bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2025–03–23
seventeen papers selected by
Henry Lamb, Queensland University of Technology
  1. Novel Cyclic Peptides Inhibiting Tumor Necrosis Factor Receptor 1 Activity.
  2. An Intracellular Peptide Library Screening Platform Identifies Irreversible Covalent Transcription Factor Inhibitors.
  3. A Novel 68Ga-Labeled 2-Azabicyclo[3.1.0]Hexane-3-Carbonitrile-Based Fibroblast Activation Protein-Targeted Tracer for Cancer Imaging With Positron Emission Tomography.
  4. Design, synthesis and evaluation of lysine- and leucine-rich hydrocarbon-stapled peptides as antibacterial agents.
  5. Peptide Stapling Using Sonogashira Coupling.
  6. Affinity selection-mass spectrometry with linearizable macrocyclic peptide libraries.
  7. N-Substituted Aza-Glycine Promotes C8 CO···HN Hydrogen Bonding: A Novel Motif to Design Constrained Peptidomimetic.
  8. Cyclization of Two Antimicrobial Peptides Improves Their Activity.
  9. Comparison of the effects of perfluoroalkyl and alkyl groups on cellular uptake in short peptides.
  10. Affinity-based protein profiling of MDM2 inhibitor Navtemadlin.
  11. Exosomes: Traversing the blood-brain barrier and their therapeutic potential in brain cancer.
  12. The Ugi Multicomponent Reaction for the One-Step Construction of Macrocycles.
  13. Self-assemblies of cell-penetrating peptides and ferrocifens: design and biological evaluation of an innovative platform for lung cancer treatment.
  14. Peripherally Restricted Fused Heterocyclic Peptidomimetic Multifunctional Opioid Agonists as Novel, Potent Analgesics.
  15. Synthesis of piperazine-based fluorinated fibroblast activation protein inhibitors for the development of a novel 18F-labeled PET imaging probe.
  16. Recent advances in de novo designed metallopeptides as tailored enzyme mimics.
  17. A Cyclic Peptide-Based Radiotheranostic Agent for Urokinase-Type Plasminogen Activator in Tumors.
  1. ACS Med Chem Lett. 2025 Mar 13. 16(3): 363-365
    Novel Cyclic Peptides Inhibiting Tumor Necrosis Factor Receptor 1 Activity.
    Qi-Long Hu, Steven H Liang.
      This patent application pertains to macrocyclic peptides, generally represented by Formula I. These compounds exhibit selective binding to tumor necrosis factor receptor 1 (TNFR1) and hold the potential for mitigating the progression of diseases or disorders associated with TNFα/TNFR1 signaling, including autoimmune and inflammatory conditions.
    DOI:  https://doi.org/10.1021/acsmedchemlett.5c00011
  2. Adv Sci (Weinh). 2025 Mar 17. e2416963
    An Intracellular Peptide Library Screening Platform Identifies Irreversible Covalent Transcription Factor Inhibitors.
    Andrew Brennan, Scott Lovell, Keith W Vance, Jody M Mason.
      The development of an intracellular peptide library screening platform is described to identify covalent transcription factor (TF) antagonists. The Transcription Block Survival (TBS) assay and subsequent hit refinement previously produced potent but reversible antagonists of the oncogenic TF cJun. TBS moves beyond a target binding readout to ensure loss of TF function by blocking TF-DNA binding. Here, the TBS methodology is significantly expanded to identify covalent and highly selective inhibitors. A 131,072-member library is probed containing a Cys option at nine positions within a non-reducing cell line. This identified a single Cys residue with the appropriate geometry for disulphide bond formation with cJun C269 in its DNA binding domain. The selection of a unique Cys in the antagonist indicates both target shutdown and concomitant disulphide formation in a single step, resulting in increased potency. Substituting Cys with an electrophile generates an irreversible yet highly selective covalent cJun inhibitor capable of penetrating human melanoma cells in culture and depleting oncogenic cJun levels to inhibit cell viability, with enhanced efficacy compared to a previous cJun-targeting peptide. This enhanced covalent-TBS screening pipeline provides a robust approach to profile target protein surfaces for ligandable cysteines, producing covalent and selective antagonists with appropriately positioned warheads.
