bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2024‒02‒04
sixteen papers selected by
Henry Lamb, Queensland University of Technology
  1. PractiCPP: a deep learning approach tailored for extremely imbalanced datasets in Cell-Penetrating peptide prediction.
  2. Structure prediction of linear and cyclic peptides using CABS-flex.
  3. De novo designed aliphatic and aromatic peptides assemble into amyloid-like cytotoxic supramolecular nanofibrils.
  4. E3MPH16: An efficient endosomolytic peptide for intracellular protein delivery.
  5. Biomacromolecule-tagged nanoscale constructs for crossing the blood-brain barrier.
  6. Fundamental Uses of Peptides as a New Model in Both Treatment and Diagnosis.
  7. Use of the MicroSiM (µSiM) Barrier Tissue Platform for Modeling the Blood-Brain Barrier.
  8. PET Imaging of Peptide Probe Al[18F]F-NOTA-PCP1 for Monitoring the Engagement of PD-L1 Antibodies in Tumors.
  9. An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021).
  10. Navigating the brain: the role of exosomal shuttles in precision therapeutics.
  11. Molecular Selectivity in the Binding of Alkali Metals, Alkaline Earth Metals, First-Row Transition Metals, and Lanthanides with Cyclic Depsipeptides.
  12. Synthesis and Structural Characterization of Macrocyclic α-ABpeptoids and Their DNA-Encoded Library.
  13. Development and validation of a combined cuproptosis and immunogenic cell death prognostic model for diffuse large B-cell lymphoma.
  14. Lactate utilization enables metabolic escape to confer resistance to BET inhibition in acute myeloid leukemia.
  15. New Oral PCSK9 Inhibitor: "MK-0616".
  16. Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography.
  1. Bioinformatics. 2024 Feb 01. pii: btae058. [Epub ahead of print]
    PractiCPP: a deep learning approach tailored for extremely imbalanced datasets in Cell-Penetrating peptide prediction.
    Kexin Shi, Yuanpeng Xiong, Yu Wang, Yifan Deng, Wenjia Wang, Bingyi Jing, Xin Gao.
      MOTIVATION: Effective drug delivery systems are paramount in enhancing pharmaceutical outcomes, particularly through the use of cell-penetrating peptides (CPPs). These peptides are gaining prominence due to their ability to penetrate eukaryotic cells efficiently without inflicting significant damage to the cellular membrane, thereby ensuring optimal drug delivery. However, the identification and characterization of CPPs remain a challenge due to the laborious and time-consuming nature of conventional methods, despite advances in proteomics. Current computational models, however, are predominantly tailored for balanced datasets, an approach that falls short in real-world applications characterized by a scarcity of known positive CPP instances.RESULTS: To navigate this shortfall, we introduce PractiCPP, a novel deep-learning framework tailored for CPP prediction in highly imbalanced data scenarios. Uniquely designed with the integration of hard negative sampling and a sophisticated feature extraction and prediction module, PractiCPP facilitates an intricate understanding and learning from imbalanced data. Our extensive computational validations highlight PractiCPP's exceptional ability to outperform existing state-of-the-art methods, demonstrating remarkable accuracy, even in datasets with an extreme positive-to-negative ratio of 1:1000. Furthermore, through methodical embedding visualizations, we have established that models trained on balanced datasets are not conducive to practical, large-scale CPP identification, as they do not accurately reflect real-world complexities. In summary, PractiCPP potentially offers new perspectives in CPP prediction methodologies. Its design and validation, informed by real-world dataset constraints, suggest its utility as a valuable tool in supporting the acceleration of drug delivery advancements.
    AVAILABILITY AND IMPLEMENTATION: The source code of PractiCPP is available on Figshare at https://doi.org/10.6084/m9.figshare.25053878.v1.
    SUPPLEMENTARY INFORMATION: Supplementary data is available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btae058
  2. Brief Bioinform. 2024 Jan 22. pii: bbae003. [Epub ahead of print]25(2):
    Structure prediction of linear and cyclic peptides using CABS-flex.
