bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2024–06–02
twelve papers selected by
Henry Lamb, Queensland University of Technology
  1. Cell-penetrating peptides with nanoparticles hybrid delivery vectors and their uptake pathways.
  2. Molecular determinants for brain targeting by peptides: a meta-analysis approach with experimental validation.
  3. Exploiting Hydrophobic Amino Acid Scanning to Develop Cyclic Peptide Inhibitors of the SARS-CoV-2 Main Protease with Antiviral Activity.
  4. FusPB-ESM2: Fusion model of ProtBERT and ESM-2 for cell-penetrating peptide prediction.
  5. Structure-guided design and cloning of peptide inhibitors targeting CDK9/cyclin T1 protein-protein interaction.
  6. Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells.
  7. De novo design of buttressed loops for sculpting protein functions.
  8. Rational design of a new short anticancer peptide with good potential for cancer treatment.
  9. Long-term clinical outcomes of [177Lu]Lu-DOTATATE in patients with metastatic neuroendocrine tumors.
  10. In vivo Targeting MEK and TNK2/SRC pathways in PTPN11 driven leukemia.
  11. In vivo phage display identifies novel peptides for cardiac targeting.
  12. Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment.
  1. Mitochondrion. 2024 May 24. pii: S1567-7249(24)00064-3. [Epub ahead of print]78 101906
    Cell-penetrating peptides with nanoparticles hybrid delivery vectors and their uptake pathways.
    Moataz Dowaidar.
      Cell-penetrating peptides (CPPs) are molecules that improve the cellular uptake of various molecular payloads that do not easily traverse the cellular membrane. CPPs can be found in pharmaceutical and medical products. The vast majority of cell-penetrating chemicals that are discussed in published research are peptide based. The paper also delves into the various applications of hybrid vectors. Because CPPs are able to carry cargo across the cellular membrane, they are a viable candidate for use as a suitable carrier for a wide variety of cargoes, such as siRNA, nanoparticles, and others. In which we discuss the CPPs, their classification, uptake mechanisms, hybrid vector systems, nanoparticles and their uptake mechanisms, etc. Further in this paper, we discuss CPPs conjugated to Nanoparticles, Combining CPPs with lipids and polymeric Nanoparticles in A Conjugated System, CPPs conjugated to nanoparticles for therapeutic purposes, and potential therapeutic uses of CPPs as delivery molecules. Also discussed the preclinical and clinical use of CPPS, intracellular trafficking of nanoparticles, and activatable and bioconjugated CPPs.
    Keywords:  CPPs; Cell-Penetrating Peptides; Drug Delivery Systems; Endocytosis Mechanisms; Hybrid Delivery Vectors; Intracellular Uptake; Nanoparticle-CPP Conjugates; Nanoparticles; Nanotechnology in Medicine; Targeted Drug Delivery; Therapeutic Nanocarriers
    DOI:  https://doi.org/10.1016/j.mito.2024.101906
  2. Fluids Barriers CNS. 2024 May 27. 21(1): 45
    Molecular determinants for brain targeting by peptides: a meta-analysis approach with experimental validation.
    Marco Cavaco, Patrícia Fraga, Javier Valle, Ruben D M Silva, Lurdes Gano, João D G Correia, David Andreu, Miguel A R B Castanho, Vera Neves.
      Blood-brain barrier (BBB) peptide-shuttles (BBBpS) are able to translocate the BBB and reach the brain. Despite the importance of brain targeting in pharmacology, BBBpS are poorly characterized. Currently, their development relies on the empiric assumption that cell-penetrating peptides (CPPs), with proven ability to traverse lipid membranes, will likewise behave as a BBBpS. The relationship between CPPs/BBBpS remains elusive and, to the best of our knowledge, has not hitherto been subject to thorough experimental scrutiny. In this work, we have identified/quantified the main physicochemical properties of BBBpS and then searched for CPPs with these properties, hence potential BBBpS. The specific features found for BBBpS are: (i) small size, (ii) none or few aromatic residues, (iii) hydrophobic, and (iv) slight cationic nature. Then, we selected the 10 scoring best in an ordinary least squares analysis, and tested them in vitro and in vivo. Overall, we identified the molecular determinants for brain targeting by peptides, devised a methodology that can be used to assist in the design of peptides with potential brain penetration from amino acid residue sequences, and found four new BBBpS within the CPP library.
