bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2024–01–28
twelve papers selected by
Henry Lamb, Queensland University of Technology
  1. Corrigendum: Cyclic Peptides for Drug Development.
  2. Cell-penetrating peptides for transmucosal delivery of proteins.
  3. Scanning mutagenesis identifies residues that improve the long-term stability and insecticidal activity of cyclotide kalata B1.
  4. MARS an improved de novo peptide candidate selection method for non-canonical antigen target discovery in cancer.
  5. Peptide-Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics.
  6. Multi_CycGT: A Deep Learning-Based Multimodal Model for Predicting the Membrane Permeability of Cyclic Peptides.
  7. An Improved In Vitro Blood-Brain Barrier Model for the Evaluation of Drug Permeability Using Transwell with Shear Stress.
  8. Involvement of Astrocytes in the Formation, Maintenance, and Function of the Blood-Brain Barrier.
  9. A Platform Approach to Cleavable Macrocycles for the Controlled Disassembly of Mechanically Caged Molecules.
  10. Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.
  11. Generation of a new therapeutic D-peptide that induces the differentiation of acute myeloid leukemia cells through A TLR-2 signaling pathway.
  12. Multiple medicinal chemistry strategies of targeting KRAS: State-of-the art and future directions.
  1. Angew Chem Int Ed Engl. 2024 Jan 22. e202319807
    Corrigendum: Cyclic Peptides for Drug Development.
      
    DOI:  https://doi.org/10.1002/anie.202319807
  2. J Control Release. 2024 Jan 23. pii: S0168-3659(24)00053-1. [Epub ahead of print]
    Cell-penetrating peptides for transmucosal delivery of proteins.
    Jiamin Wu, Sophie Roesger, Natalie Jones, Che-Ming J Hu, Shyh-Dar Li.
      Enabling non-invasive delivery of proteins across the mucosal barriers promises improved patient compliance and therapeutic efficacies. Cell-penetrating peptides (CPPs) are emerging as a promising and versatile tool to enhance protein and peptide permeation across various mucosal barriers. This review examines the structural and physicochemical attributes of the nasal, buccal, sublingual, and oral mucosa that hamper macromolecular delivery. Recent development of CPPs for overcoming those mucosal barriers for protein delivery is summarized and analyzed. Perspectives regarding current challenges and future research directions towards improving non-invasive transmucosal delivery of macromolecules for ultimate clinical translation are discussed.
    Keywords:  Buccal and sublingual; Cell-penetrating peptides (CPPs); Intranasal; Oral; Peptides; Proteins; Transmucosal delivery
    DOI:  https://doi.org/10.1016/j.jconrel.2024.01.038
  3. J Biol Chem. 2024 Jan 23. pii: S0021-9258(24)00058-9. [Epub ahead of print] 105682
    Scanning mutagenesis identifies residues that improve the long-term stability and insecticidal activity of cyclotide kalata B1.
    Yen-Hua Huang, Zhihao Jiang, Qingdan Du, Kuok Yap, Aurélien Bigot, Quentin Kaas, Conan K Wang, David J Craik.
      Cyclotides are plant-derived disulfide-rich cyclic peptides that have a natural function in plant defence and potential for use as agricultural pesticides. Due to their highly constrained topology, they are highly resistant to thermal, chemical or enzymatic degradation. However, the stability of cyclotides at alkaline pH for incubation times of longer than a few days is poorly studied, but important since these conditions could be encountered in the environment, during storage or field application as insecticides. In this study, kalata B1 (kB1), the prototypical cyclotide, was engineered to improve its long-term stability and retain its insecticidal activity via point mutations. We found that substituting either Asn29 or Gly1 to lysine or leucine increased the stability of kB1 by two-fold when incubated in an alkaline buffer (pH 9.0) for seven days, while retaining its insecticidal activity. In addition, when Gly1 was replaced with lysine or leucine, the mutants could be cyclised using an asparaginyl endopeptidase, in vitro with a yield of ∼90% within 5 min. These results demonstrate the potential to manufacture kB1 mutants with increased stability and insecticidal activity recombinantly or in planta. Overall, the discovery of mutants of kB1 that have enhanced stability could be useful in leading to longer term activity in the field as bioinsecticides.
    Keywords:  asparaginyl endopeptidase (AEP); cyclic peptide; cyclotide; insecticidal peptide; nuclear magnetic resonance (NMR); peptide chemical synthesis; surface plasmon resonance (SPR)
    DOI:  https://doi.org/10.1016/j.jbc.2024.105682
  4. Nat Commun. 2024 Jan 22. 15(1): 661
    MARS an improved de novo peptide candidate selection method for non-canonical antigen target discovery in cancer.
