Role of Tat-Mediated PDZ Peptide Delivery in Pain Therapy

Haiying Wu,Feng Tao

doi:10.4236/jbnb.2011.225071

Abstract

Delivery of therapeutic peptides or proteins into tissues is severely limited by the size and biochemical properties of the molecules. Protein transduction domain (PTD)-mediated cargo transduction represents a novel and promising strategy to deliver biologically active peptides in vivo. The first PTD was identified from the HIV-1 transactivating transcriptional activator protein Tat in 1988. Since then, other PTDs have also been identified, including the third α-helix of the antennapedia homeotic transcription factor and synthetic peptide carriers. However, Tat PTD (amino acids 47 - 57) has shown markedly better ability for intracellular delivery than other PTDs. It has been demonstrated that fusion peptides containing the Tat PTD enter the central nervous system after systemic administration. Our previous study has shown that i.p. injected Tat-PSD-95 PDZ2 expresses in the central nervous system and significantly disrupts PDZ domain-mediated protein interactions between PSD-95 and N-methyl-D-aspartate receptor subunit NR2A/2B, thereby alleviating chronic pain. Therefore, Tat-mediated intracellular delivery can be used for systemic administration of analgesics in pain management.

Highlights

The discovery of small cationic peptides (8 - 16 amino acids in length) termed protein transduction domains (PTDs) or cell-penetrating peptides [1,2], which cross biological membranes, has emerged as a venerable Trojan horse to transport large, biologically active molecules, such as peptides, proteins, and oligonucleotides, into mammalian cells in vitro, as well as in preclinical models and clinical trials in vivo
Our previous study has shown that i.p. injected transcriptional activator protein (Tat)-PSD-95 PDZ2 expresses in the central nervous system and significantly disrupts PDZ domain-mediated protein interactions between PSD-95 and N-methyl-D-aspartate receptor subunit NR2A/2B, thereby alleviating chronic pain
Considerable evidence indicates that the development of central hyperexcitability and persistent pain involves the activation of N-methylD-aspartate receptors (NMDARs), which play an important role in the processing of nociceptive information [11,12,13,14]

Summary

Introduction

The discovery of small cationic peptides (8 - 16 amino acids in length) termed protein transduction domains (PTDs) or cell-penetrating peptides [1,2], which cross biological membranes, has emerged as a venerable Trojan horse to transport large, biologically active molecules, such as peptides, proteins, and oligonucleotides, into mammalian cells in vitro, as well as in preclinical models and clinical trials in vivo. Contain the domain: PSD-95, Dlg, and ZO-1). The second (PSD-95 PDZ2) interacts with NMDAR NR2 subunits at a seven-amino acid, COOH-terminal domain that contains a terminal tSXV motif (where S is serine, X is any amino acid, and V is valine) [15]

PDZ Domain-Mediated Protein Interactions in the CNS

Mechanisms Underlying Tat-Mediated Intracellular Delivery

Tat-Mediated PDZ Peptide Delivery in Chronic Pain Treatment

Perspectives