Design and synthesis of novel dual-cyclic RGD peptides for αvβ3 integrin targeting

Liu, Junjie; Cheng, Xiaozhong; Tian, Xiaobo; Guan, Dongliang; Ao, Jiwei; Wu, Zhimeng; Huang, Wei; Zhang, Le

doi:10.1016/j.bmcl.2019.01.043

Cited by 19 publications

(6 citation statements)

References 22 publications

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“…Herein, we report the study of RGD1-R6 carrier, developed by combination of iRGD ligand-modified RGD1 carrier with cysteine-flanked R6 peptide [29,42]. The specific binding of RGD ligand to integrin αvβ3 offers a promising strategy aimed at the delivery of therapeutic molecules to tumor cells [34]. The tumor-penetrating iRGD peptide not only has a high affinity to integrin αvβ3 but also helps to reach the depth of tumors by subsequent binding to neuropilin-1 [40].…”

Section: Carrier Designmentioning

confidence: 99%

“…Among the various peptide ligands for targeted tumor therapy, the motif RGD specific to αv-integrins is actively studied. These integrins are overexpressed on the surface of tumor cells, but their expression is lesser in normal tissues [34]. For example, αvβ3 integrins are significantly upregulated in uterine leiomyoma cells as compared to normal myometrium that makes this receptors perspective for targeted gene therapy of UL [35].…”

Section: Introductionmentioning

confidence: 99%

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Development of iRGD-Modified Peptide Carriers for Suicide Gene Therapy of Uterine Leiomyoma

et al. 2021

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Uterine leiomyoma (UL) is one of the most common benign tumors in women that often leads to many reproductive complications. Suicide genetherapy was suggested as a promising approach for UL treatment. In the present study, we describe iRGD ligand-conjugated cysteine-rich peptide carrier RGD1-R6 for targeted DNA delivery to αvβ3 integrin-expressing primary UL cells. The physico-chemical properties, cytotoxicity, transfection efficiency and specificity of DNA/RGD1-R6 polyplexes were investigated. TheHSV-1thymidine kinase encoding plasmid delivery to PANC-1pancreatic carcinoma cells and primary UL cells resulted in significant suicide gene therapy effects. Subsequent ganciclovir treatment decreased cells proliferative activity, induced of apoptosis and promoted cells death.The obtained results allow us to concludethatthe developed RGD1-R6 carrier can be considered a promising candidate for suicide gene therapy of uterine leiomyoma.

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Section: Carrier Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of iRGD-Modified Peptide Carriers for Suicide Gene Therapy of Uterine Leiomyoma

et al. 2021

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“…The engineered sfGFP 13 was expressed as a soluble protein without a decrease in fluorescence intensity (Figure S16). A list of cancer-targeting peptides 14a – f − was prepared for use in the ligation reaction with sfGFP 13 . Each peptide (500 μM) was reacted with 50 μM of sfGFP 13 in the presence of 250 nM of VyPAL2 at pH 4.5 for 4 h. All of the reactions afforded the products in moderate to good yields (50–85%) (Figure A and Figures S17–S22) as analyzed by HPLC.…”

Section: Resultsmentioning

confidence: 99%

pH-Controlled Protein Orthogonal Ligation Using Asparaginyl Peptide Ligases

Zhang

Wang

et al. 2021

J. Am. Chem. Soc.

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Peptide asparaginyl ligases (PALs) catalyze transpeptidation at the Asn residue of a short Asn-Xaa 1 -Xaa 2 tripeptide motif. Due to their high catalytic activity toward the P1-Asn substrates at around neutral pH, PALs have been used extensively for peptide ligation at asparaginyl junctions. PALs also bind to aspartyl substrates, but only when the γ COOH of P1-Asp remains in its neutral, protonated form, which usually requires an acidic pH. However, this limits the availability of the amine nucleophile and, consequently, the ligation efficiency at aspartyl junctions. Because of this perceived inefficiency, the use of PALs for Asp-specific ligation remains largely unexplored. We found that PAL enzymes, such as VyPAL2, display appreciable catalytic activities toward P1-Asp substrates at pH 4−5, which are at least 2 orders of magnitude higher than that of sortase A, making them practically useful for both intra-and intermolecular ligations. This also allows sequential ligations, first at Asp and then at Asn junctions, because the newly formed aspartyl peptide bond is resistant to the ligase at the pH used for asparaginyl ligation in the second step. Using this pH-controlled orthogonal ligation method, we dually labeled truncated sfGFP with a cancer-targeting peptide and a doxorubicin derivative at the respective N-and C-terminal ends in the N-to-C direction. In addition, a fluorescein tag and doxorubicin derivative were tagged to an EGFR-targeting affibody in the C-to-N direction. This study shows that the pHdependent catalytic activity of PAL enzymes can be exploited to prepare multifunction protein biologics for pharmacological applications.

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“…Liu et al have recently generated dual-cyclic RGD-peptide derivatives with increased selectivity for targeting monomethyl auristatin E (MMAE) to tumor cells. These peptide-drug conjugates display 2-fold higher cytotoxicity than unmodified MMAE [47]. The RGD motif has also been incorporated into larger peptide structures such as knottins, whose highly constrained structure also confers high proteolytical stability.…”

Section: Cyclic Targeting Peptidesmentioning

confidence: 99%

Protease-Resistant Peptides for Targeting and Intracellular Delivery of Therapeutics

et al. 2021

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Peptides show high promise in the targeting and intracellular delivery of next-generation bio- and nano-therapeutics. However, the proteolytic susceptibility of peptides is one of the major limitations of their activity in biological environments. Numerous strategies have been devised to chemically enhance the resistance of peptides to proteolysis, ranging from N- and C-termini protection to cyclization, and including backbone modification, incorporation of amino acids with non-canonical side chains and conjugation. Since conjugation of nanocarriers or other cargoes to peptides for targeting and cell penetration may already provide some degree of shielding, the question arises about the relevance of using protease-resistant sequences for these applications. Aiming to answer this question, here we provide a critical review on protease-resistant targeting peptides and cell-penetrating peptides (CPPs). Two main approaches have been used on these classes of peptides: enantio/retro-enantio isomerization and cyclization. On one hand, enantio/retro-enantio isomerization has been shown to provide a clear enhancement in peptide efficiency with respect to parent L-amino acid peptides, especially when applied to peptides for drug delivery to the brain. On the other hand, cyclization also clearly increases peptide transport capacity, although contribution from enhanced protease resistance or affinity is often not dissected. Overall, we conclude that although conjugation often offers some degree of protection to proteolysis in targeting peptides and CPPs, modification of peptide sequences to further enhance protease resistance can greatly increase homing and transport efficiency.

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Design and synthesis of novel dual-cyclic RGD peptides for αvβ3 integrin targeting

Cited by 19 publications

References 22 publications

Development of iRGD-Modified Peptide Carriers for Suicide Gene Therapy of Uterine Leiomyoma

Development of iRGD-Modified Peptide Carriers for Suicide Gene Therapy of Uterine Leiomyoma

pH-Controlled Protein Orthogonal Ligation Using Asparaginyl Peptide Ligases

Protease-Resistant Peptides for Targeting and Intracellular Delivery of Therapeutics

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