    Hanqing Liao, Carolina Barra, Zhicheng Zhou, Xu Peng, Isaac Woodhouse, Arun Tailor, Robert Parker, Alexia Carré, Persephone Borrow, Michael J Hogan, Wayne Paes, Laurence C Eisenlohr, Roberto Mallone, Morten Nielsen, Nicola Ternette.
      Understanding the nature and extent of non-canonical human leukocyte antigen (HLA) presentation in tumour cells is a priority for target antigen discovery for the development of next generation immunotherapies in cancer. We here employ a de novo mass spectrometric sequencing approach with a refined, MHC-centric analysis strategy to detect non-canonical MHC-associated peptides specific to cancer without any prior knowledge of the target sequence from genomic or RNA sequencing data. Our strategy integrates MHC binding rank, Average local confidence scores, and peptide Retention time prediction for improved de novo candidate Selection; culminating in the machine learning model MARS. We benchmark our model on a large synthetic peptide library dataset and reanalysis of a published dataset of high-quality non-canonical MHC-associated peptide identifications in human cancer. We achieve almost 2-fold improvement for high quality spectral assignments in comparison to de novo sequencing alone with an estimated accuracy of above 85.7% when integrated with a stepwise peptide sequence mapping strategy. Finally, we utilize MARS to detect and validate lncRNA-derived peptides in human cervical tumour resections, demonstrating its suitability to discover novel, immunogenic, non-canonical peptide sequences in primary tumour tissue.
    DOI:  https://doi.org/10.1038/s41467-023-44460-z
  5. J Med Chem. 2024 Jan 26.
    Peptide-Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics.
    Trevor T Dean, Juliet Jelú-Reyes, A'Lester C Allen, Terry W Moore.
      Building on recent advances in peptide science, medicinal chemists have developed a hybrid class of bioconjugates, called peptide-drug conjugates, that demonstrate improved efficacy compared to peptides and small molecules independently. In this Perspective, we discuss how the conjugation of synergistic peptides and small molecules can be used to overcome complex disease states and resistance mechanisms that have eluded contemporary therapies because of their multi-component activity. We highlight how peptide-drug conjugates display a multi-factor therapeutic mechanism similar to that of antibody-drug conjugates but also demonstrate improved therapeutic properties such as less-severe off-target effects and conjugation strategies with greater site-specificity. The many considerations that go into peptide-drug conjugate design and optimization, such as peptide/small-molecule pairing and chemo-selective chemistries, are discussed. We also examine several peptide-drug conjugate series that demonstrate notable activity toward complex disease states such as neurodegenerative disorders and inflammation, as well as viral and bacterial targets with established resistance mechanisms.
    DOI:  https://doi.org/10.1021/acs.jmedchem.3c01835
  6. J Med Chem. 2024 Jan 25.
    Multi_CycGT: A Deep Learning-Based Multimodal Model for Predicting the Membrane Permeability of Cyclic Peptides.
    Lujing Cao, Zhenyu Xu, Tianfeng Shang, Chengyun Zhang, Xinyi Wu, Yejian Wu, Silong Zhai, Zhajun Zhan, Hongliang Duan.
      Cyclic peptides are gaining attention for their strong binding affinity, low toxicity, and ability to target "undruggable" proteins; however, their therapeutic potential against intracellular targets is constrained by their limited membrane permeability, and researchers need much time and money to test this property in the laboratory. Herein, we propose an innovative multimodal model called Multi_CycGT, which combines a graph convolutional network (GCN) and a transformer to extract one- and two-dimensional features for predicting cyclic peptide permeability. The extensive benchmarking experiments show that our Multi_CycGT model can attain state-of-the-art performance, with an average accuracy of 0.8206 and an area under the curve of 0.8650, and demonstrates satisfactory generalization ability on several external data sets. To the best of our knowledge, it is the first deep learning-based attempt to predict the membrane permeability of cyclic peptides, which is beneficial in accelerating the design of cyclic peptide active drugs in medicinal chemistry and chemical biology applications.
    DOI:  https://doi.org/10.1021/acs.jmedchem.3c01611
  7. Pharmaceutics. 2023 Dec 28. pii: 48. [Epub ahead of print]16(1):
    An Improved In Vitro Blood-Brain Barrier Model for the Evaluation of Drug Permeability Using Transwell with Shear Stress.
    Junhyeong Kim, Seong-Ah Shin, Chang Sup Lee, Hye Jin Chung.
