Synthesis of a pH-Sensitive Nitrilotriacetic Linker to Peptide Transduction Domains To Enable Intracellular Delivery of Histidine Imidazole Ring-Containing Macromolecules
نویسندگان
چکیده
Intracellular delivery of functional macromolecules using peptide transduction domains (PTDs) is an exciting technology with both experimental and therapeutic applications. Recent data indicate that PTD-mediated transduction occurs via fluid-phase macropinocytosis involving an intracellular pH drop to approximately 5. Nitrilotriacetic acid (NTA)-coordinated metals avidly bind hexahistidine-tagged macromolecules, including peptides and proteins. Histidine's imidazole ring has a pK(a) of 6, making this an attractive target for the biological pH drop of PTD-mediated macropinocytotic delivery. The objective of this study was to develop a pH-sensitive PTD delivery peptide (NTA(3)-PTD). We demonstrate the in vitro function of this novel peptide by delivering fluorescently labeled peptides (1.6 kDa) and functional enzymes, beta-galactosidase (119 kDa) and Cre recombinase (37 kDa). Furthermore, the NTA(3)-PTD peptide was able to deliver functional Cre recombinase in an in vivo mouse model.
منابع مشابه
Smart polymeric carriers for enhanced intracellular delivery of therapeutic macromolecules.
Limited cytoplasmic delivery of enzyme-susceptible drugs remains a significant challenge facing the development of protein and nucleic acid therapies that act in intracellular compartments. Researchers have examined several approaches, including fusogenic proteins and protein transduction domains, to enhance the intracellular delivery of the therapeutic cargo. This review summarises efforts to ...
متن کاملPreparation and characterization of different liposomal formulations containing P5 HER2/neu-derived peptide and evaluation of their immunological responses and antitumor effects
Objective(s):Tumor-associated antigen (TAA) subunit-based vaccines constitute promising tools for anticancer immunotherapy. However, a major limitation in the development of such vaccines is the poor immunogenicity of peptides when used alone.The aim of this study was to develop an efficient vaccine delivery system and adjuvant to enhance anti-tumor activity of a synthetic HER2/neu derived pept...
متن کاملStudies on Nickel(II)-Pyridoxamine-Imidazole Containing Mixed Ligand Complex Systems
The stability constants of species present in the systems Ni(II)-pyridoxamine(pym)(A) and Ni(II)-pyridoxamine(pym)(A)-imidazole containing ligands(B) [B = imidazole(him), benzimidazole(bim), histamine(hist) and L-histidine(his)] have been determined pH-metrically using the MINIQUAD computer program. The existence of the species NiAH, NiA and NiA2 was proven for the Ni(II)-pym(A)...
متن کاملComparison of chelating ability of dipeptide (histidine-β-alanine) and (tetrakis(4-sulfonatophenyl)porphyrin) (TPPS4) for in vitro removal of toxic metals
Peptides are one of the best candidates for drug development due to their high specificity and low toxicity and porphyrins are significant macromolecules in biological systems with important roles. In this works ynthesis of dipeptide (histidine-β-alanine) was done by solid-phase peptide synthesis method (SPPS) and tetrakis(4-sulfonatophenyl)porphyrin (TPPS4) was synthesized by Adler method. The...
متن کاملDesign, Synthesis and Biological Evaluation of Novel Peptide-Like Analogues as Selective COX-2 Inhibitors
A new series of peptide-like derivatives containing different aromatic amino acids andpossessing pharmacophores of COX-2 inhibitors as SO2Me or N3 attached to the para positionof an end phenyl ring was synthesized for evaluation as selective cyclooxygenase-2 (COX-2)inhibitors. The synthetic reactions were based on the solid phase peptide synthesis methodusing Wang resin. One of the analogues, i...
متن کامل