    Keywords:  Blood–brain barrier (BBB); Blood–brain barrier peptide shuttles (BBBpS); Brain delivery; Cell-penetrating peptides (CPPs); Neurological disorders
    DOI:  https://doi.org/10.1186/s12987-024-00545-5
  3. Chemistry. 2024 May 27. e202401606
    Exploiting Hydrophobic Amino Acid Scanning to Develop Cyclic Peptide Inhibitors of the SARS-CoV-2 Main Protease with Antiviral Activity.
    Katriona Harrison, Patrick Carlos, Sven Ullrich, Anupriya Aggarwal, Jason Johansen-Leete, Vishnu Mini Sasi, Isabel Barter, Joshua Maxwell, Max Bedding, Mark Larance, Stuart Turville, Colin Jackson, Alexander Norman, Christoph Nitsche, Richard J Payne.
      The development of novel antivirals is crucial not only for managing current COVID-19 infections but for addressing potential future zoonotic outbreaks. SARS-CoV-2 main protease (Mpro) is vital for viral replication and viability and therefore serves as an attractive target for antiviral intervention. Herein, we report the optimization of a cyclic peptide inhibitor that emerged from an mRNA display selection against the SARS-CoV-2 Mpro to enhance its cell permeability and in vitro antiviral activity. By identifying mutation-tolerant amino acid residues within the peptide sequence, we describe the development of a second-generation Mpro inhibitor bearing five cyclohexylalanine residues. This cyclic peptide analogue exhibited significantly improved cell permeability and antiviral activity compared to the parent peptide. This approach highlights the importance of optimizing cyclic peptide hits for activity against intracellular targets such as the SARS-CoV-2 Mpro.
    Keywords:  COVID-19; SARS-CoV-2; antiviral; cyclic peptides; main protease
    DOI:  https://doi.org/10.1002/chem.202401606
  4. Comput Biol Chem. 2024 May 17. pii: S1476-9271(24)00086-0. [Epub ahead of print]111 108098
    FusPB-ESM2: Fusion model of ProtBERT and ESM-2 for cell-penetrating peptide prediction.
    Fan Zhang, Jinfeng Li, Zhenguo Wen, Chun Fang.
      Cell-penetrating peptides have attracted much attention for their ability to break through cell membrane barriers, which can improve drug bioavailability, reduce side effects, and promote the development of gene therapy. Traditional wet-lab prediction methods are time-consuming and costly, and computational methods provide a short-time and low-cost alternative. Still, the accuracy and reliability need to be further improved. To solve this problem, this study proposes a feature fusion-based prediction model, where the protein pre-trained language models ProtBERT and ESM-2 are used as feature extractors, and the extracted features from both are fused to obtain a more comprehensive and effective feature representation, which is then predicted by linear mapping. Validated by many experiments on public datasets, the method has an AUC value as high as 0.983 and shows high accuracy and reliability in cell-penetrating peptide prediction.
    Keywords:  Cell-penetrating peptide prediction; Feature fusion; Protein language pre-training model
    DOI:  https://doi.org/10.1016/j.compbiolchem.2024.108098
  5. Front Pharmacol. 2024 ;15 1327820
    Structure-guided design and cloning of peptide inhibitors targeting CDK9/cyclin T1 protein-protein interaction.
    Mohammad Sadegh Taghizadeh, Mohsen Taherishirazi, Ali Niazi, Alireza Afsharifar, Ali Moghadam.