      The development of drugs targeting the central nervous system (CNS) is challenging because of the presence of the Blood-Brain barrier (BBB). Developing physiologically relevant in vitro BBB models for evaluating drug permeability and predicting the activity of drug candidates is crucial. The transwell model is one of the most widely used in vitro BBB models. However, this model has limitations in mimicking in vivo conditions, particularly in the absence of shear stress. This study aimed to overcome the limitations of the transwell model using immortalized human endothelial cells (hCMEC/D3) by developing a novel dish design for an orbital shaker, providing shear stress. During optimization, we assessed cell layer integrity using trans-endothelial electrical resistance measurements and the % diffusion of lucifer yellow. The efflux transporter activity and mRNA expression of junctional proteins (claudin-5, occludin, and VE-cadherin) in the newly optimized model were verified. Additionally, the permeability of 14 compounds was evaluated and compared with published in vivo data. The cell-layer integrity was substantially increased using the newly designed annular shaking-dish model. The results demonstrate that our model provided robust conditions for evaluating the permeability of CNS drug candidates, potentially improving the reliability of in vitro BBB models in drug development.
    Keywords:  annular shaking dish; blood-brain barrier; hCMEC/D3; immortalized human brain microvascular endothelial cell; in vitro BBB model; permeability; shear stress; transwell
    DOI:  https://doi.org/10.3390/pharmaceutics16010048
  8. Cells. 2024 Jan 12. pii: 150. [Epub ahead of print]13(2):
    Involvement of Astrocytes in the Formation, Maintenance, and Function of the Blood-Brain Barrier.
    Gabriella Schiera, Carlo Maria Di Liegro, Giuseppe Schirò, Gabriele Sorbello, Italia Di Liegro.
      The blood-brain barrier (BBB) is a fundamental structure that protects the composition of the brain by determining which ions, metabolites, and nutrients are allowed to enter the brain from the blood or to leave it towards the circulation. The BBB is structurally composed of a layer of brain capillary endothelial cells (BCECs) bound to each other through tight junctions (TJs). However, its development as well as maintenance and properties are controlled by the other brain cells that contact the BCECs: pericytes, glial cells, and even neurons themselves. Astrocytes seem, in particular, to have a very important role in determining and controlling most properties of the BBB. Here, we will focus on these latter cells, since the comprehension of their roles in brain physiology has been continuously expanding, even including the ability to participate in neurotransmission and in complex functions such as learning and memory. Accordingly, pathological conditions that alter astrocytic functions can alter the BBB's integrity, thus compromising many brain activities. In this review, we will also refer to different kinds of in vitro BBB models used to study the BBB's properties, evidencing its modifications under pathological conditions.
    Keywords:  astrocytes; blood–brain barrier; brain capillary endothelial cell; extracellular vesicles (EVs); in vitro BBB models
    DOI:  https://doi.org/10.3390/cells13020150
  9. Angew Chem Int Ed Engl. 2024 Jan 26. e202400344
    A Platform Approach to Cleavable Macrocycles for the Controlled Disassembly of Mechanically Caged Molecules.
    Abed Saady, Georgia Malcolm, Matthew Fitzpatrick, Noel Pairault, Graham Tizzard, Soran Mohammed, Ali Tavassoli, Stephen Michael Goldup.
      Inspired by interlocked oligonucleotides, peptides and knotted proteins, synthetic systems where a macrocycle cages a bioactive species that is "switched on" by breaking the mechanical bond have been reported. However, to date, each example uses a bespoke chemical design. Here we present a platform approach to mechanically caged structures wherein a single macrocycle precursor is diversified at a late stage to include a range of trigger units that control ring opening in response to enzymatic, chemical, or photochemical stimuli. We also demonstrate that our approach is applicable to other classes of macrocycles suitable for rotaxane and catenane formation.
    Keywords:  caged; catenanes; rotaxane; self-imolative
    DOI:  https://doi.org/10.1002/anie.202400344
  10. Sci Transl Med. 2024 Jan 26. eadg7162
    Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.
