Ribosome-inactivating proteins: current status and biomedical applications

Puri, Munish; Kaur, Inderdeep; Perugini, Matthew A.; Gupta, Raghbir Chand

doi:10.1016/j.drudis.2012.03.007

Cited by 144 publications

(132 citation statements)

References 62 publications

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“…As potent toxins with N-glycosidase activity on 28S rRNA, several gelonin molecules are sufficient to kill a cell if they can enter the tumor cell and fully access the ribosomes inside the cell. However, gelonin by itself is not effective for cancer treatment because it does not have a cell binding-domain to mediate internalization into the cells [20,22] . Peptide ligands such as F3 peptide can facilitate the intracellular transport of cargoes by binding to nucleolins, cell surface receptors that are selectively expressed on tumor cell membranes [17] .…”

Section: Discussionmentioning

confidence: 99%

“…With unmatched potency and selectivity, macromolecular drugs (ie, proteins or genes) have drawn interest over the past few decades for overcoming the limitations of small molecular drugs, which are accompanied by side effects and toxicity at therapeutic dosages [20][21][22] . Gelonin, a plant-derived protein toxin, is one of the macromolecular drug candidates.…”

Section: Introductionmentioning

confidence: 99%

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Molecular tumor targeting of gelonin by fusion with F3 peptide

2017

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Therapeutically potent macromolecular drugs have shown great promise for overcoming the limitations of small-molecule anti-cancer drugs. But tumor cell-selective intracellular delivery of the macromolecules remains a major hurdle for their successful clinical application. To overcome this challenge, we engineered a novel genetic fusion protein (F3-Gel) that composed of F3 peptide, a tumorhoming peptide, and gelonin, a plant-derived ribosome-inactivating protein (RIP), and then evaluated its anti-cancer activity in vitro and in vivo. The F3-Gel-encoding gene was synthesized by genetic recombination, and F3-Gel was successfully expressed in E coli. The anti-cancer activity of the produced F3-Gel was evaluated by various in vitro assays, which revealed that F3-Gel maintained equipotent protein synthesis inhibition activity (IC 50 =11 pmol/L) as unmodified gelonin (IC 50 =10 pmol/L). Furthermore, F3-Gel displayed enhanced cellular uptake into cancer cells (U87 MG, HeLa, LnCaP and 9L) than noncancerous cells (293 HEK and SVGp12). Compared with gelonin, F3-Gel exerted significantly higher cytotoxicity against these cancer cells. F3-Gel displayed significantly greater inhibition of protein translation in U87 MG cells: F3-Gel (0.5 μmol/L) was able to reduce the protein level to less than 50%, while gelonin (1 μmol/L) did not affect the intracellular protein level. In a U87 MG xenograft tumor-bearing mouse model, F3-Gel was accumulated in the tumor site at much higher levels and maintained for a prolonged time compared with gelonin. Administration of F3-Gel (0.5, 0.75 mol/kg, iv) caused 36% and 66%, respectively, inhibition of tumor growth in U87 MG xenograft mice, suggesting that it is a promising candidate drug for cancer treatment. Furthermore, this study demonstrates that fusion of F3 peptide to a potent macromolecule could provides an effective method for targeting tumors and eventually could improve their druggability.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular tumor targeting of gelonin by fusion with F3 peptide

2017

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“…As previously mentioned, bacterial toxins and Type-II-RIPs possess an intrinsic translocation domain in their B chain whereas Type-I-RIPs and vertebrate toxins do not [19,39]. Thus, in the majority of cases, diphtheria toxin and Pseudomonas exotoxin A are administered in a truncated form with the cell binding domain deleted and the membrane transfer domain retained [17,40].…”

Section: Endosomal Escapementioning

confidence: 99%

“…The catalytic A chain cleaves a specific N-glycosidic bond in mammalian 28S ribosomal RNA resulting in the release of an adenine that is required to bind the eukaryotic elongation factors 1 and 2 [21], resulting ultimately in the arrest of protein biosynthesis. Since Type-I-RIPs lack a cell binding domain, they are on the one hand ideal for the design of targeted toxins; however, they do not possess a domain for internalization or efficient transfer across the endosomal membrane; they are therefore on the other hand limited in their stand alone use, though they do efficiently mediate cell death once they have gained entry to the cytosol [19]. Thus, devising strategies to enhance the endosomal escape of Type-I-RIPs is of great practical interest.…”

Section: Introductionmentioning

confidence: 99%

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Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins

Fuchs

Bachran²,

Flavell

et al. 2013

Antibodies

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Membranes are vital barriers by which cells control the flux of molecules and energy between their exterior and interior and also between their various intracellular compartments. While numerous transport systems exist for ions and small molecules, the cytosolic uptake of larger biological molecules and in particular antibody-targeted drugs, is a big challenge. Inducing leakage of the plasma membrane is unfavorable since the target cell specificity mediated by the antibody would likely be lost in this case. After binding and internalization, the antibody drug conjugates reach the endosomes. Thus, enforcing the endosomal escape of anti-tumor toxins without affecting the integrity of other cellular membranes is of paramount importance. Different strategies have been developed in the last decades to overcome endosomal accumulation and subsequent lysosomal degradation of targeted protein-based drugs. In this review we summarize the various efforts made to establish efficient techniques to disrupt the endosomal membrane barrier including the use of molecular ferries such as cell penetrating peptides or viral membrane fusion proteins, endosomal leakage inducing molecules such as saponins or monensin and physicochemical methods as represented by photochemical internalization.

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Introduction and History

Stirpe

2014

Ribosome‐inactivating Proteins

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Ribosome-inactivating proteins: current status and biomedical applications

Cited by 144 publications

References 62 publications

Molecular tumor targeting of gelonin by fusion with F3 peptide

Molecular tumor targeting of gelonin by fusion with F3 peptide

Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins

Introduction and History

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