      CDK9 (cyclin-dependent kinase 9) plays a significant role in numerous pathological conditions, such as HIV-1 infection and cancer. The interaction between CDK9 and cyclin T1 is crucial for maintaining the kinase's active state. Therefore, targeting this protein-protein interaction offers a promising strategy for inhibiting CDK9. In this study, we aimed to design and characterize a library of mutant peptides based on the binding region of cyclin T1 to CDK9. Using Osprey software, a total of 7,776 mutant peptides were generated. After conducting a comprehensive analysis, three peptides, namely, mp3 (RAADVEGQRKRRE), mp20 (RAATVEGQRKRRE), and mp29 (RAADVEGQDKRRE), were identified as promising inhibitors that possess the ability to bind to CDK9 with high affinity and exhibit low free binding energy. These peptides exhibited favorable safety profiles and displayed promising dynamic behaviors. Notably, our findings revealed that the mp3 and mp29 peptides interacted with a conserved sequence in CDK9 (residues 60-66). In addition, by designing the structure of potential peptides in the plasmid vector pET28a (+), we have been able to pave the way for facilitating the process of their recombinant production in an Escherichia coli expression system in future studies. Predictions indicated good solubility upon overexpression, further supporting their potential for downstream applications. While these results demonstrate the promise of the designed peptides as blockers of CDK9 with high affinity, additional experimental studies are required to validate their biological activity and assess their selectivity. Such investigations will provide valuable insights into their therapeutic potential and pave the way for the future development of peptide-based inhibitors targeting the CDK9-cyclin T1 complex.
    Keywords:  MMPBSA; drug discovery; molecular docking; molecular dynamics simulation; mutagenesis; peptide inhibitor
    DOI:  https://doi.org/10.3389/fphar.2024.1327820
  6. Front Pharmacol. 2024 ;15 1394685
    Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells.
    Emily M Esquea, Lorela Ciraku, Riley G Young, Jessica Merzy, Alexandra N Talarico, Nusaiba N Ahmed, Mangalam Karuppiah, Anna Ramesh, Adam Chatoff, Claudia V Crispim, Adel A Rashad, Simon Cocklin, Nathaniel W Snyder, Joris Beld, Nicole L Simone, Mauricio J Reginato, Alexej Dick.
      Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors in the brain rely on the conversion of acetate to acetyl-CoA by the enzyme acetyl-CoA synthetase 2 (ACSS2), a key regulator of fatty acid synthesis and protein acetylation. Here, we used a computational pipeline to identify novel brain-penetrant ACSS2 inhibitors combining pharmacophore-based shape screen methodology with absorption, distribution, metabolism, and excretion (ADME) property predictions. We identified compounds AD-5584 and AD-8007 that were validated for specific binding affinity to ACSS2. Treatment of BCBM cells with AD-5584 and AD-8007 leads to a significant reduction in colony formation, lipid storage, acetyl-CoA levels and cell survival in vitro. In an ex vivo brain-tumor slice model, treatment with AD-8007 and AD-5584 reduced pre-formed tumors and synergized with irradiation in blocking BCBM tumor growth. Treatment with AD-8007 reduced tumor burden and extended survival in vivo. This study identifies selective brain-penetrant ACSS2 inhibitors with efficacy towards breast cancer brain metastasis.
    Keywords:  ACSS2; acetate; acetyl-CoA; brain metastasis; breast cancer; cancer; computational-aided drug design font: italic formatted: left; metabolism
    DOI:  https://doi.org/10.3389/fphar.2024.1394685
  7. Nat Chem Biol. 2024 May 30.
    De novo design of buttressed loops for sculpting protein functions.
    Hanlun Jiang, Kevin M Jude, Kejia Wu, Jorge Fallas, George Ueda, T J Brunette, Derrick R Hicks, Harley Pyles, Aerin Yang, Lauren Carter, Mila Lamb, Xinting Li, Paul M Levine, Lance Stewart, K Christopher Garcia, David Baker.
      In natural proteins, structured loops have central roles in molecular recognition, signal transduction and enzyme catalysis. However, because of the intrinsic flexibility and irregularity of loop regions, organizing multiple structured loops at protein functional sites has been very difficult to achieve by de novo protein design. Here we describe a solution to this problem that designs tandem repeat proteins with structured loops (9-14 residues) buttressed by extensive hydrogen bonding interactions. Experimental characterization shows that the designs are monodisperse, highly soluble, folded and thermally stable. Crystal structures are in close agreement with the design models, with the loops structured and buttressed as designed. We demonstrate the functionality afforded by loop buttressing by designing and characterizing binders for extended peptides in which the loops form one side of an extended binding pocket. The ability to design multiple structured loops should contribute generally to efforts to design new protein functions.