    Aleksandra Badaczewska-Dawid, Karol Wróblewski, Mateusz Kurcinski, Sebastian Kmiecik.
      The structural modeling of peptides can be a useful aid in the discovery of new drugs and a deeper understanding of the molecular mechanisms of life. Here we present a novel multiscale protocol for the structure prediction of linear and cyclic peptides. The protocol combines two main stages: coarse-grained simulations using the CABS-flex standalone package and an all-atom reconstruction-optimization process using the Modeller program. We evaluated the protocol on a set of linear peptides and two sets of cyclic peptides, with cyclization through the backbone and disulfide bonds. A comparison with other state-of-the-art tools (APPTEST, PEP-FOLD, ESMFold and AlphaFold implementation in ColabFold) shows that for most cases, AlphaFold offers the highest resolution. However, CABS-flex is competitive, particularly when it comes to short linear peptides. As demonstrated, the protocol performance can be further improved by combination with the residue-residue contact prediction method or more efficient scoring. The protocol is included in the CABS-flex standalone package along with online documentation to aid users in predicting the structure of peptides and mini-proteins.
    Keywords:  cyclic peptides; drug design; multiscale modeling; peptide; structural modeling
    DOI:  https://doi.org/10.1093/bib/bbae003
  3. RSC Adv. 2024 Jan 31. 14(7): 4382-4388
    De novo designed aliphatic and aromatic peptides assemble into amyloid-like cytotoxic supramolecular nanofibrils.
    Satyabrata Samui, Soumi Biswas, Shubhanwita Basak, Shreya Ghosh, K Muniyappa, Jishu Naskar.
      Peptides are very interesting biomolecules that upon self-association form a variety of thermodynamically stable supramolecular structures of nanometric dimension e.g. nanotubes, nanorods, nanovesicles, nanofibrils, nanowires and many others. Herein, we report six peptide molecules having a general chemical structure, H-Gaba-X-X-OH (Gaba: γ-aminobutyric acid, X: amino acid). Out of these six peptides, three are aromatic and the others are aliphatic. Atomic force microscopic (AFM) studies reveal that except peptide 6 (H-Gaba-Trp-Trp-OH), all the reported peptides adopt nanofibrillar morphology upon aggregation in aqueous medium. These supramolecular assemblies can recognize amyloid-specific molecular probe congo red (CR) and thioflavine t (ThT) and exhibit all the characteristic properties of amyloids. The MTT cell viability assay reveals that the toxicity of both aliphatic and aromatic peptides increases with increasing concentration of the peptides to both cancer (HeLa) and non-cancer (HEK 293) cells. Of note, the aromatic peptides show a slightly higher cytotoxic effect compared to the aliphatic peptides. Overall, the studies highlight the self-assembling nature of the de novo designed aliphatic and aromatic peptides and pave the way towards elucidating the intricacies of pathogenic amyloid assemblies.
    DOI:  https://doi.org/10.1039/d3ra07869h
  4. J Control Release. 2024 Jan 30. pii: S0168-3659(24)00082-8. [Epub ahead of print]
    E3MPH16: An efficient endosomolytic peptide for intracellular protein delivery.
    Yoshimasa Kawaguchi, Yuki Kawamura, Hisaaki Hirose, Megumi Kiyokawa, Momo Hirate, Tsuyoshi Hirata, Yuriko Higuchi, Shiroh Futaki.