    Keywords:  activator protein‐1; cJun; covalent inhibitor; peptide antagonist; protein–protein interactions; transcription factor
    DOI:  https://doi.org/10.1002/advs.202416963
  3. J Labelled Comp Radiopharm. 2025 Mar;68(3): e4143
    A Novel 68Ga-Labeled 2-Azabicyclo[3.1.0]Hexane-3-Carbonitrile-Based Fibroblast Activation Protein-Targeted Tracer for Cancer Imaging With Positron Emission Tomography.
    Chao-Cheng Chen, Lei Wang, Antonio A W L Wong, Wing Sum Lau, Pauline Ng, Helen Merkens, François Bénard, Kuo-Shyan Lin.
      Most of the reported small molecule-based fibroblast activation protein (FAP)-targeted radioligands are derived from UAMC1110 and contain a 4-difluoro-2-cyanopyrrolidine moiety. In this study, we investigated the effect of replacing the 4-difluoro-2-cyanopyrrolidine moiety of [68Ga]Ga-FAPI-04 with 2-azabicyclo[3.1.0]hexane-3-carbonitrile on the in vitro/vivo FAP-targeting capability. The newly derived 68Ga-labeled FAP-targeted tracer, [68Ga]Ga-JC02076, was obtained in 43.5 ± 10.4% decay-corrected radiochemical yield within 33.5 ± 5.8 min (n = 4). The radiochemical purity and molar activity were 97.2 ± 3.4% and 411.6 ± 232.5 GBq/μmol, respectively. Ga-JC02076 showed good binding affinity for FAP (IC50 = 29.7 ± 3.5 nM). Most importantly, [68Ga]Ga-JC02076 enabled clear visualization of HEK293T:hFAP tumor xenografts in PET images and had good tumor uptake (7.17 ± 2.19 %ID/g) and excellent tumor-to-bone (17.3 ± 6.99) and tumor-to-muscle (32.3 ± 12.5) uptake ratios at 1 h post-injection. Our data suggest that N-(4-quinolinoyl)-Gly-(2-azabicyclo[3.1.0]hexane-3-carbonitrile) is a promising pharmacophore for the design of FAP-targeted tracers.
    Keywords:  azabicyclohexane; fibroblast activation protein inhibitor; gallium‐68; positron emission tomography
    DOI:  https://doi.org/10.1002/jlcr.4143
  4. Eur J Med Chem. 2025 Feb 24. pii: S0223-5234(25)00210-7. [Epub ahead of print]290 117445
    Design, synthesis and evaluation of lysine- and leucine-rich hydrocarbon-stapled peptides as antibacterial agents.
    Małgorzata Lobka, Izabela Siekierska, Piotr Chyży, Michał Burmistrz, Julia Macyszyn, Renata Grzela, Monika Wojciechowska, Joanna Trylska.
      To address the challenge of antimicrobial resistance, we investigated new antibacterial peptides based on lysine- and leucine-rich sequences. We stabilised their membrane-active secondary structures by applying hydrocarbon stapling at sequence positions i and i+4. Stapling improved peptide structural stability in both aqueous and lipid environments, regardless of the staple position. It also enhanced antibacterial efficiency against both gram-negative and gram-positive bacteria, including antibiotic-resistant strains, with minimum inhibitory concentrations (MICs) of 2-4 μM (2.5-5.5 μg/mL). The stapled peptides showed increased resistance to enzymatic degradation, particularly with staples incorporated near the N-terminus, and were not haemolytic or cytotoxic at their MICs. Molecular dynamics simulations revealed how stapling aids in (i) stabilising the membrane-active secondary structure of amphipathic peptides and (ii) accelerating their membrane insertion. Our results provide insight into peptide design for antimicrobial use. We show that hydrocarbon stapling of lysine- and leucine-rich short sequences may offer a pathway towards more stable and effective antibacterial agents.
    Keywords:  Antibacterial peptides; Antimicrobial resistance; Cell-penetrating peptides; Hydrocarbon stapling; Peptide-membrane interactions
    DOI:  https://doi.org/10.1016/j.ejmech.2025.117445
  5. Chembiochem. 2025 Mar 14. e202500041
    Peptide Stapling Using Sonogashira Coupling.