    Sahba Seddighi, Yue A Qi, Anna-Leigh Brown, Oscar G Wilkins, Colleen Bereda, Cedric Belair, Yong-Jie Zhang, Mercedes Prudencio, Matthew J Keuss, Aditya Khandeshi, Sarah Pickles, Sarah E Kargbo-Hill, James Hawrot, Daniel M Ramos, Hebao Yuan, Jessica Roberts, Erika Kelmer Sacramento, Syed I Shah, Mike A Nalls, Jennifer M Colón-Mercado, Joel F Reyes, Veronica H Ryan, Matthew P Nelson, Casey N Cook, Ziyi Li, Laurel Screven, Justin Y Kwan, Puja R Mehta, Matteo Zanovello, Martina Hallegger, Anantharaman Shantaraman, Lingyan Ping, Yuka Koike, Björn Oskarsson, Nathan P Staff, Duc M Duong, Aisha Ahmed, Maria Secrier, Jernej Ule, Steven Jacobson, Daniel S Reich, Jonathan D Rohrer, Andrea Malaspina, Dennis W Dickson, Jonathan D Glass, Alessandro Ori, Nicholas T Seyfried, Manolis Maragkakis, Leonard Petrucelli, Pietro Fratta, Michael E Ward.
      Functional loss of TDP-43, an RNA-binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We discovered that inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Finally, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.
    DOI:  https://doi.org/10.1126/scitranslmed.adg7162
  11. Cell Death Discov. 2024 Jan 26. 10(1): 51
    Generation of a new therapeutic D-peptide that induces the differentiation of acute myeloid leukemia cells through A TLR-2 signaling pathway.
    Fei Yu, Yingshi Chen, Mo Zhou, Lingling Liu, Bingfeng Liu, Jun Liu, Ting Pan, Yuewen Luo, Xu Zhang, Hailan Ou, Wenjing Huang, Xi Lv, Zhihui Xi, Ruozhi Xiao, Wenyu Li, Lixue Cao, Xiancai Ma, Jingwen Zhang, Lijuan Lu, Hui Zhang.
      Acute myeloid leukemia (AML) is caused by clonal disorders of hematopoietic stem cells. Differentiation therapy is emerging as an important treatment modality for leukemia, given its less toxicity and wider applicable population, but the arsenal of differentiation-inducing agents is still very limited. In this study, we adapted a competitive peptide phage display platform to search for candidate peptides that could functionally induce human leukemia cell differentiation. A monoclonal phage (P6) and the corresponding peptide (pep-P6) were identified. Both L- and D-chirality of pep-P6 showed potent efficiency in inducing AML cell line differentiation, driving their morphologic maturation and upregulating the expression of macrophage markers and cytokines, including CD11b, CD14, IL-6, IL-1β, and TNF-α. In the THP-1 xenograft animal model, administration of D-pep-P6 was effective in inhibiting disease progression. Importantly, exposure to D-pep-P6 induced the differentiation of primary human leukemia cells isolated AML patients in a similar manner to the AML cell lines. Further mechanism study suggested that D-pep-P6 induced human leukemia cell differentiation by directly activating a TLR-2 signaling pathway. These findings identify a novel D-peptide that may promote leukemia differentiation therapy.
    DOI:  https://doi.org/10.1038/s41420-024-01822-w
  12. Bioorg Chem. 2024 Jan 04. pii: S0045-2068(23)00753-8. [Epub ahead of print]144 107092
    Multiple medicinal chemistry strategies of targeting KRAS: State-of-the art and future directions.
    Yanguo Shang, Shengnan Fu, Qingjing Hao, Hanjie Ying, Jinxin Wang, Tao Shen.
      KRAS is the most frequently mutated oncogene and drives the development and progression of malignancies, most notably non-small cell lung cancer (NSCLS), pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). However, KRAS proteins have maintained the reputation of being "undruggable" due to the lack of suitable deep pockets on its surface. One major milestone for KRAS inhibition was the discovery of the covalent inhibitors bond to the allosteric switch-II pocket of the KRASG12C protein. To date, the FDA has approved two KRASG12C inhibitors, sotorasib and adagrasib, for the treatment of patients with KRASG12C-driven cancers. Researchers have paid close attention to the development of inhibitors for other KRAS mutations and upstream regulatory factors. The KRAS targeted drug discovery has entered a state of rapid development. This article has aimed to present the current state of the art of drug development in the KRAS field. We systematically summarize recent advances in the discovery and optimization processes of direct KRAS inhibitors (including KRASG12C, KRASG12D, KRASG12A and KRASG12R inhibitors), indirect KRAS inhibitors (SOS1 and SHP2 inhibitors), pan-KRAS inhibitors, as well as proteolysis-targetingchimeras degrades and molecular chaperone modulators from the perspective of medicinal chemistry. We also discuss the current challenges and opportunities of KRAS inhibition and hope to shed light on future KRAS drug discovery.
    Keywords:  Anticancer; Inhibitor; KRAS-mutant cancer; PROTAC; Scaffold hopping
    DOI:  https://doi.org/10.1016/j.bioorg.2023.107092
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