bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2025–06–01
six papers selected by
Henry Lamb, Queensland University of Technology
  1. Ribosomal incorporation of N-acetyl-3,5-bis(chloromethyl)benzylthio-L-alanine for developing an mRNA-displayed bicyclic peptide library cyclized via 1,3,5-tris(methyl)benzene.
  2. Exploring Macrocyclic Chemical Space: Strategies and Technologies for Drug Discovery.
  3. Peptide-Drug Conjugates as Next-Generation Therapeutics: Exploring the Potential and Clinical Progress.
  4. A hydrophobic loop of the spider-venom peptide Tl1a drives activity at NaV1.8.
  5. Cell-Penetrating Peptide Based on Myosin Phosphatase Target Subunit Sequence Mediates Myosin Phosphatase Activity.
  6. Developing Potent and Selective Anticancer Therapy through Chemical Approaches and the Combination of Cationic Amphipathic Oncolytic Peptides.
  1. Org Biomol Chem. 2025 May 27.
    Ribosomal incorporation of N-acetyl-3,5-bis(chloromethyl)benzylthio-L-alanine for developing an mRNA-displayed bicyclic peptide library cyclized via 1,3,5-tris(methyl)benzene.
    Maolin Li, Haipeng Yu, Jie Cheng, Wenfeng Cai, Youming Zhang, Yizhen Yin.
      We report a novel method for constructing an mRNA-displayed bicyclic peptide library cyclized through 1,3,5-tris(methyl)benzene by ribosomally incorporating N-acetyl-3,5-bis(chloromethyl)benzylthio-L-alanine, enabling the selection of bicyclic peptides against specific targets. Using this method, we successfully identified bicyclic peptides that bind to human Trop2 and VEGF165, providing a new strategy for selecting bicyclic peptides cyclized by trimethylbenzene.
    DOI:  https://doi.org/10.1039/d5ob00693g
  2. Pharmaceuticals (Basel). 2025 Apr 24. pii: 617. [Epub ahead of print]18(5):
    Exploring Macrocyclic Chemical Space: Strategies and Technologies for Drug Discovery.
    Taegwan Kim, Eunbee Baek, Jonghoon Kim.
      Macrocycles have emerged as significant therapeutic candidates in drug discovery due to their unique capacity to target complex and traditionally inaccessible biological interfaces. Their structurally constrained three-dimensional configurations facilitate high-affinity interactions with challenging targets, notably protein-protein interfaces. However, despite their potential, the synthesis and optimization of macrocyclic compounds present considerable challenges related to structural complexity, synthetic accessibility, and the attainment of favorable drug-like properties, particularly cell permeability and oral bioavailability. Recent advancements in synthetic methodologies have expanded the chemical space accessible to macrocycles, enabling the creation of structurally diverse and pharmacologically active compounds. Concurrent developments in computational strategies have further enhanced macrocycle design, providing valuable insights into structural optimization and predicting molecular properties essential for therapeutic efficacy. Additionally, a deeper understanding of macrocycles' conformational adaptability, especially their ability to internally shield polar functionalities to improve membrane permeability, has significantly informed their rational design. This review discusses recent innovations in synthetic and computational methodologies that have advanced macrocycle drug discovery over the past five years. It emphasizes the importance of integrating these strategies to overcome existing challenges, illustrating how their synergy expands the therapeutic potential and chemical diversity of macrocycles. Selected case studies underscore the practical impact of these integrated approaches, highlighting promising therapeutic applications across diverse biomedical targets.
    Keywords:  computational design; macrocyclic ring synthesis; molecular diversity; natural product mimics drug discovery
    DOI:  https://doi.org/10.3390/ph18050617
  3. Bioengineering (Basel). 2025 Apr 30. pii: 481. [Epub ahead of print]12(5):
    Peptide-Drug Conjugates as Next-Generation Therapeutics: Exploring the Potential and Clinical Progress.
    Krishna Jadhav, Ashwin Abhang, Eknath B Kole, Dipak Gadade, Apurva Dusane, Aditya Iyer, Ankur Sharma, Saroj Kumar Rout, Amol D Gholap, Jitendra Naik, Rahul K Verma, Satish Rojekar.
      Peptide-drug conjugates (PDCs) have emerged as a next-generation therapeutic platform, combining the target specificity of peptides with the pharmacological potency of small-molecule drugs. As an evolution beyond antibody-drug conjugates (ADCs), PDCs offer distinct advantages, including enhanced cellular permeability, improved drug selectivity, and versatile design flexibility. This review provides a comprehensive analysis of the fundamental components of PDCs, including homing peptide selection, linker engineering, and payload optimization, alongside strategies to address their inherent challenges, such as stability, bioactivity, and clinical translation barriers. Therapeutic applications of PDCs span oncology, infectious diseases, metabolic disorders, and emerging areas like COVID-19, with several conjugates advancing in clinical trials and achieving regulatory milestones. Innovations, including bicyclic peptides, supramolecular architectures, and novel linker technologies, are explored as promising avenues to enhance PDC design. Additionally, this review examines the clinical trajectory of PDCs, emphasizing their therapeutic potential and highlighting ongoing trials that exemplify their efficacy. By addressing limitations and leveraging emerging advancements, PDCs hold immense promise as targeted therapeutics capable of addressing complex disease states and driving progress in precision medicine.
    Keywords:  linkers; peptide; peptide–drug conjugates; stability; targeted therapeutics; theranostic
    DOI:  https://doi.org/10.3390/bioengineering12050481
  4. Eur J Pharmacol. 2025 May 23. pii: S0014-2999(25)00505-9. [Epub ahead of print] 177751
    A hydrophobic loop of the spider-venom peptide Tl1a drives activity at NaV1.8.