    Devki Nandan, Susanta Kumar Behera, Ramesh Ramapanicker.
      An efficient method for the stapling of peptides by linking residues at the i and i+4 or i and i+7 positions through Sonagashira coupling is reported. The alkyne and aryl iodide functionality required are introduced by modifying tyrosine residues to 4-iodophenylalanine (PhI) and 4-propargyloxyphenylalanine (TyP) residues. Comparing the conformations of a stapled peptide with the corresponding linear peptide using CD spectroscopy reveals a more helical structure for the stapled peptide.
    Keywords:  CD spectroscopy; Sonogashira coupling; peptides; stapled peptides; α-helix
    DOI:  https://doi.org/10.1002/cbic.202500041
  6. Sci Adv. 2025 Mar 21. 11(12): eadr1018
    Affinity selection-mass spectrometry with linearizable macrocyclic peptide libraries.
    Michael A Lee, Joseph S Brown, Charlotte E Farquhar, Andrei Loas, Bradley L Pentelute.
      Despite their potential, the preparation of large synthetic macrocyclic libraries for ligand discovery and development has been limited. Here, we produce 100-million-membered macrocyclic libraries containing natural and nonnatural amino acids. Near-quantitative intramolecular disulfide formation is facilitated by rapid oxidation with iodine in solution. After use in affinity selection, treatment with dithiothreitol enables near-quantitative reduction, rendering linear peptide analogs for standard tandem mass spectrometry. We use these libraries to discover macrocyclic binders to cadherin-2 and anti-hemagglutinin antibody clone 12ca5. Structure-activity relationship studies of an initial cadherin-binding peptide [CBP; apparent dissociation constant (Kd) = 53 nanomolar] reveal residues responsible for driving affinity (hotspots) and mutation-tolerant residues (coldspots). Two original macrocyclic libraries are prepared in which these hotspots and coldspots are derivatized with nonnatural amino acids. Following discovery and validation, high-affinity ligands are discovered from the coldspot library, with NCBP-4 demonstrating improved affinity (Kd = 29 nanomolar). Overall, we expect that this work will improve the use of macrocyclic libraries in therapeutic peptide development.
    DOI:  https://doi.org/10.1126/sciadv.adr1018
  7. Chem Asian J. 2025 Mar 15. e202500035
    N-Substituted Aza-Glycine Promotes C8 CO···HN Hydrogen Bonding: A Novel Motif to Design Constrained Peptidomimetic.
    Bani Kanta Sarma, Anshulata Anshulata, Amar Ghosh.
      Peptidomimetic modifications enhance their rigidity, cell permeability, and proteolytic stability of peptides, presenting significant promise for drug development. One such modification involves the isosteric replacement of the peptide backbone CαH with a nitrogen (N) atom, resulting in azapeptides. In azapeptides, there are two backbone N atoms within a single residue, with the possibility of substituting either one or both simultaneously. Previous studies have effectively mimicked the side chain substitution patterns in peptides by focusing on substituents on the nitrogen at the Cα position of azapeptides. In this study, explored the unconventional substitution at the N-terminus nitrogen by using N-substituted aza-glycine (azGly). We investigated peptide-azapeptide dimers featuring N-acetyl-proline at the N-terminus of an N-methyl azGly residue. These hybrid peptides produced turn structures stabilized by an unusual C8 CO∙∙∙HN hydrogen bond, stabilizing the proline amide in its trans conformation. Computational studies confirmed the stabilizing effect of this C8 hydrogen bond, which was further validated by NMR and CD spectroscopic studies. Overall, we provide a novel strategy for introducing non-natural C8 hydrogen bond into peptide backbone via the incorporation of N-substituted azGly, which could be leveraged to design of more rigid and stable peptidomimetics, with potential applications in drug development.
    Keywords:  Hydrogen bond; N-substitution; azapeptide; cis-trans isomerization; proline
    DOI:  https://doi.org/10.1002/asia.202500035
  8. ACS Omega. 2025 Mar 11. 10(9): 9728-9740
    Cyclization of Two Antimicrobial Peptides Improves Their Activity.