      To facilitate the introduction of proteins, such as antibodies, into cells, a variety of delivery peptides have been engineered. These peptides are typically highly cationic and somewhat hydrophobic, enabling cytosolic protein delivery at the cost of causing cell damage by rupturing membranes. This balance between delivery effectiveness and cytotoxicity presents obstacles for their real-world use. To tackle this problem, we designed a new endosome-disruptive cytosolic delivery peptide, E3MPH16, inspired by Mastoparan X (MP). E3MPH16 was engineered to incorporate three Glu (E3) and 16 His (H16) residues at the N- and C-termini of MP, respectively. The negative charges of E3 substantially mitigate the cell-surface damage induced by MP. The H16 segment is known to enhance cell-surface adsorption and endocytic uptake of the associated molecules. With these modifications, E3MPH16 was successfully trapped within endosomes. The acidification of endosomes is expected to protonate the side chains of E3 and H16, enabling E3MPH16 to rupture endosomal membranes. As a result, nearly 100% of cells achieved cytosolic delivery of a model biomacromolecule, Alexa Fluor 488-labeled dextran (10 kDa), via endosomal escape by co-incubation with E3MPH16. The delivery process also suggested the involvement of macropinocytosis and caveolae-mediated endocytosis. With the assistance of E3MPH16, Cre recombinase and anti-Ras-IgG delivered into HEK293 cells and HT1080 cells enabled gene recombination and inhibited cell proliferation, respectively. The potential for in vivo application of this intracellular delivery method was further validated by topically injecting the green fluorescent protein fused with a nuclear localization signal (NLS-GFP) along with E3MPH16 into Colon-26 tumor xenografts in mice.
    Keywords:  Attenuated amphiphilic lytic peptide; Cytosolic protein delivery; Endocytosis; Endosomal membrane disruption; Glutamic acid; Polyhistidine
    DOI:  https://doi.org/10.1016/j.jconrel.2024.01.067
  5. Nanoscale. 2024 Feb 02.
    Biomacromolecule-tagged nanoscale constructs for crossing the blood-brain barrier.
    Tyler L Odom, Hayden D LeBroc, Cassandra E Callmann.
      Access to the brain is restricted by the low permeability of the blood-brain barrier (BBB), greatly hampering modern drug delivery efforts. A promising approach to overcome this boundary is to utilize biomacromolecules (peptides, nucleic acids, carbohydrates) as targeting ligands on nanoscale delivery vehicles to shuttle cargo across the BBB. In this mini-review, we highlight the most recent approaches for crossing the BBB using synthetic nanoscale constructs decorated with members of these general classes of biomacromolecules to safely and selectively deliver therapeutic materials to the brain.
    DOI:  https://doi.org/10.1039/d3nr06154j
  6. Recent Pat Biotechnol. 2024 ;18(2): 110-127
    Fundamental Uses of Peptides as a New Model in Both Treatment and Diagnosis.
    Hend Okasha.
      An amino acid short chain is known as a peptide. Peptide bonds are the connections that hold the amino acids of a peptide together in a particular order. Characteristically, the shorter length of peptides helps to identify them from proteins. Different ways are used to classify peptides, including chain length, source of peptides, or their biological functions. The fact that peptides serve several purposes suggests that there is a foundation for improvement in peptide production and structure to enhance action. In addition, many patents on peptides for therapeutic and diagnostic approaches have been obtained. This review aims to give an overview of peptides used recently in treatment and diagnosis.
    Keywords:  Anticancer peptides; amino acid; antimicrobial peptides; diagnostic peptides; peptide bonds.; peptide synthesis
    DOI:  https://doi.org/10.2174/1872208317666230512143508
  7. J Vis Exp. 2024 Jan 12.
    Use of the MicroSiM (µSiM) Barrier Tissue Platform for Modeling the Blood-Brain Barrier.
    Molly C McCloskey, Pelin Kasap, Michelle Trempel, Louis P Widom, Julia Kuebel, Kaihua Chen, Thomas R Gaborski, Britta Engelhardt, James L McGrath.
      The microSiM (µSiM) is a membrane-based culture platform for modeling the blood-brain barrier (BBB). Unlike conventional membrane-based platforms, the µSiM provides experimentalists with new capabilities, including live cell imaging, unhindered paracrine signaling between 'blood' and 'brain' chambers, and the ability to directly image immunofluorescence without the need for the extraction/remounting of membranes. Here we demonstrate the basic use of the platform to establish monoculture (endothelial cells) and co-culture (endothelial cells and pericytes) models of the BBB using ultrathin nanoporous silicon-nitride membranes. We demonstrate compatibility with both primary cell cultures and human induced pluripotent stem cell (hiPSC) cultures. We provide methods for qualitative analysis of BBB models via immunofluorescence staining and demonstrate the use of the µSiM for the quantitative assessment of barrier function in a small molecule permeability assay. The methods provided should enable users to establish their barrier models on the platform, advancing the use of tissue chip technology for studying human tissues.
