Tat‐mediated peptide intervention in analgesia and anesthesia

Abstract

Membrane-permeable peptide carriers are attractive drug delivery tools. Among such carriers, the protein transduction domain (PTD) of the human immunodeficiency virus-type 1 Tat protein is most frequently used and has been successfully shown to deliver a large variety of cargoes. The Tat PTD can facilitate the uptake of large, biologically active molecules into mammalian cells, and recent studies have shown that it can mediate the delivery of different cargoes into tissues throughout a living organism. Given that the Tat PTD-mediated delivery is size-independent, this technology could make previously non-applicable large molecules usable to modulate biological function in vivo and treat human diseases. It is likely that the peptide carrier-mediated intracellular delivery process encompasses multiple mechanisms, but endocytic pathways are the predominant internalization routes. Tat PTD has been successfully used in preclinical models for the study of cancer, ischemia, inflammation, analgesia, and anesthesia. Our recent studies have shown that intraperitoneally injected fusion Tat peptide Tat-PSD-95 PDZ2 can be delivered into the spinal cord to dose-dependently disrupt protein-protein interactions between PSD-95 and NMDA receptors. This peptide significantly inhibits chronic inflammatory pain and reduces the threshold for halothane anesthesia. The ability of the Tat PTD to target any cell is advantageous in some respects. However, the drug delivery system will be more attractive if we can modify the Tat PTD to deliver cargo only into desired organs to avoid possible side effects.

Sustained relief of neuropathic pain by AAV-targeted expression of CBD3 peptide in rat dorsal root ganglion

“…Short in vivo half-life has been a general challenge for TAT-conjugated drugable small interfering peptides (designated as peptide aptamers), 18 , 19 , 20 including TAT-CBD3, which is unstable and produces only transient pain relief. 10 Scaffold proteins such as GFP have been successfully used to provide a framework for the expression stable peptide aptamers.…”

“…A number of synthetic peptide inhibitors, including CBD3 conjugated to the TAT motif, have shown efficacy for pain caused by various pathological conditions, 9 , 28 , 29 and systemic administration of TAT-mediated analgesic peptides has been proposed as a promising alternative approach for the treatment of chronic pain. 20 , 30 However, this strategy also has some limitations, including the inability to target specific organs or cells. Another major obstacle in using TAT as a delivery vector is its rapid clearance when administrated in vivo , resulting in total clearance in as rapidly as 2 h after a bolus tail vein injection.…”

TAT‐MTS‐MCM fusion proteins reduce MMA levels and improve mitochondrial activity and liver function in MCM‐deficient cells

“…In addition, comprehensive toxicity studies including cell viability, proliferation and leakage of lactate dehydrogenase showed no toxic effects of TAT compared to other PTDs . Other advantages of TAT are its high transduction efficiency, little perturbation to the plasma membrane and its ability to transfer the blood–brain barrier , which is necessary for the treatment of MMA pathology.…”

Cell-SELEX Aptamer for Highly Specific Radionuclide Molecular Imaging of Glioblastoma In Vivo

“…Key features of nanoparticles such as versatile composition, unique physical properties, passive targeting abilities, as well as tunable surface functionality for active targeting, enable the transportation of diagnostic or therapeutic agents across the BBB [20] . Another alternative is to employ membrane-permeable peptide carriers, usually oligopeptides that can rapidly cross the plasma membrane, even the BBB and deliver a range of bioactive molecules to the cytoplasm or nucleus, to mediate in vivo delivery of the complex [21] . Some problems such as pharmacokinetics and toxicity of 188 Re-labeled U2 upon systemic delivery are worthy of detailed research.…”