Design and evaluation of variants of the protein transduction domain originated from translationally controlled tumor protein

Kim, Moonhee; Maeng, Jeehye; Jung, Jae‐Hoon; Kim, Hyo Young; Kim, Hwa Jung; Kwon, Young Joo; Lee, Kyunglim

doi:10.1016/j.ejps.2011.03.007

Cited by 11 publications

(12 citation statements)

References 26 publications

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“…Our previous study confirmed that the overall hydrophobicity of L-TCTP-PTD 13 was essential for the cellular uptake activity, taking into account the results of alanine substitution analysis of each residue of wild-type TCTP-PTD and biochemical properties such as peptide charge, isoelectric point and polarity (Kim et al. 2011b ). Thus, we replaced the 6th residue A with more hydrophobic residue, L at the 6-ALI-8 position to increase the overall hydrophobicity of L-TCTP-PTD 13.…”

Section: Resultssupporting

confidence: 76%

“…In attempts to increase the absorption of insulin delivered intranasally, we substituted residues at position 6-ALI-8 of l -TCTP-PTD 13. We did not alter the 1-MIIFR-5 and 9-SHKK-12 residues of l -TCTP-PTD 13 to preserve the capacity for translocation through the cell membrane as well as the water solubility of the peptide ( Figure 1(a) ) (Kim et al., 2011b ). Additionally, previous studies have shown that a TCTP-PTD analog, l -TCTP-PTD 8, amino acids 1-MIIYRIAASHKK-12 with positions 6-IAA-8 did not significantly enhance the nasal insulin absorption.…”

Section: Resultsmentioning

confidence: 99%

“…To improve the penetration of peptides through the cell membrane, we designed variant peptides modified from TCTP-PTD. Several variants of TCTP-PTD significantly enhanced the transduction compared with that of the wild-type TCTP-PTD (Kim et al., 2011b ). Among them, TCTP-PTD 13 consisting of l -amino acids (1-MIIFRALISHKK-12), enhanced nasal absorption compared to administration of insulin alone (Bae & Lee, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin

et al. 2018

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Carrier peptides, termed protein transduction domains (PTDs), serve as provide promising vehicles for intranasal delivery of macromolecular drugs. A mutant PTD derived from human translationally controlled tumor protein (TCTP-PTD 13, MIIFRALISHKK) was reported to provide enhanced intranasal delivery of insulin. In this study, we tested whether its efficiency could be further improved by replacing amino acids in TCTP-PTD 13 or changing the amino acids in the carrier peptides from the l- to the d-form. We assessed the pharmacokinetics of PTD-mediated transmucosal delivery of insulin in normal rats and the activity of insulin in alloxan-induced diabetic rats. The safety/toxicity profile of the carrier peptides was evaluated based on the release of lactate dehydrogenase (LDH) in nasal wash fluid, body weight changes, and several biochemical parameters. Pharmacokinetic and pharmacodynamic studies showed that the l-form of a double substitution A6L, I8A (MIIFRLLASHKK), designated as l-TCTP-PTD 13M2 was the most effective carrier for intranasal insulin delivery. The relative bioavailability of insulin co-administered intranasally with l-TCTP-PTD 13M2 was 37.1% of the value obtained by the subcutaneous route, which was 1.68-fold higher than for insulin co-administered with l-TCTP-PTD 13. Moreover, co-administration of insulin plus l-TCTP-PTD 13M2 reduced blood glucose levels compared to levels in diabetic rats treated with insulin plus l-TCTP-PTD 13. There was no evidence of toxicity. These results suggest that the newly designed PTD is a useful carrier peptide for the intranasal delivery of drugs or biomolecules.