    Saheli Mitra, Mei-Tung Chen, Francisca Stedman, Jedidiah Hernandez, Grace Kumble, Xi Kang, Churan Zhang, Grace Tang, Iris Reed, Ian Q Daugherty, Wanqing Liu, Kevin Raphael Klucznik, Jeremy L Ocloo, Alexander Anzhi Li, Jessie Klousnitzer, Frank Heinrich, Berthony Deslouches, Stephanie Tristram-Nagle.
      One promising strategy to combat worldwide antimicrobial resistance involves using cyclic peptides as antibacterial agents. Cyclization of peptides can confer several advantages, including enhanced stability to proteolysis, decreased toxicity and increased bactericidal efficacy. This paper examines two cyclic peptides CE-03 (12 AAs) and CE-05 (16 AAs) and evaluates their effectiveness in combating bacterial infections, their stability and toxicity. We compare them to their linear versions. Circular dichroism (CD) reveals that CE-03 and CE-05 both adopt random coil and β-sheet structures in lipid model membranes (LMMs) mimicking G(-) and G(+) bacteria, where they are both bactericidal. Using X-ray diffuse scattering (XDS), their effects on lipid model membranes show a deep penetration of both peptides into eukaryotic LMMs where they are nontoxic, while a headgroup location in bacterial LMMs correlates with bacterial killing. Neutron reflectometry (NR) confirms the AMP locations determined using XDS. Further, solution small-angle X-ray scattering demonstrates that both peptides induce vesicle fusion in bacterial LMMs without affecting eukaryotic LMMs. Proteolytic degradation studies show that both CE-05 and CE-03 do not lose activity when incubated with the elastase enzyme, while the helical E2-35 AMP becomes inactive upon proteolysis.
    DOI:  https://doi.org/10.1021/acsomega.4c11466
  9. RSC Adv. 2025 Mar 17. 15(11): 8189-8194
    Comparison of the effects of perfluoroalkyl and alkyl groups on cellular uptake in short peptides.
    Koji Kadota, Ai Kohata, Shinsuke Sando, Jumpei Morimoto, Kohsuke Aikawa, Takashi Okazoe.
      The differences in the effects of perfluoroalkyl (RF) and alkyl (RH) groups on the cellular uptake of short peptides were evaluated. A facile synthetic method was established to produce Fmoc-protected amino acids bearing RF and RH groups on their side chains. The synthesized Fmoc-protected amino acids were successfully incorporated into peptides using solid-phase peptide synthesis. Peptides with an RF group exhibited higher cellular uptake efficiency compared to peptides with an RH group of the same side-chain length. Intriguingly, the cytotoxicity of the AF647-RF-tripeptide (RF = C8F17) was lower than that of the AF647-RH-tripeptide (RH = C12H25), despite similar cellular uptake efficiencies. An evaluation of the binding affinity of the peptides to liposome membranes suggested that the higher lipophobicity of the RF group, compared to the RH group, contributed to the lower cytotoxicity observed in the peptide with the RF group. These findings indicate that the introduction of an RF group into peptides has considerable potential for developing drug-delivery carriers with enhanced uptake efficiency and low cytotoxicity.
    DOI:  https://doi.org/10.1039/d5ra00304k
  10. Chem Sci. 2025 Mar 12.
    Affinity-based protein profiling of MDM2 inhibitor Navtemadlin.
    Amrita Date, Archie Wall, Peiyu Zhang, Jack W Houghton, Jianan Lu, Adam M Thomas, Tristan Kovačič, Andrew J Wilson, Edward W Tate, Anna Barnard.
      Navtemadlin is a potent inhibitor of the p53-MDM2 protein-protein interaction, which plays a critical role in the proliferation of p53-wildtype tumours. Whilst Navtemadlin has progressed to multiple Phase III clinical trials in oncology, little has been disclosed regarding its selectivity for MDM2 in cells. Here, we report the synthesis and validation of photoactivatable clickable probes of Navtemadlin, and their application to de novo target discovery for Navtemadlin through affinity-based protein profiling. MDM2 was robustly identified as the main target, across two cell lines, using two distinct probe designs. While off-targets were identified, these were not consistent across cell lines and probe designs, consistent with a high degree of selectivity for the target protein. Whole proteome profiling experiments across different time points confirmed p53-mediated phenotypic activity and revealed novel expression patterns for key proteins in the p53 pathway.