    DOI:  https://doi.org/10.3791/65258
  8. Mol Pharm. 2024 Jan 30.
    PET Imaging of Peptide Probe Al[18F]F-NOTA-PCP1 for Monitoring the Engagement of PD-L1 Antibodies in Tumors.
    Yang Zhang, Yong Wang, Yunhao Chen, Xingchen Ding, Shijie Wang, Wei Liu, Man Hu, Zhiguo Liu.
      Immune checkpoint inhibitors (ICIs) are a powerful treatment modality for various types of cancer. The effectiveness of ICIs is intimately connected to the binding status of antibodies to receptors. However, validated means to accurately evaluate target specificity and predict antibody efficacy in vivo are lacking. A novel peptide-based probe called Al[18F]F-NOTA-PCP1 was developed and validated for its specificity to PD-L1 in A549, U87MG, GL261, and GL261-iPDL1 cell lines, as well as in xenograft models. Then the probe was used in PET/CT scans to determine the binding status of PD-L1 antibodies (atezolizumab, avelumab, and durvalumab) in U87MG xenograft model mice. Moreover, Al[18F]F-NOTA-PCP1 was used to evaluate the impact of different treatment times and doses. Al[18F]F-NOTA-PCP1 PET/CT can be used to evaluate the interaction between PD-L1 and antibodies to determine the effectiveness of immunotherapy. By quantifying target engagement, the probe has the potential to predict the efficacy of immunotherapy and optimize the dose and treatment schedules for PD-L1 immunotherapy. This imaging agent could be a valuable tool in guiding personalized treatment strategies and improving cancer patient outcomes.
    Keywords:  PD-L1 antibody; PET/CT imaging; glioma; immunotherapy; peptide tracer
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.3c01151
  9. Anticancer Agents Med Chem. 2024 Jan 29.
    An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021).
    Vishakha S, Navneesh N, Balak Das Kurmi, Ghanshyam Das Gupta, Sant Kumar Verma, Ankit Jain, Preeti Patel.
      New drugs being established in the market every year produce specified structures for selective biological targeting. With medicinal insights into molecular recognition, these begot molecules open new rooms for designing potential new drug molecules. In this review, we report the compilation and analysis of a total of 56 drugs including 33 organic small molecules (Mobocertinib, Infigratinib, Sotorasib, Trilaciclib, Umbralisib, Tepotinib, Relugolix, Pralsetinib, Decitabine, Ripretinib, Selpercatinib, Capmatinib, Pemigatinib, Tucatinib, Selumetinib, Tazemetostat, Avapritinib, Zanubrutinib, Entrectinib, Pexidartinib, Darolutamide, Selinexor, Alpelisib, Erdafitinib, Gilteritinib, Larotrectinib, Glasdegib, Lorlatinib, Talazoparib, Dacomitinib, Duvelisib, Ivosidenib, Apalutamide), 6 metal complexes (Edotreotide Gallium Ga-68, fluoroestradiol F-18, Cu 64 dotatate, Gallium 68 PSMA-11, Piflufolastat F-18, 177Lu (lutetium)), 16 macromolecules as monoclonal antibody conjugates (Brentuximabvedotin, Amivantamab-vmjw, Loncastuximabtesirine, Dostarlimab, Margetuximab, Naxitamab, Belantamabmafodotin, Tafasitamab, Inebilizumab, SacituzumabGovitecan, Isatuximab, Trastuzumab, Enfortumabvedotin, Polatuzumab, Cemiplimab, Mogamulizumab) and 1 peptide enzyme (Erwiniachrysanthemi-derived asparaginase) approved by the U.S. FDA between 2018 to 2021. These drugs act as anticancer agents against various cancer types, especially non-small cell lung, lymphoma, breast, prostate, multiple myeloma, neuroendocrine tumor, cervical, bladder, cholangiocarcinoma, myeloid leukemia, gastrointestinal, neuroblastoma, thyroid, epithelioid and cutaneous squamous cell carcinoma. The review comprises the key structural features, approval times, target selectivity, mechanisms of action, therapeutic indication, formulations, and possible synthetic approaches of these approved drugs. These crucial details will benefit the scientific community for futuristic new developments in this arena.