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Section: Resultssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin

et al. 2018

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“…The amino acid residues 76–110, part of the helical domain of Pm Fortilin are contained within a Ca 2+ -binding domain, forming a helical domain between the H2-helix (residues 81–99) and the H3-helix (residues 106–122) producing an EF-hand structure (Figure 1). Importantly, a small section at the N-terminus (residues 1–10) contains protein transduction domains (PTDs), 1-MKVFKDMLTG-10, allowing for the delivery of active molecules into the cells through the lipid bilayer [35]–[37]. Pm Fortilin contains two signature patterns.…”

Section: Resultsmentioning

confidence: 99%

Characterization of a Novel Binding Protein for Fortilin/TCTP — Component of a Defense Mechanism against Viral Infection in Penaeus monodon

et al. 2012

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The Fortilin (also known as TCTP) in Penaeus monodon (PmFortilin) and Fortilin Binding Protein 1 (FBP1) have recently been shown to interact and to offer protection against the widespread White Spot Syndrome Virus infection. However, the mechanism is yet unknown. We investigated this interaction in detail by a number of in silico and in vitro analyses, including prediction of a binding site between PmFortilin/FBP1 and docking simulations. The basis of the modeling analyses was well-conserved PmFortilin orthologs, containing a Ca2+-binding domain at residues 76–110 representing a section of the helical domain, the translationally controlled tumor protein signature 1 and 2 (TCTP_1, TCTP_2) at residues 45–55 and 123–145, respectively. We found the pairs Cys59 and Cys76 formed a disulfide bond in the C-terminus of FBP1, which is a common structural feature in many exported proteins and the “x–G–K–K” pattern of the amidation site at the end of the C-terminus. This coincided with our previous work, where we found the “x–P–P–x” patterns of an antiviral peptide also to be located in the C-terminus of FBP1. The combined bioinformatics and in vitro results indicate that FBP1 is a transmembrane protein and FBP1 interact with N-terminal region of PmFortilin.

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“…In attempts to increase the penetrating activity of natural TCTP-PTD, we prepared several analogous mutants and examined their ability to increase to serve as transport vehicles for peptide/protein into cells. We found that TCTP-PTD 13 (MIIFRALISHKK) exhibited increased ability to penetrate cell membrane with no cytotoxic side effects (Kim et al., 2011b ). Recently, we reported that the co-administration of mixtures of insulin with TCTP-PTD 13 or its mutant analogs efficiently delivered bioavailable insulin into the nasal mucosal membrane of both normal and diabetic rats without causing nasal membrane damage (Bae et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Modified translationally controlled tumor protein-derived protein transduction domain enhances nasal delivery of exendin-4 as shown with insulin

et al. 2018

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Protein transduction domains (PTDs) have been shown to promote the delivery of therapeutic proteins or peptides into the living cells. In a previous study, we showed that the double mutant of TCTP-PTD 13, TCTP-PTD 13M2, was more effective in the delivery of insulin than the wild-type TCTP-PTD 13. In this study, we applied this approach to the nasal delivery of a different peptide, exendin-4, using as carriers, several modified TCTP-PTDs, such as TCTP-PTD 13M1, 13M2, and 13M3. Nasal co-administration of TCTP-PTD 13M2 with exendin-4 showed the highest exendin-4 uptake among the three analogs in normal rats, and also decreased blood glucose levels by 43.3% compared with that of exendin-4 alone and by 18.6% compared with that of exendin-4 plus TCTP-PTD 13 in diabetic mice. We also designed an additional covalently linked conjugate of TCTP-PTD 13M2 and exendin-4 and evaluated its hypoglycemic effect after subcutaneous or intranasal delivery. Subcutaneous administration of exendin-4 that its C-terminus is covalently linked to TCTP-PTD 13M2 showed hypoglycemic effect of 42.2% compared to that in untreated group, whereas intranasal delivery was not successful in diabetic mice. We conclude that a simple mixing TCTP-PTD 13M2 with peptide/protein drugs can be potentially a generally applicable approach for intranasal delivery into animals.

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Design and evaluation of variants of the protein transduction domain originated from translationally controlled tumor protein

Cited by 11 publications

References 26 publications

Modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin

Modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin

Characterization of a Novel Binding Protein for Fortilin/TCTP — Component of a Defense Mechanism against Viral Infection in Penaeus monodon

Modified translationally controlled tumor protein-derived protein transduction domain enhances nasal delivery of exendin-4 as shown with insulin

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