    DOI:  https://doi.org/10.1038/s41589-024-01632-2
  8. Eur J Med Chem. 2024 May 20. pii: S0223-5234(24)00399-4. [Epub ahead of print]273 116519
    Rational design of a new short anticancer peptide with good potential for cancer treatment.
    Xiaoyan Wu, Yali Tian, Kaixin Ran, Jia Yao, Yuxia Wang, Xu Ouyang, Wenbo Mao, Jingying Zhang, Beibei Li, Ping Yang, Zufang Ba, Hui Liu, Sanhu Gou, Chao Zhong, Yun Zhang, Jingman Ni.
      Anticancer peptides (ACPs) have regarded as a new generation of promising antitumor drugs due to the unique mode of action. The main challenge is to develop potential anticancer peptides with satisfied antitumor activity and low toxicity. Here, a series of new α-helical anticancer peptides were designed and synthesized based on the regular repeat motif KLLK. The optimal peptides 14E and 14Aad were successfully derived from the new short α-helical peptide KL-8. Our results demonstrated that 14E and 14Aad had good antitumor activity and low toxicity, exhibiting excellent selectivity index. This result highlighted that the desirable modification position and appropriate hydrophobic side-chain structure of acidic amino acids played critical roles in regulating the antitumor activity/toxicity of new peptides. Further studies indicated that they could induce tumor cell death via the multiple actions of efficient membrane disruption and intracellular mechanisms, displaying apparent superiority in combination with PTX. In addition, the new peptides 14E and 14Aad showed excellent antitumor efficacy in vivo and low toxicity in mice compared to KL-8 and PTX. Particularly, 14Aad with the longer side chain at the 14th site exhibited the best therapeutic performance. In conclusion, our work provided a new avenue to develop promising anticancer peptides with good selectivity for tumor therapy.
    Keywords:  Anticancer peptides; Antitumor; High efficiency; Low toxicity; Repeat motif KLLK
    DOI:  https://doi.org/10.1016/j.ejmech.2024.116519
  9. Front Oncol. 2024 ;14 1393317
    Long-term clinical outcomes of [177Lu]Lu-DOTATATE in patients with metastatic neuroendocrine tumors.
    Sabah Iqbal, Eric Zhuang, Moses Raj, Nathan Bahary, Dulabh K Monga.
      The incidence of gastroenteropancreatic neuroendocrine tumors has been rising and these tumors are usually only diagnosed at a metastatic stage. Present first line treatments include somatostatin analogs, targeted therapies and peptide receptor radionuclide therapy. The Lutetium-177 [177Lu] based radiotracer [177Lu]Lu-DOTATATE has only been approved as first-line treatment of metastatic midgut NETs however its efficacy as a third line or above treatment in patients with non ileal primaries has not been tested. In our study, we identified 25 patients with histologically confirmed well-differentiated metastatic neuroendocrine tumors and administered [177Lu]Lu-DOTATATE as a second line, third line and fourth line treatment. Our study demonstrated a notable response in patients with non-ileal primaries and heavily pretreated disease, warranting further studies for additional cycles of treatment.
    Keywords:  [177Lu]Lu-DOTATATE; [68Ga]Ga-DOTATATE; gastroenteropancreatic neuroendocrine tumors; metastatic neuroendocrine tumors; peptide receptor radionuclide therapy
    DOI:  https://doi.org/10.3389/fonc.2024.1393317
  10. bioRxiv. 2024 May 18. pii: 2024.05.16.594555. [Epub ahead of print]
    In vivo Targeting MEK and TNK2/SRC pathways in PTPN11 driven leukemia.
    Bill H Chang, Karina Thiel-Klare, Jeffrey W Tyner.
