interaction (PPI); Structure-based virtual screening; d-amino acid-containing peptides (DAACPs)
    DOI:  https://doi.org/10.1016/j.ejmech.2025.117248
  7. Chem Soc Rev. 2025 Jan 16.
    Peptide design to control protein-protein interactions.
    Suzanne P van Wier, Andrew M Beekman.
      Targeting of protein-protein interactions has become of huge interest in every aspect of medicinal and biological sciences. The control of protein interactions selectively offers the opportunity to control biological processes while limiting off target effects. This interest has massively increased with the development of cryo-EM and protein structure prediction with tools such as RosettaFold and AlphaFold. When designing molecules to control protein interactions, either inhibition or stabilisation, a starting point is commonly peptide design. This tutorial review describes that process, highlighting the selection of an initial sequence with and without structural information. Subsequently, methods for how the sequence can be analysed for key residues and how this information can be used to optimise the ligand efficiency are highlighted. Finally a discussion on how peptides can be further modified to increase their affinity and cell permeability, improving their drug-like properties, is presented.
    DOI:  https://doi.org/10.1039/d4cs00243a
  8. Int J Pharm. 2025 Jan 08. pii: S0378-5173(25)00034-1. [Epub ahead of print] 125198
    To conjugate or not to conjugate? evaluating the potential use of cell-penetrating peptides for conjugation or complexation with oligonucleotides by surface plasmon resonance.
    Rikke Dueholm, Jakob Ewald, Franziska Zosel, Petteri Heljo, Bhavesh Premdjee, Alexander Davies, Stephen T Buckley, Lars Hovgaard, Hanne Mørck Nielsen.
      Oligonucleotides represent a class of molecules that exhibit remarkable therapeutic potential due to their unparalleled target specificity, yet they suffer from limited cellular uptake and lack of tissue selectivity. Extensive research is conducted with cell-penetrating peptides (CPPs) as delivery excipients due to their ability to translocate across cellular membranes and deliver cargo into cells. This study aims to investigate an innovative approach to rapidly, and with small amounts of compound, analyze and compare complexation of CPPs to oligonucleotides. The study applies surface plasmon resonance (SPR) to evaluate a comprehensive library of CPPs regarding their interaction with a double-stranded oligonucleotide to assess their potential as complexing molecules or whether the CPP should be chemically linked to the negatively charged oligonucleotide to ensure proximity. Specifically, a small interfering RNA (siRNA) was immobilized on a biotinylated chip, and solutions of 66 CPPs were subsequently injected to determine their binding stoichiometry with the siRNA. The most influential molecular properties of the CPPs were determined to be the positive charge-to-length ratio, the total number of positive charges, and the overall hydrophobicity of the CPP. These findings demonstrate the effectiveness and utility of SPR as a high throughput screening tool for selecting peptide/oligonucleotide pairs intended for complexation or conjugation.
    Keywords:  Binding; Cell-penetrating peptides; Complexation; Drug delivery; Interaction; Oligonucleotides; Surface plasmon resonance; siRNA
    DOI:  https://doi.org/10.1016/j.ijpharm.2025.125198
  9. Anal Chem. 2025 Jan 14.
    Directed Evolution of Multicyclic Peptides Using Yeast Display for Sensitive and Selective Fluorescent Analysis of CD28 on the Cell Surface.
    Chaoying Xu, Xiaoting Meng, Ping Chai, Hongtan Liu, Zengping Duan, Yu-Hsuan Tsai, Chuanliu Wu.
      CD28 is a costimulatory receptor that provides the second signal necessary for T-cell activation and is associated with diseases, including rheumatoid arthritis, asthma, and cancer. Targeting CD28 is crucial for both functional bioanalysis and therapeutic development. Molecular probes, particularly fluorescent probes, can enhance our understanding of CD28's cellular roles. However, existing antibody-based probes face challenges such as high production costs, low stability, and large size, which limit their bioanalytical applications. Thus, there is a need for smaller, robust probes that enable the sensitive and selective targeting of CD28. Multicyclic peptides have emerged as promising candidates for novel therapeutics and molecular probes. Recently, we identified disulfide-directed multicyclic peptides (DDMPs) that bind CD28 with submicromolar affinity; however, their relatively low affinity limits further applications. In this study, we develop a DDMP evolving system based on yeast display and error-prone PCR to identify high-affinity peptide binders. We obtained DDMPs with a picomolar affinity for CD28, exceptional binding specificity, and remarkable oxidative folding efficiency. Furthermore, we developed fluorescent probes and labeling strategies for detecting and visualizing CD28 expression in human T cells. This advancement opens new avenues for studying T-cell dynamics and activation states, which are essential for understanding immune responses and developing targeted therapies. Our study not only produces potent CD28 binders and probes but also establishes a robust platform for optimizing other multicyclic peptide-based probes and therapeutics.
