Internalizing RGD, a great motif for targeted peptide and protein delivery: a review article

Davoodi, Zeinabosadat; Shafiee, Fatemeh

doi:10.1007/s13346-022-01116-7

Cited by 20 publications

(15 citation statements)

References 79 publications

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“…The mechanism includes the specific binding of iRGD to integrins αVβ3 or αVβ5, followed by a proteolytical cleavage and obtains specificity to the NRP-1 receptor, resulting in an NRP-1-dependent transcytosis [ 4 ]. Therefore, it is widely used as both a tumor-homing and a tumor-penetrating peptide for low molecules and macromolecular compounds [ 35 , 36 ]. Fusion with iRGD is of particular interest for targeting glioblastoma, since its unique properties allow for improving the penetration of various drugs through the BBB, which is one of the main obstacles to successful glioblastoma treatment.…”

Section: Discussionmentioning

confidence: 99%

DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma

Yagolovich

Isakova

Artykov

et al. 2022

IJMS

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TRAIL (TNF-related apoptosis-inducing ligand) and its derivatives are potentials for anticancer therapy due to the selective induction of apoptosis in tumor cells upon binding to death receptors DR4 or DR5. Previously, we generated a DR5-selective TRAIL mutant variant DR5-B overcoming receptor-dependent resistance of tumor cells to TRAIL. In the current study, we improved the antitumor activity of DR5-B by fusion with a tumor-homing iRGD peptide, which is known to enhance the drug penetration into tumor tissues. The obtained bispecific fusion protein DR5-B-iRGD exhibited dual affinity for DR5 and integrin αvβ3 receptors. DR5-B-iRGD penetrated into U-87 tumor spheroids faster than DR5-B and demonstrated an enhanced antitumor effect in human glioblastoma cell lines T98G and U-87, as well as in primary patient-derived glioblastoma neurospheres in vitro. Additionally, DR5-B-iRGD was highly effective in a xenograft mouse model of the U-87 human glioblastoma cell line in vivo. We suggest that DR5-B-iRGD may become a promising candidate for targeted therapy for glioblastoma.

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Section: Discussionmentioning

confidence: 99%

DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma

Yagolovich

Isakova

Artykov

et al. 2022

IJMS

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“…35 Peptides 1 and 2 are variants of a Leu-Enkephalin, an endogenous opioid peptide neurotransmitter, found naturally in the brain of many animals, including humans. Peptides 3 and 4 are two arginine-bearing peptides, an arginylglycylaspartic acid 4 (RGD)-the most common peptide motif responsible for cell adhesion to the extracellular matrix, found in species ranging from Drosophila to humans, 36,37 and a glutaminylarginylasparaginylalanine 3 was chosen as a model peptide to demonstrate the ASPPS without side-chain protecting groups-an additional step to greener peptide synthesis in view of atom economy.…”

Section: Applicationmentioning

confidence: 99%

Novel amino‐Li resin for water‐based solid‐phase peptide synthesis

Uth¹,

Englert²,

Avrutina

et al. 2023

Journal of Peptide Science

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We report the first application of a novel amino‐Li resin to water‐based solid‐phase peptide synthesis (SPPS) applying the Smoc‐protecting group approach. We demonstrated that it is a suitable support for the sustainable water‐based alternative to a classical SPPS approach. The resin possesses good swelling properties in aqueous milieu, provides significant coupling sites, and may be applicable to the synthesis of difficult sequences and aggregation‐prone peptides.

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“…For these reasons, anticancer compounds often need to be administered at high doses to exert relevant pharmacological effects, with the rise of serious adverse reactions. − A feasible solution to the tissue penetration problem is represented by smart carriers that can vehicle the desired drug to extravascular cancer tissue. Carriers of different natures have been developed such as gold nanoparticles, − liposomes, , polymer micelles, or receptor-selective peptides. − In this context, Ruoslahti and co-workers identified an RGD integrins-targeting cyclic nonapeptide, namely, i RGD (internalizing RGD, CRGDKGPDC, 1 Chart ), endowed with remarkable tumor-homing properties. , Notably, this peptide can improve the tumor penetration and efficacy of chemotherapeutics through two alternative mechanisms. ,− In fact, i RGD can be either covalently bioconjugatedusually functionalizing the C-terminal Cys 9 to organic and peptidic drugs or attached to the surface of other delivering systems like nanoparticles, liposomes, or oncolytic viruses. − On the other hand, the tumor endocytosis of cytotoxic agents such as cisplatin, gemcitabine, doxorubicin, nab-paclitaxel, and trastuzumab is enhanced by the simple coadministration of 1 . ,, As a result, hundreds of distinct applications involving i RGD have been published during the past decade, − claiming the p...…”

Section: Introductionmentioning

confidence: 99%

Molecular View on the iRGD Peptide Binding Mechanism: Implications for Integrin Activity and Selectivity Profiles

D’Amore,

Donati,

Lenci

et al. 2023

J. Chem. Inf. Model.

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Receptor-selective peptides are widely used as smart carriers for specific tumor-targeted delivery. A remarkable example is the cyclic nonapeptide iRGD (CRGDKPGDC, 1) that couples intrinsic cytotoxic effects with striking tumor-homing properties. These peculiar features are based on a rather complex multistep mechanism of action, where the primary event is the recognition of RGD integrins. Despite the high number of preclinical studies and the recent success of a phase I trial for the treatment of pancreatic ductal adenocarcinoma (PDAC), there is little information available about the iRGD three-dimensional (3D) structure and integrin binding properties. Here, we re-evaluate the peptide’s affinity for cancer-related integrins including not only the previously known targets αvβ3 and αvβ5 but also the αvβ6 isoform, which is known to drive cell growth, migration, and invasion in many malignancies including PDAC. Furthermore, we use parallel tempering in the well-tempered ensemble (PT-WTE) metadynamics simulations to characterize the in-solution conformation of iRGD and extensive molecular dynamics calculations to fully investigate its binding mechanism to integrin partners. Finally, we provide clues for fine-tuning the peptide’s potency and selectivity profile, which, in turn, may further improve its tumor-homing properties.

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Internalizing RGD, a great motif for targeted peptide and protein delivery: a review article

Cited by 20 publications

References 79 publications

DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma

DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma

Novel amino‐Li resin for water‐based solid‐phase peptide synthesis

Molecular View on the iRGD Peptide Binding Mechanism: Implications for Integrin Activity and Selectivity Profiles

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