    DOI:  https://doi.org/10.1039/d5sc00120j
  11. Biochim Biophys Acta Rev Cancer. 2025 Mar 15. pii: S0304-419X(25)00042-3. [Epub ahead of print] 189300
    Exosomes: Traversing the blood-brain barrier and their therapeutic potential in brain cancer.
    Xiaopei Zhang, Nichole Artz, Dennis A Steindler, Shawn Hingtgen, Andrew Benson Satterlee.
      The blood-brain barrier (BBB) presents a major challenge for the effective delivery of therapeutic agents to the brain tumor cells from the peripheral blood circulation, making the treatment of central nervous system (CNS)-related cancers more difficult and resistant to both standard treatments and emerging therapies. Exosomes, which serve as messengers for intercellular communication throughout the body, have the ability to naturally penetrate the BBB. Recently, exosomes have been increasingly explored as a non-invasive approach for delivering therapeutic agents to the CNS. With their low immunogenicity, ease of modification, excellent cargo protection, and inherent ability to cross the BBB, exosomes hold great promise for revolutionizing targeted therapy for CNS-related diseases, including brain cancer. In this review, we highlight the latest discoveries and insights into the mechanisms exosomes use to penetrate the BBB, as well as their emerging roles in transporting therapeutic compounds for the treatment of brain cancer and other neurological disorders.
    Keywords:  Blood-brain barrier; Brain cancer; Brain targeting; Drug loading; Exosomes
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189300
  12. Chem Rec. 2025 Mar 21. e202500002
    The Ugi Multicomponent Reaction for the One-Step Construction of Macrocycles.
    Yi-Ming Chen, Xue Li, Zhi-Gang Xu.
      The exploration of macrocycles began in the 20th century, coinciding with the progressive advancement of synthetic chemistry methodologies. From numerous synthetic strategies, the Ugi reaction stands out as an efficacious four-component reaction (4-CR). The Ugi reaction is particularly distinguished by its robust functional group tolerance, enabling the creation of macrocycles that are both diverse and complex in a singular synthetic step. This review collates contemporary examples of synthetic macrocycles, all of which have been crafted using the Ugi reaction to construct these macrocyclic frameworks. The employment of various bifunctional reagents (with the same or different groups), has introduced a plethora of cyclization tactics, resulting in the synthesis of a multitude of macrocyclic or cage molecules. In order to offer invaluable insights into the construction of macrocycles, the use of distinct colors for the various reactants in the Ugi reaction has made the entire macrocyclic construction process transparently visible, thereby enhancing readers' understanding and sparking their interest.
    Keywords:  Ugi reaction; cage peptide; macrocycles; macrocyclic peptides; multicomponent reaction (MCR)
    DOI:  https://doi.org/10.1002/tcr.202500002
  13. Nanoscale. 2025 Mar 19.
    Self-assemblies of cell-penetrating peptides and ferrocifens: design and biological evaluation of an innovative platform for lung cancer treatment.
    Léna Guyon, Abdallah Ladaycia, Agnese Bosio, Laurent Lemaire, Florence Franconi, Bénédicte Lelièvre, Nolwenn Lautram, Pascal Pigeon, Gérard Jaouen, Catherine Passirani, Elise Lepeltier.