    DOI:  https://doi.org/10.1021/acs.analchem.4c05681
  10. ACS Med Chem Lett. 2025 Jan 09. 16(1): 157-162
    Re-evaluation of Cyclic Peptide Binding to Neurotensin Receptor 1 by Shifting the Peptide Register during Synthesis.
    Lazarus Andrew de Zhang, Mengjie Liu, Daniel J Scott, David K Chalmers.
      The head-to-tail cyclic peptide cyclo[Arg-Lys-Pro-Tyr-Tle-Leu] (peptide 1, where Tle is l-tert-Leu) has previously been reported to bind to neurotensin receptor 1 (NTS1) (pKi = 5.97). Upon seeking to reproduce this finding, we found that peptide 1 did not have a measurable affinity for NTS1. However, a semipurified preparation of peptide 1 appeared to bind to NTS1 with pKi = 5.83 ± 0.25 SEM. Resynthesis of peptide 1 using a shifted peptide register gave linear and cyclic forms of peptide 1 that were both unable to bind to NTS1. We observe that the previously reported activity of peptide 1 may be due to the presence of high affinity linear contaminants. Approximately 3% contamination with the linear variant would explain the apparent binding of the semipure peptide 1 sample. From this study, we propose that shifting the peptide register during synthesis as a strategy to minimize the presence of potent precursor contaminants.
    DOI:  https://doi.org/10.1021/acsmedchemlett.4c00542
  11. Int J Mol Sci. 2024 Dec 25. pii: 59. [Epub ahead of print]26(1):
    Exploring the Chemical Features and Biomedical Relevance of Cell-Penetrating Peptides.
    Liliana Marisol Moreno-Vargas, Diego Prada-Gracia.
      Cell-penetrating peptides (CPPs) are a diverse group of peptides, typically composed of 4 to 40 amino acids, known for their unique ability to transport a wide range of substances-such as small molecules, plasmid DNA, small interfering RNA, proteins, viruses, and nanoparticles-across cellular membranes while preserving the integrity of the cargo. CPPs exhibit passive and non-selective behavior, often requiring functionalization or chemical modification to enhance their specificity and efficacy. The precise mechanisms governing the cellular uptake of CPPs remain ambiguous; however, electrostatic interactions between positively charged amino acids and negatively charged glycosaminoglycans on the membrane, particularly heparan sulfate proteoglycans, are considered the initial crucial step for CPP uptake. Clinical trials have highlighted the potential of CPPs in diagnosing and treating various diseases, including cancer, central nervous system disorders, eye disorders, and diabetes. This review provides a comprehensive overview of CPP classifications, potential applications, transduction mechanisms, and the most relevant algorithms to improve the accuracy and reliability of predictions in CPP development.
    Keywords:  cargo delivery; cell-penetrating peptides; cellular uptake; physical–chemical properties; prediction of CPPs
    DOI:  https://doi.org/10.3390/ijms26010059
  12. Methods Mol Biol. 2025 Jan 17.
    Protocol for the Generation and 3D Culture of Fluorescently Labeled Multicellular Spheroids.
    Emily C Liu, Amy L Ryan, Sinem Koc-Günel.
      Spheroid culture systems have been extensively used to model the three-dimensional (3D) behavior of cells in vitro. Traditionally, spheroids consist of a single cell type, limiting their ability to fully recapitulate the complex inter-cellular interactions observed in vivo. Here we describe a protocol for generating cocultured spheroids composed of two distinct cell types, embedded within a 3D extracellular matrix (ECM) to better study cellular interactions. Fluorescent labeling of each cell type enables clear distinction and visualization, facilitating the analysis of cell invasion, proliferation, and behavior within the matrix. This method is particularly suited for studying matrix invasion, an essential process in cancer metastasis, using both fixed and live cell microscopy. The protocol is versatile and can be adapted for various cell types, providing a robust platform for investigating cell-cell interactions in cancer research, tissue remodeling, and drug screening.
