ArticleProceedings of the National Academy of Sciences of the United States of America2000
The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 454 papers.
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Who cites it
454 citing papers in PubMed, 1,582 citations in OpenAlex.
- Cell-Penetrating Peptide Delivery for CRISPR Applications.Methods in molecular biology (Clifton, N.J.) · 2027Article
- Recent progress in the structure-activity relationship of antibacterial peptoids.RSC advances · 2026Review
- Protein Modifications for Cellular Protein Delivery.Chemical reviews · 2026Review
- Article
- Edge-Grafted Polyarginine Functionalization of Graphene Nanocarriers Maintains Noncovalent Aromatic Drug Loading.Journal of peptide science : an official publication of the European Peptide Society · 2026Article
- Tetrazine-Enabled Peptide Macrocyclization and Bioorthogonal Cell Penetration Profiling.JACS Au · 2026Article
- HPV Capsid-Derived Cationic Peptides for Cargo Delivery and Antiviral Activity.bioRxiv : the preprint server for biology · 2026Article
- Macrocyclic Peptides Containing an Imidazopyridinium (IPJournal of the American Chemical Society · 2026Article
- Discovery of a Minimally Charged Cell-Penetrating Peptide.Biochemistry · 2026Article
- From Membrane Composition to Antimicrobial Strategies: Experimental and Computational Approaches to AMP Design and Selectivity.Small (Weinheim an der Bergstrasse, Germany) · 2026Review
- A Streamlined High Performance Liquid Chromatography with Tandem Mass Spectrometry Based Workflow for Rapid Screening of Cellular Accumulation of Small Molecules.ChemMedChem · 2026Article
- Enhancing diabetes treatment by targeted nucleic acid and drug delivery using cell-penetrating peptides, peptide nucleic acids, and receptor targeting.Frontiers in pharmacology · 2026Review
- Spatial control of PEG-lipid interfaces at cell surface enables on-demand adhesion and enzymatic detachment of suspension cells.Science and technology of advanced materials · 2026Article
- Fine-Tuning Side Chain Substitutions: Impacts on the Lipophilicity-Solubility-Permeability Interplay in Macrocyclic Peptides.Marine drugs · 2025Article
- Cell penetrating peptide-functionalized small interfering RNA nanoparticles knock down HER expression in breast cancer cells.The Journal of pharmacology and experimental therapeutics · 2025Article
- Modular Platform for Therapeutic Drug Delivery Using Trifunctional Bio-Orthogonal Macromolecular Conjugates.Bioconjugate chemistry · 2025Article
- Thermo-responsive targeting of polymeric micelles by controlling the cellular uptake based on the change of their surface arginine density.Communications chemistry · 2025Article
- Macrocyclic Peptides Containing an Imidazopyridinium (IPbioRxiv : the preprint server for biology · 2025Article
- Amphipathic Proline-Rich Cell Penetrating Peptides for Targeting Mitochondria.ACS chemical biology · 2025Article
- Intracellular Delivery of Native Proteins by BioReversible Arginine Modification (BioRAM) on Amino Groups.Angewandte Chemie (International ed. in English) · 2025Article
394 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Certain proteins contain subunits that enable their active translocation across the plasma membrane into cells. In the specific case of HIV-1, this subunit is the basic domain Tat(49-57) (RKKRRQRRR). To establish the optimal structural requirements for this translocation process, and thereby to develop improved molecular transporters that could deliver agents into cells, a series of analogues of Tat(49-57) were prepared and their cellular uptake into Jurkat cells was determined by flow cytometry. All truncated and alanine-substituted analogues exhibited diminished cellular uptake, suggesting that the cationic residues of Tat(49-57) play a principal role in its uptake. Charge alone, however, is insufficient for transport as oligomers of several cationic amino acids (histidine, lysine, and ornithine) are less effective than Tat(49-57) in cellular uptake. In contrast, a 9-mer of l-arginine (R9) was 20-fold more efficient than Tat(49-57) at cellular uptake as determined by Michaelis-Menton kinetic analysis. The d-arginine oligomer (r9) exhibited an even greater uptake rate enhancement (>100-fold). Collectively, these studies suggest that the guanidinium groups of Tat(49-57) play a greater role in facilitating cellular uptake than either charge or backbone structure. Based on this analysis, we designed and synthesized a class of polyguanidine peptoid derivatives. Remarkably, the subset of peptoid analogues containing a six-methylene spacer between the guanidine head group and backbone (N-hxg), exhibited significantly enhanced cellular uptake compared to Tat(49-57) and even to r9. Overall, a transporter has been developed that is superior to Tat(49-57), protease resistant, and more readily and economically prepared.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.