      Chemotherapy, currently used for lung cancer treatment, often consists in a combination of drugs with a moderate efficacy and severe side effects. A major drawback of the classical inorganic drugs used is their hydrophobicity, leading to a very low blood availability and weak efficacy. To overcome this constraint, a nanoplatform was set up in order to vectorize a ferrocifen drug, an organometallic tamoxifen derivative known for its really potent in vitro activity, but as well for its poor water solubility. Two different ferrocifens were tested: P54 and P819. The covalent conjugation of a cell-penetrating peptide (CPP) to the ferrocifen was performed, leading to an amphiphilic prodrug, potentially able to self-assemble. The CPPs used in this study are polyarginines and RLW. Moreover, in order to bring stealth and mucopenetration properties, polyethylene glycol (PEG) was incorporated into the nanostructure. The co-nanoprecipitation of CPP-ferrocifen and PEG-ferrocifen was investigated to achieve self-assemblies. A comparison of the biological activities of different suspensions was performed in vitro on a healthy cell line and on two different lung cancer cell lines. The biological activity of P54 was increased by a factor of 9 with the Arg9-P54 suspension by increasing the cell internalization. Moreover, the P54-based-self-assemblies were chosen to test their in vivo activity on mice bearing lung tumors. The results showed that the intratracheal nebulization of Arg9-P54/PEG-P54 or Arg9-P54 suspensions slowed up significantly the evolution of lung cancer in mice: the suspension with PEG brought an additional comfort to the animal during the administration.
    DOI:  https://doi.org/10.1039/d5nr00643k
  14. ACS Med Chem Lett. 2025 Mar 13. 16(3): 388-396
    Peripherally Restricted Fused Heterocyclic Peptidomimetic Multifunctional Opioid Agonists as Novel, Potent Analgesics.
    Haylee R Hammond, Prakash Chaudhari, Ashley Bunnell, Khadija Nefzi, Chongguang Chen, Pingwei Zhao, Shainnel O Eans, Sabrina R Masood, Colette T Dooley, Lee-Yuan Liu-Chen, Jay P McLaughlin, Adel Nefzi.
      Heterocyclic peptidomimetics are constrained compounds that mimic the biological efficacy of peptides while offering increased stability. We have previously generated a diazaheterocyclic peripherally selective, mixed-opioid agonist peptidomimetic that produced synergistic antinociception with decreased side effects. Working from two earlier templates, we report here the synthesis of 15 new diazaheterocyclic analogues. In vitro screening with radioligand competition binding assays and [35S]GTPγS assays demonstrated variable affinity for and activity at μ (MOR), δ (DOR), and κ (KOR) opioid receptors across the series, with three (2663-48, 2638-28 and 2638-33) displaying good affinity for DOR and/or KOR. All three compounds produced dose-dependent, opioid-receptor mediated antinociception in the mouse 55 °C warm-water tail-withdrawal and acetic-acid writhing assay, although a ratio of ED50 values in these assays suggested poor BBB penetration by 2638-33; results confirmed by testing with naloxone-methiodide. The data suggest these diazaheterocyclic mixed-activity, peripherally restricted opioid receptor agonists may hold potential as new, safer analgesics.
    DOI:  https://doi.org/10.1021/acsmedchemlett.4c00333
  15. Eur J Med Chem. 2025 Mar 14. pii: S0223-5234(25)00278-8. [Epub ahead of print]290 117513
    Synthesis of piperazine-based fluorinated fibroblast activation protein inhibitors for the development of a novel 18F-labeled PET imaging probe.
    Ricardo Köchel, Stefan Wagner, Katrin Schwegmann, Michael Schäfers, Hans-Jörg Breyholz, Bernhard Wünsch.
      Radiolabeled probes addressing the fibroblast activation protein (FAP) expressed among others by cancer associated fibroblasts in the microenvironment of tumors emerged as promising drugs for diagnostic imaging and therapy of tumors. 68Ga-chelator-based FAP inhibitors are clinically used for the diagnosis of various tumor types. To enhance the imaging quality and improve the applicability, we started to develop covalently 18F-labeled PET tracers for imaging of FAP in various diseases. For this purpose, four fluorinated quinolinecarboxamides 4a-d were synthesized and biologically evaluated. The seven-step synthesis of 4a comprised a Pd-catalyzed Buchwald-Hartwig reaction of bromoquinoline 6 and a Cu-catalyzed 1,3-dipolar cycloaddition of alkyne 12 with 1-azido-2-fluoroethane (Click reaction) as key steps. The fluorinated quinolinecarboxamides 4a-d showed low nanomolar inhibitory activity on FAP and high selectivity against related enzymes. Due to its low lipophilicity (logD7.4 = 0.08) and high metabolic stability (78 % intact after incubation with murine liver microsomes for 90 min), fluoroethyltriazole 4a (IC50 = 1.7 nM) was selected for radiosynthesis. The two-step radiosynthesis with [18F]-1-azido-2-fluoroethane provided the PET tracer [18F]4a in acceptable radiochemical yields (10.8 %) and high radiochemical purities (>97.0 %) within a total synthesis time of 156 min. The molar activities were 0.1-5.8 GBq/μmol. In vitro [18F]4a was stable in human and mouse serum over 90 min. In the biodistribution studies in mice [18F]4a showed fast renal and hepatobiliary elimination. In a mouse xenograft model with a tumor expressing FAP only very low accumulation in the tumor tissue was observed. This unexpected result was confirmed by the relative low uptake of [18F]4a by FAP expressing HT1080 cells.