      PTPN11 encodes for a tyrosine phosphatase implicated in the pathogenesis of hematologic malignancies such as Juvenile Myelomonocytic Leukemia (JMML), Acute Myeloid Leukemia (AML), and Acute Lymphoblastic Leukemia (ALL). Since activating mutations of PTPN11 increase proliferative signaling and cell survival through the RAS/MAPK proliferative pathway there is significant interest in using MEK inhibitors for clinical benefit. Yet, single agent clinical activity has been minimal. Previously, we showed that PTPN11 is further activated by upstream tyrosine kinases TNK2/SRC, and that PTPN11-mutant JMML and AML cells are sensitive to TNK2 inhibition using dasatinib. In these studies, we adopted a genetically engineered mouse model of PTPN11 driven leukemia using the mouse strain 129S/Sv- Ptpn11 tm6Bgn /Mmucd crossed with B6.129P2- Lyz2 tm1(cre)Ifo /J. The F1 progeny expressing Ptpn11 D61Y within hematopoietic cells destined along the granulocyte-monocyte progenitor lineage developed a myeloproliferative disorder. Cohorts of animals treated with combination of dasatinib and trametinib had a significant effect in mitigating disease parameters compared to single agents. Further, a primary patient-derived xenograft model using a myeloid leukemia with PTPN11 F71L also displayed improved response to combination. Collectively, these studies point to combined therapies targeting MEK and TNK2/SRC as a promising therapeutic potential for PTPN11-mutant leukemias.
    Key Points: Combining MEK and TNK2/SRC inhibitors has therapeutic potential in PTPN11 mutant JMML and AML.
    DOI:  https://doi.org/10.1101/2024.05.16.594555
  11. Sci Rep. 2024 05 28. 14(1): 12177
    In vivo phage display identifies novel peptides for cardiac targeting.
    Alena Ivanova, Franziska Kohl, Hernán González-King Garibotti, Renata Chalupska, Aleksander Cvjetkovic, Mike Firth, Karin Jennbacken, Sofia Martinsson, Andreia M Silva, Ida Viken, Qing-Dong Wang, John Wiseman, Niek Dekker.
      Heart failure remains a leading cause of mortality. Therapeutic intervention for heart failure would benefit from targeted delivery to the damaged heart tissue. Here, we applied in vivo peptide phage display coupled with high-throughput Next-Generation Sequencing (NGS) and identified peptides specifically targeting damaged cardiac tissue. We established a bioinformatics pipeline for the identification of cardiac targeting peptides. Hit peptides demonstrated preferential uptake by human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and immortalized mouse HL1 cardiomyocytes, without substantial uptake in human liver HepG2 cells. These novel peptides hold promise for use in targeted drug delivery and regenerative strategies and open new avenues in cardiovascular research and clinical practice.
    DOI:  https://doi.org/10.1038/s41598-024-62953-9
  12. Front Oncol. 2024 ;14 1402128
    Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment.
    Szu-Aun Long, Amber M Amparo, Grace Goodhart, Syed A Ahmad, Andrew M Waters.
      Despite significant advancements in the treatment of other cancers, pancreatic ductal adenocarcinoma (PDAC) remains one of the world's deadliest cancers. More than 90% of PDAC patients harbor a Kirsten rat sarcoma (KRAS) gene mutation. Although the clinical potential of anti-KRAS therapies has long been realized, all initial efforts to target KRAS were unsuccessful. However, with the recent development of a new generation of KRAS-targeting drugs, multiple KRAS-targeted treatment options for patients with PDAC have entered clinical trials. In this review, we provide an overview of current standard of care treatment, describe RAS signaling and the relevance of KRAS mutations, and discuss RAS isoform- and mutation-specific differences. We also evaluate the clinical efficacy and safety of mutation-selective and multi-selective inhibitors, in the context of PDAC. We then provide a comparison of clinically relevant KRAS inhibitors to second-line PDAC treatment options. Finally, we discuss putative resistance mechanisms that may limit the clinical effectiveness of KRAS-targeted therapies and provide a brief overview of promising therapeutic approaches in development that are focused on mitigating these resistance mechanisms.
    Keywords:  KRAS; KRAS inhibition; KRAS inhibitor; PDAC; pancreatic cancer
    DOI:  https://doi.org/10.3389/fonc.2024.1402128
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