    Keywords:  FDA-approved anticancer drugs; anticancer agents.; synthetic approaches; target selectivity
    DOI:  https://doi.org/10.2174/0118715206259585240105051941
  10. Front Neurol. 2023 ;14 1324216
    Navigating the brain: the role of exosomal shuttles in precision therapeutics.
    Shaheera Fatima, Ariba Qaiser, Saadia Andleeb, Asraf Hussain Hashmi, Sobia Manzoor.
      Brain diseases have become one of the leading roots of mortality and disability worldwide, contributing a significant part of the disease burden on healthcare systems. The blood-brain barrier (BBB) is a primary physical and biological obstacle that allows only small molecules to pass through it. Its selective permeability is a significant challenge in delivering therapeutics into the brain for treating brain dysfunction. It is estimated that only 2% of the new central nervous system (CNS) therapeutic compounds can cross the BBB and achieve their therapeutic targets. Scientists are exploring various approaches to develop effective cargo delivery vehicles to promote better therapeutics targeting the brain with minimal off-target side effects. Despite different synthetic carriers, one of the natural brain cargo delivery systems, "exosomes," are now employed to transport drugs through the BBB. Exosomes are naturally occurring small extracellular vesicles (EVs) with unique advantages as a therapeutic delivery system for treating brain disorders. They have beneficial innate aspects of biocompatibility, higher stability, ability to cross BBB, low cytotoxicity, low immunogenicity, homing potential, targeted delivery, and reducing off-site target effects. In this review, we will discuss the limitations of synthetic carriers and the utilization of naturally occurring exosomes as brain-targeted cargo delivery vehicles and highlight the methods for modifying exosome surfaces and drug loading into exosomes. We will also enlist neurodegenerative disorders targeted with genetically modified exosomes for their treatment.
    Keywords:  BBB; central nervous system (CNS); drug delivery; exosomes; therapeutic targets
    DOI:  https://doi.org/10.3389/fneur.2023.1324216
  11. J Phys Chem B. 2024 Jan 31.
    Molecular Selectivity in the Binding of Alkali Metals, Alkaline Earth Metals, First-Row Transition Metals, and Lanthanides with Cyclic Depsipeptides.
    Emmanuel Nkyaagye, Miranda N Limbach, Thanh D Do.
      Beauvericin (BEA) and enniatins (ENN) are cyclic hexadepsipeptide mycotoxins known for their ionophoric activities across cell membranes. While their ability to selectively bind alkali ions to form binary complexes has been studied, their interaction with multivalent metal ions to form higher-order complexes remains less explored. We report the unique characteristics of the 1:2, Mn+:BEA or ENN complexes with monovalent, divalent, and trivalent metal ions. A thorough IMS-MS analysis underscores the substantial interplay among ionic radii, coordination numbers, and their impact on conformational selection within higher-order complexes that is pertinent to ion transport. Transition metals offer insights into the effects of ion radii and ligand side chains on conformational selection, while lanthanide complexes enable a direct evaluation of coordination chemistry. An intriguing finding concerning the lanthanide complexes involves an unexpected C-H bond activation, wherein water ligands may catalyze the deprotonation of the cyclic peptides.
    DOI:  https://doi.org/10.1021/acs.jpcb.3c08385
  12. Org Lett. 2024 Jan 31.
    Synthesis and Structural Characterization of Macrocyclic α-ABpeptoids and Their DNA-Encoded Library.