    Ashvriya Thapa, Hue Tran, Lotten Ragnarsson, Angelo Keramidas, Volker Herzig, Nina Brinkwirth, Jennifer R Deuis, Irina Vetter.
      Voltage-gated sodium (NaVs) channels are pore-forming transmembrane proteins that regulate the influx of sodium ions across cell membranes. Spider venoms are a rich source of NaV-modulating peptides with high selectivity and potency, making them important tools for understanding NaV structure and function. NaV1.8 is tetrodotoxin-resistant, expressed in the peripheral nervous system and contributes to the propagation of action potentials in nociceptive neurons, making it a potential therapeutic target for pain. We identified Tl1a, a 36 amino acid residue peptide isolated from the crude venom of the Peruvian tarantula species, Thrixopelma longicolli, as a modulator of NaV1.8. Tl1a was synthesized using solid-phase peptide synthesis, and activity was assessed using automated whole-cell patch-clamp recordings. Tl1a inhibited NaV1.8 peak current (IC50 210 nM), delayed the kinetics of activation, inhibited fast inactivation, and caused a persistent current as well as a depolarising shift in the voltage dependence of activation (ΔV1/2 +11 mV). Tl1a inhibited peak current with similar potency at NaV1.5 (IC50 282 nM) and KV2.1 (IC50 156 nM) and was 8-fold selective over the tetrodotoxin-sensitive NaV1.4 (IC50 1769 nM), NaV1.1 (2201 nM) and 6-fold selective over NaV1.7 (IC50 1278 nM) channels. Tl1a analogues with an increased number of charged amino acids in loop 4 of the peptide lost activity at NaV1.8 due to altered interactions with the domain IV S3-S4 extracellular loop. The results of this work contribute to a better understanding of the structure-activity relationships at tetrodotoxin-resistant NaV channels and may be useful for the future rational design of selective NaV1.8 peptide modulators.
    Keywords:  Na(V)1.7; Na(V)1.8; peptide; spider; venom; voltage-gated sodium channel
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177751
  5. Biomolecules. 2025 May 12. pii: 705. [Epub ahead of print]15(5):
    Cell-Penetrating Peptide Based on Myosin Phosphatase Target Subunit Sequence Mediates Myosin Phosphatase Activity.
    Andrea Kiss, Mohamad Mahfood, Zsófia Bodogán, Zoltán Kónya, Bálint Bécsi, Ferenc Erdődi.
      Myosin phosphatase (MP) holoenzyme consists of protein phosphatase-1 (PP1) catalytic subunit (PP1c) associated with myosin phosphatase target subunit-1 (MYPT1) and it plays an important role in mediating the phosphorylation of the 20 kDa light chain (MLC20) of myosin, thereby regulating cell contractility. The association of MYPT1 with PP1c increases the phosphatase activity toward myosin; therefore, disrupting/dissociating this interaction may result in inhibition of the dephosphorylation of myosin. In this study, we probed how MYPT132-58 peptide including major PP1c interactive regions coupled with biotin and cell-penetrating TAT sequence (biotin-TAT-MYPT1) may influence MP activity. Biotin-TAT-MYPT1 inhibited the activity of MP holoenzyme and affinity chromatography as well as surface plasmon resonance (SPR) binding studies established its stable association with PP1c. Biotin-TAT-MYPT1 competed for binding to PP1c with immobilized GST-MYPT1 in SPR assays and it partially relieved PP1c inhibition by thiophosphorylated (on Thr696 and Thr853) MYPT1. Moreover, biotin-TAT-MYPT1 dissociated PP1c from immunoprecipitated PP1c-MYPT1 complex implying its holoenzyme disrupting ability. Biotin-TAT-MYPT1 penetrated into A7r5 smooth muscle cells localized in the cytoplasm and nucleus and exerted inhibition on MP with a parallel increase in MLC20 phosphorylation. Our results imply that the biotin-TAT-MYPT1 peptide may serve as a specific MP regulatory cell-penetrating peptide as well as possibly being applicable to further development for pharmacological interventions.
    Keywords:  cell-penetrating MYPT1 peptide; myosin phosphatase; myosin phosphatase target subunit-1 (MYPT1); protein phosphatase-1 (PP1) catalytic subunit (PP1c); transactivating transcriptional activator (TAT)-peptide
    DOI:  https://doi.org/10.3390/biom15050705
  6. J Med Chem. 2025 May 30.
    Developing Potent and Selective Anticancer Therapy through Chemical Approaches and the Combination of Cationic Amphipathic Oncolytic Peptides.
    Hai Bui Thi Phuong, Bao Loc Nguyen, Linyu Huang, Thi Oanh Oanh Nguyen, Ngoc Duy Le, Beomsu Kim, Basavaraj Rudragouda Patil, Thang Nguyen Quoc, Jeonghwan Kim, Huy Xuan Luong, And Jong Oh Kim.
      This study explores the structure-activity relationships of cationic amphipathic Mastoparan AF derivatives and their combination with the oncolytic peptide LTX315 to enhance the anticancer efficacy. The original peptide was modified to improve its selective interaction with cancer cell membranes, thereby increasing anticancer potency while minimizing hemolytic activity. Circular dichroism spectroscopy and molecular dynamics simulations were employed to evaluate structural changes and self-association tendencies. Among the derivatives, MAF-10L exhibited superior anticancer activity but elevated hemolysis, which was mitigated through combination therapy with LTX315. These findings underscore the potential of cationic amphipathic peptides as a basis for selective anticancer treatments and highlight the benefits of peptide combinations in reducing adverse effects while enhancing the therapeutic efficacy.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c00699
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