    Keywords:  3D spheroids; Extracellular matrix; Fluorescence imaging; Human lung fibroblasts; Invasion; Lymphatic endothelium; Multicellular interactions
    DOI:  https://doi.org/10.1007/7651_2024_592
  13. J Chem Inf Model. 2025 Jan 17.
    Computational Insights into Membrane Disruption by Cell-Penetrating Peptides.
    Eric Catalina-Hernandez, Marcel Aguilella-Arzo, Alex Peralvarez-Marin, Mario Lopez-Martin.
      Cell-penetrating peptides (CPPs) can translocate into cells without inducing cytotoxicity. The internalization process implies several steps at different time scales ranging from microseconds to minutes. We combine adaptive Steered Molecular Dynamics (aSMD) with conventional Molecular Dynamics (cMD) to observe nonequilibrium and equilibrium states to study the early mechanisms of peptide-bilayer interaction leading to CPPs internalization. We define three membrane compositions representing bilayer sections, neutral lipids (i.e., upper leaflet), neutral lipids with cholesterol (i.e., hydrophobic core), and neutral/negatively charged lipids with cholesterol (i.e., lower leaflet) to study the energy barriers and disruption mechanisms of Arg9, MAP, and TP2, representing cationic, amphiphilic, and hydrophobic CPPs, respectively. Cholesterol and negatively charged lipids increase the energetic barriers for the peptide-bilayer crossing. TP2 interacts with the bilayer by hydrophobic insertion, while Arg9 disrupts the bilayer by forming transient or stable pores. MAP has shown both behaviors. Collectively, these findings underscore the significance of innovative computational approaches in studying membrane-disruptive peptides and, more specifically, in harnessing their potential for cell penetration.
    DOI:  https://doi.org/10.1021/acs.jcim.4c01940
  14. J Chem Inf Model. 2025 Jan 14.
    Discovery of Brain-Penetrative Negative Allosteric Modulators of NMDA Receptors Using FEP-Guided Structure Optimization and Membrane Permeability Prediction.
    Fabao Zhao, Liyang Jiang, Jieying Xie, Na Liu, Zhen Gao, Yue Yang, Yu Wang, Boshi Huang, Dongwei Kang, Peng Zhan, Feng Yi, Xinyong Liu.
      N-Methyl-d-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors in the central nervous system (CNS), have garnered attention for their role in brain disorders. Specifically, GluN2A-containing NMDA receptors have emerged as a potential therapeutic target for the treatment of depressive disorders and epilepsy. However, the development of GluN2A-containing NMDA receptor-selective antagonists, represented by N-(4-(2-benzoylhydrazine-1-carbonyl)benzyl)-3-chloro-4-fluorobenzenesulfonamide (TCN-201) and its derivatives, faces a significant challenge due to their limited ability to penetrate the blood-brain barrier (BBB), hampering their in vivo characterization and further advancement. In this study, we reported a series of 2-((5-(phemylamino)-1,3,4-thiadiazol-2-yl)thio)-N-(cyclohexylmethyl)acetamide derivatives, achieved through a structure-guided optimization strategy using free energy perturbation (FEP) and BBB permeability estimation. Through systematic exploration of various phenyl substitutions, compound 1f emerged as a standout compound, demonstrating substantially enhanced inhibitory activity compared with the lead compound TCN-213. Compound 1f not only displayed satisfactory BBB permeability but also showed antidepressant-like potency in the hydrocortisone-induced zebrafish depression-like model. All results position it as a promising candidate for developing innovative therapeutics for NMDA receptor-related disorders.
    DOI:  https://doi.org/10.1021/acs.jcim.4c01636
  15. Drug Resist Updat. 2025 Jan 09. pii: S1368-7646(25)00002-0. [Epub ahead of print]79 101202
    Peptide-based PET/CT imaging visualizes PD-L1-driven radioresistance in glioblastoma.
    Yong Wang, Zhiguo Liu, Yang Li, Kelin Wang, Chunhui Yuan, Jian Shi, Jiazhong Ren, Shijie Wang, Jinping Wang, Miaoqing Zhao, Man Hu.