    Keywords:  Cu-catalyzed azide-alkyne cycloaddition (click chemistry); Fibroblast activation protein (FAP); Fluorinated PET tracers; In vivo tumor imaging; Lipophilicity; Pharmacokinetics; Positron emission tomography (PET); Radiochemistry; Structure activity relationships
    DOI:  https://doi.org/10.1016/j.ejmech.2025.117513
  16. Curr Opin Chem Biol. 2025 Mar 20. pii: S1367-5931(25)00018-3. [Epub ahead of print]86 102586
    Recent advances in de novo designed metallopeptides as tailored enzyme mimics.
    Salvatore La Gatta, Vincent L Pecoraro.
      Advances in de novo design of metallopeptides have paved the way for customized metalloenzyme mimics with impressive catalytic capabilities. Over the last few years, incorporation of transition metals into simplified peptide scaffolds has allowed for catalytic efficiencies similar to or greater than those found in natural metalloenzymes. Artificial de novo peptide scaffolds highlight how precise modifications to metal coordination environments can improve scaffold stability and catalytic efficiency for a wide range of applications towards redox, non redox, synthetic, and energy conversion chemistry. These insights deepen our understanding of enzyme evolution and set a solid foundation for new directions in biocatalysis.
    DOI:  https://doi.org/10.1016/j.cbpa.2025.102586
  17. Chemistry. 2025 Mar 18. e202500479
    A Cyclic Peptide-Based Radiotheranostic Agent for Urokinase-Type Plasminogen Activator in Tumors.
    Kuan Hu, Xingkai Wang, Dong Dai, Jieting Shen, Siqi Zhang, Takayuki Ohkubo, Lin Xie, Yiding Zhang, Guoqing Li, Can Liu, Hao Tian, Yingzi Zhang, Ming-Rong Zhang, Rui Wang.
      The plasminogen activator system is critically involved in tumor progression regulation. Aberrant activation of urokinase-type plasminogen activator (uPA) induces proteolytic degradation of cellular membranes and the extracellular matrix, thereby promoting tumor invasion and metastasis. Consequently, uPA has emerged as a promising diagnostic and therapeutic target. Herein, we designed and evaluated three cyclic peptide-based radioligands ([⁶⁴Cu]CAP-1, [⁶⁴Cu]CAP-2, and [⁶⁴Cu]CAP-3) as potential PET tracers for uPA visualization in murine tumor models, assessing their binding ability, specificity, and pharmacokinetic profiles. Among them, [⁶⁴Cu]CAP-1, featuring a native disulfide bond, emerged as the optimal candidate. This radioligand demonstrated superior tumor uptake and reduced hepatic accumulation compared to the clinically advanced uPAR-targeted tracer [⁶⁴Cu]DOTA-AE105, currently in phase 2 trials. A single administration of [⁶⁴Cu]CAP-1 (2 mCi/mouse) significantly suppressed tumor growth and prolonged survival in murine models. These findings position [⁶⁴Cu]CAP-1 as a potent radiotheranostic agent for uPA-overexpressing tumors, offering a novel strategy for precision targeting of the uPA/uPAR axis.
    Keywords:  urokinase-type plasminogen activator * cyclized peptide * PET imaging * theranostic * radiopharmaceuticals
    DOI:  https://doi.org/10.1002/chem.202500479
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