    Soobin Lee, Hyunchul Kwon, Eun-Kyoung Jee, Jaelim Kim, Kang Ju Lee, Jungyeon Kim, Nakeun Ko, Eunsung Lee, Hyun-Suk Lim.
      The first synthesis of macrocyclic α-ABpeptoids with varying lengths is described. X-ray crystal structures reveal that cyclic trimer displays a chair-like conformation with a cct amide sequence and cyclic tetramer has a saddle-like structure with an uncommon cccc amide arrangement. The creation of a DNA-encoded combinatorial library of macrocyclic α-ABpeptoids is described.
    DOI:  https://doi.org/10.1021/acs.orglett.3c04387
  13. Aging (Albany NY). 2024 Jan 26. 15
    Development and validation of a combined cuproptosis and immunogenic cell death prognostic model for diffuse large B-cell lymphoma.
    Nana Wang, Shanshan Shi, Moran Li, Xiaoning Yu, Guangxin Ma.
      BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide with a high degree of heterogeneity. Cuproptosis and immunogenic cell death (ICD) have been considered to be vital for tumor progression. However, current understanding of cuproptosis and immunogenic cell death in DLBCL is still very limited. We aim to explore a prognostic model combining cuproptosis and immunogenic cell death in DLBCL.METHODS: Pearson's correlation analysis was utilized to acquire lncRNAs associated with cuproptosis and immunogenic cell death. Prognostic biomarker identification and model construction involved the use of univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox regression. We assessed the predictive capability of the risk model by conducting Kaplan-Meier analysis and time-dependent ROC analysis. The analysis and comparison of immune infiltration and drug sensitivity were conducted in this study. Moreover, RT-qPCR was employed to validate the expression of lncRNAs associated with cuproptosis and immunogenic cell death in DLBCL cell lines.
    RESULTS: We identified 4 prognosis-related lncRNAs (ANKRD10-IT1, HOXB-AS1, LINC00520 and LINC01165) that were correlated with cuproptosis and immunogenic cell death. The model was verified to have a good and independent predictive ability in the prognostic prediction of DLBCL patients. Moreover, significant difference was observed in immune infiltration and drug sensitivity between high- and low-risk groups.
    CONCLUSION: Our discoveries could enhance the comprehension of the role of cuproptosis and ICD in DLBCL, potentially offering novel viewpoints and knowledge for personalized and precise treatment of DLBCL individuals.
    Keywords:  DLBCL; cuproptosis; immunogenic cell death; lncRNA; prognostic model
    DOI:  https://doi.org/10.18632/aging.205399
  14. Cancer Res. 2024 Jan 29.
    Lactate utilization enables metabolic escape to confer resistance to BET inhibition in acute myeloid leukemia.
    Andrew J Monteith, Haley E Ramsey, Alexander J Silver, Donovan Brown, Dalton Greenwood, Brianna N Smith, Ashley D Wise, Juan Liu, Sarah D Olmstead, Jackson Watke, Maria P Arrate, Agnieszka E Gorska, Londa Fuller, Jason W Locasale, Matthew C Stubbs, Jeffrey C Rathmell, Michael R Savona.
      Impairing the BET-family co-activator BRD4 with small molecule inhibitors (BETi) showed encouraging pre-clinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy. Herein, we demonstrated that mitochondria-associated lactate dehydrogenase allows AML myeloblasts to utilize lactate as a metabolic bypass to fuel mitochondrial respiration and maintain cellular viability. Pharmacologically and genetically impairing lactate utilization rendered resistant myeloblasts susceptible to BET inhibition. Low-dose combinations of BETi and oxamate, a lactate dehydrogenase inhibitor, reduced in vivo expansion of BETi-resistant AML in cell line and patient-derived murine models. These results elucidate how AML myeloblasts metabolically adapt to BETi by consuming lactate and demonstrate that combining BETi with inhibitors of lactate utilization may be useful in AML treatment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0291
  15. Cardiol Rev. 2024 Jan 29.
    New Oral PCSK9 Inhibitor: "MK-0616".