      Radioresistance remains a great challenge for radiotherapy in the treatment of glioblastoma (GBM). PD-L1 expression is a key contributor to radioresistance and immune escape in GBM. The lack of effective methods to monitor the change of PD-L1 during radiotherapy in patients limits timely intervention and management of the resistance. Here, we developed a novel peptide tracer [18F]AlF-NOTA-PCP2 for PET/CT to visualize the changes of PD-L1 expression in response to radiotherapy, revealing PD-L1-driven radioresistance in GBM. The [18F]AlF-NOTA-PCP2 demonstrated high specificity and binding affinity to PD-L1 in vitro. The uptake of [18F]AlF-NOTA-PCP2 on PET/CT showed a strong positive correlation with PD-L1 expression by immunohistochemistry (IHC) (R² = 0.861, P < 0.001) in GBM xenograft tumors. The radiotracer uptake in PD-L1-positive tumors significantly increased post-radiotherapy (21.25 ± 0.91 % vs. 25.12 ± 0.82 %, P = 0.008), aligning with the radioresistance observed in these tumors. In vitro studies revealed that PD-L1-driven radioresistance by enhancing DNA damage repair through upregulation of RAD51 after activation of the PI3K-Akt pathway in cells. Preliminary clinical application in a radiotherapy-treated GBM patient demonstrated the ability to monitor PD-L1 dynamics, supporting its potential for clinical translation. Collectively, this peptide-based small molecule PET/CT radiotracers offer a noninvasive, real-time, and quantitative method to dynamically visualize PD-L1-driven radioresistance in GBM. It could serve as a potential radiotracer for facilitating patient stratification, adjusting radiotherapy regimens, and guiding personalized immunotherapy strategies.
    Keywords:  Glioblastoma; PD-L1; PET/CT; Peptide radiotracer; Radioresistance
    DOI:  https://doi.org/10.1016/j.drup.2025.101202
  16. Chem Sci. 2025 Jan 07.
    A versatile entry to unnatural, disulfide-linked amino acids and peptides through the disulfuration of azlactones.
    Masaki Iwata, Yuzuki Takami, Hayato Asanuma, Kenya Hosono, Hibiki Ohno, Naohiko Yoshikai, Kazuya Kanemoto.
      Despite the evident demand and promising potential of disulfide-functionalized amino acids and peptides in linker chemistry and peptide drug discovery, those disulfurated specifically at the α-position constitute a unique yet rather highly underexplored chemical space. In this study, we have developed a method for preparing SS-linked amino acid/peptide derivatives through a base-catalyzed disulfuration reaction of azlactones, followed by the ring-opening functionalization. The disulfuration reaction proceeds under mild conditions, yielding disulfurated azlactones in excellent yields across a variety of N-dithiophthalimides and diverse azlactones derived from various amino acids and peptides. Leveraging the ready availability of N-dithiophthalimides from several bilateral disulfurating reagents, this method allows for the modular integration of functional molecules and azlactones into SS-linkage in two-step operations. Furthermore, due to the transformability of the azlactone moiety through ring-opening with various nucleophiles, our method provides a wide variety of functional molecule-tagged amino acids and oligopeptides bearing SS-linkages in a modular and time-efficient manner, serving as a valuable tool for linker chemistry and peptide chemistry.
    DOI:  https://doi.org/10.1039/d4sc07187e
  17. ACS Med Chem Lett. 2025 Jan 09. 16(1): 109-115
    A Conjugate of an EGFR-Binding Peptide and Doxorubicin Shows Selective Toxicity to Triple-Negative Breast Cancer Cells.
    Phi-Phung Than, Shih-Jing Yao, Emad Althagafi, Kamaljit Kaur.
      Selective targeting of cancer cells via overexpressed cell-surface receptors is a promising strategy to enhance chemotherapy efficacy and minimize off-target side effects. In this study, we designed peptide 31 (YHWYGYTPERVI) to target the overexpressed epidermal growth factor receptor (EGFR) in triple-negative breast cancer (TNBC) cells. Peptide 31 is internalized by TNBC cells through EGFR-mediated endocytosis and shares sequence and structural similarities with human EGF (hEGF), a natural EGFR ligand. Unlike hEGF, peptide 31 does not induce cell migration in TNBC cells. A novel conjugate of peptide 31 with doxorubicin (Dox) retains selectivity for TNBC cells and exhibits significant toxicity comparable to that of unconjugated Dox. Importantly, this conjugate shows no toxicity toward normal breast epithelial cells up to a high concentration (25 μM). Thus, peptide 31 serves as a versatile targeting ligand for developing novel conjugates with high selectivity for EGFR-positive cancers.
    DOI:  https://doi.org/10.1021/acsmedchemlett.4c00480
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