A Novel Class of Intrinsic Proteasome Inhibitory Gene Transfer Peptides

Martin, Molly E.; Rice, Kevin G.

doi:10.1021/bc700362b

Cited by 8 publications

(11 citation statements)

References 32 publications

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“…The vinyl ester head of inhibitors Leu-ve was synthesized with a modified method reported by Rice et al 16 Boc-Leu-OH was reacted with N,O-dimethylhydroxylamine under excess DIPEA and kept in basylous condition for 3 h. The product was converted completely to aldehyde derivatives Boc-Leu-al by LAH within 30 min. 19 The mixture was added to potassium hydrogen sulfate solution in an ice bath.…”

Section: Methodsmentioning

confidence: 99%

“…The inhibition mechanism was similar to that of peptide vinyl sulfone inhibitors with a Michael addition with the N-terminal catalytic threonine residue of β subunit. 15 Martin et al 16 constructed another class of intrinsic proteasome inhibitory peptides such as WK 18 -LLL-ve, WK 18 -LLLnV-ve, and WK 18 -FQL-ve. The C-terminal side of the linear peptide WK 18 was modified with a tripeptide vinyl ester inhibitor sequence Leu-Leu-Leu-ve or Phe-Gln-Leu-ve.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and inhibition study on tripeptide inhibitor modified poly(l-lysine) dendrimers

et al. 2010

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Peptide dendrimers are attractive nonviral gene vectors. But a biological barrier for their application in gene delivery is the fast degradation catalyzed by proteasomes. Proteasome inhibitors are efficient at prohibiting the degradation of peptide nonviral vectors, thus enhancing gene transfection efficiency. In this study, N(α)-Boc-protected leucine vinyl ester proteasome inhibitor Boc-Leu-Leu-Leu-ve was synthesized by the liquid-phase method and was then immobilized onto poly(L-lysine) dendrimers. Suc-Leu-Leu-Val-Tyr-AMC was used as fluorimetric substrate and the inhibition capacity of Boc-Leu-Leu-Leu-ve immobilized onto G(3) and G(6) poly(L-lysine) dendrimers for the chymotrypsin-like activity of ACHN cell proteasome was tested. The results indicated that both Boc-Leu-Leu-Leu-ve peptide and the peptide immobilized on G(3) dendrimer showed low inhibition capacity when the concentration was below 0.2 μM. When the inhibitor concentrations were increased to 5.0 μM, however, the percentage inhibition of Boc-Leu-Leu-Leu-ve peptide and the peptide immobilized on G(3) dendrimer became about 50% and 25%, and that of peptide immobilized on the G(6) dendrimer was 7.5% only. These results indicated that dendritic structure and linker length could be the main factors affecting proteasome inhibition capacity. The cytotoxicity of the dendritic inhibitors was found to be low. Thus, whilst the synthetic production of poly(L-lysine) dendrimers immobilized with peptide inhibitors was successful and these modified dendrimers could work to inhibit proteasome activity, further studies will need to be carried out to improve inhibition capacity.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and inhibition study on tripeptide inhibitor modified poly(l-lysine) dendrimers

et al. 2010

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“…In addition to the use of lipoplexes as a dual-function vectore, Rice et al (2008) designed a type of novel cationic polypeptides capable of incorporating peptides with an intrinsic proteasome inhibitory function in order to improve transfection activity of plasmid DNA [80]. Proteasomes are important cellular enzymes responsible for the degradation of a variety of proteins.…”

Section: Delivery Strategies For Drug-nucleic Acid Combinationsmentioning

confidence: 99%

Recent advances in delivery of drug–nucleic acid combinations for cancer treatment

Wang

Zhu

et al. 2013

Journal of Controlled Release

185

128

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Cancer treatment that uses a combination of approaches with the ability to affect multiple disease pathways has been proven highly effective in the treatment of many cancers. Combination therapy can include multiple chemotherapeutics or combinations of chemotherapeutics with other treatment modalities like surgery or radiation. However, despite the widespread clinical use of combination therapies, relatively little attention has been given to the potential of modern nanocarrier delivery methods, like liposomes, micelles, and nanoparticles, to enhance the efficacy of combination treatments. This lack of knowledge is particularly notable in the limited success of vectors for the delivery of combinations of nucleic acids with traditional small molecule drugs. The delivery of drug-nucleic acid combinations is particularly challenging due to differences in the physicochemical properties of the two types of agents. This review discusses recent advances in the development of delivery methods using combinations of small molecule drugs and nucleic acid therapeutics to treat cancer. This review primarily focuses on the rationale used for selecting appropriate drug-nucleic acid combinations as well as progress in the development of nanocarriers suitable for simultaneous delivery of drug-nucleic acid combinations.

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“…A vinyl ester tripeptide has been recently incorporated at the C-end of a gene delivery peptide [159]. The resulting peptide forms DNA condensates that enhance gene expression 100-fold compared to a control peptide lacking the inhibitor.…”

Section: Peptide Vinyl Estersmentioning

confidence: 99%

Proteasome Inhibitors: Recent Advances and New Perspectives In Medicinal Chemistry

Genin¹,

Reboud‐Ravaux²,

Vidal

2010

CTMC

107

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The search for proteasome inhibitors began fifteen years ago. These inhibitors proved to be powerful tools for investigating many important cellular processes regulated by the ubiquitin-proteasome pathway. Targeting the proteasome pathway can also lead to new treatments for disorders like cancer, muscular dystrophies, inflammation and immune diseases. This is already true for cancer; the FDA approved bortezomib, a potent proteasome inhibitor, for treating multiple myeloma in 2003, and mantle cell lymphoma in 2006. The chemical structures identified in some of the early proteasome inhibitors have led to the development of new anti-cancer drugs (CEP-18770, Carfilzomib, NPI-0052). All these molecules are covalent bonding inhibitors that react with the catalytic Thr1-O(gamma) of the three types of active site. This review covers recent developments in medicinal chemistry of natural and synthetic proteasome inhibitors. Advances in non-covalent inhibitors that have no reactive group will be highlighted as they should minimize side-effects. New structures and new modes of action have been recently identified that open the door to new drug candidates for treating a range of diseases.

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A Novel Class of Intrinsic Proteasome Inhibitory Gene Transfer Peptides

Cited by 8 publications

References 32 publications

Synthesis and inhibition study on tripeptide inhibitor modified poly(l-lysine) dendrimers

Synthesis and inhibition study on tripeptide inhibitor modified poly(l-lysine) dendrimers

Recent advances in delivery of drug–nucleic acid combinations for cancer treatment

Proteasome Inhibitors: Recent Advances and New Perspectives In Medicinal Chemistry

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