    Zoya Siddiqui, William Frishman.
      MK-0616, a novel oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), represents a significant advancement in the treatment of hypercholesterolemia. Unlike current PCSK9 inhibitors, which are injectable monoclonal antibodies and siRNA molecules, MK-0616 offers a patient-friendly alternative. The development of MK-0616 involved innovative synthetic chemistry and in vitro mRNA display technology. This cutting-edge approach led to the creation of an orally administered peptide with the ability to cover a larger portion of PCSK9 compared to smaller, linear peptides. Phase 1 and 2b clinical trials have demonstrated MK-0616's safety, efficacy, and pharmacokinetics. These trials indicate the drug's dose-dependent systemic absorption and long half-life. Notably, MK-0616 has exhibited comparable low-density lipoprotein cholesterol-lowering effects to currently available PCSK9 inhibitors, all while maintaining good tolerability in diverse patient populations, including those concurrently on statin therapy. As MK-0616 advances to Phase 3 trials, its lipid-lowering potential for heterozygous familial hypercholesterolemia and its impact on reducing the time to adverse cardiac events will be evaluated in a broad and diverse population, including underrepresented groups. The results achieved so far are promising for individuals with hypercholesterolemia, as they offer a potential solution for effectively lowering low-density lipoprotein cholesterol in patients on statin therapy and mitigating the risk of cardiovascular events. Ongoing research and monitoring will be critical to establish its long-term safety and efficacy, but MK-0616 may emerge as a valuable addition to the array of lipid-lowering therapies available to patients.
    DOI:  https://doi.org/10.1097/CRD.0000000000000655
  16. EJNMMI Radiopharm Chem. 2024 Feb 02. 9(1): 8
    Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography.
    Lei Wang, Hsiou-Ting Kuo, Zhengxing Zhang, Chengcheng Zhang, Chao-Cheng Chen, Devon Chapple, Ryan Wilson, Nadine Colpo, François Bénard, Kuo-Shyan Lin.
      BACKGROUND: Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, internalization of agonists may lead to longer tumor retention and better treatment efficacy. In this study, we systematically investigated unnatural amino acid substitutions to improve in vivo stability and tumor uptake of a previously reported GRPR-targeted agonist tracer, [68Ga]Ga-TacBOMB2 (68Ga-DOTA-Pip-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Leu13-Thz14-NH2).RESULTS: Unnatural amino acid substitutions were conducted for Gln7, Trp8, Ala9, Val10, Gly11 and His12, either alone or in combination. Out of 25 unnatural amino acid substitutions, tert-Leu10 (Tle10) and NMe-His12 substitutions were identified to be preferable modifications especially in combination. Compared with the previously reported [68Ga]Ga-TacBOMB2, the Tle10 and NMe-His12 derived [68Ga]Ga-LW01110 showed retained agonist characteristics and improved GRPR binding affinity (Ki = 7.62 vs 1.39 nM), in vivo stability (12.7 vs 89.0% intact tracer in mouse plasma at 15 min post-injection) and tumor uptake (5.95 vs 16.6 %ID/g at 1 h post-injection).
    CONCLUSIONS: Unnatural amino acid substitution is an effective strategy to improve in vivo stability and tumor uptake of peptide-based radiopharmaceuticals. With excellent tumor uptake and tumor-to-background contrast, [68Ga]Ga-LW01110 is promising for detecting GRPR-expressing cancer lesions with PET. Since agonists can lead to internalization upon binding to receptors and foreseeable long tumor retention, our optimized GRPR-targeted sequence, [Tle10,NMe-His12,Thz14]Bombesin(7-14), is a promising template for use for the design of GRPR-targeted radiotherapeutic agents.
    Keywords:  Agonist; Gastrin-releasing peptide receptor; In vivo stability; Pancreas uptake; Positron emission tomography
    DOI:  https://doi.org/10.1186/s41181-024-00241-7
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