Development of novel cyclic peptides as pro-apoptotic agents

Brindisi, Margherita; Maramai, Samuele; Brogi, Simone; Fanigliulo, Emanuela; Butini, Stefania; Guarino, Egeria; Casagni, Alice; Lamponi, Stefania; Bonechi, Claudia; Nathwani, Seema M.; Finetti, Federica; Ragonese, Francesco; Arcidiacono, Paola; Campiglia, Pietro; Valenti, Salvatore; Novellino, Ettore; Spaccapelo, Roberta; Morbidelli, Lucia; Zisterer, Daniela M.; Williams, Clive D.; Donati, Alessandro; Baldari, Cosima T.; Campiani, Giuseppe; Ulivieri, Cristina

doi:10.1016/j.ejmech.2016.04.001

Cited by 23 publications

(20 citation statements)

References 50 publications

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“…Cyclic peptides named mimotopes were generated and proved to be more effective than linear epitopes in establishment of anti-ErbB-2 monoclonal antibodies [23]. Cyclic peptides, of which the structure is similar to paclitaxel, efficaciously induced apoptosis in many cancer cell lines [24]. Cyclic peptides blocking intracellular protein-protein interaction of Ras signaling components were also suggested as a new anti-cancer agent [25].…”

Section: Discussionmentioning

confidence: 99%

Anti-metastatic effect of the TM4SF5-specific peptide vaccine and humanized monoclonal antibody on colon cancer in a mouse lung metastasis model

Kim

et al. 2016

Oncotarget

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Transmembrane 4 superfamily member 5 protein (TM4SF5) is a potential therapeutic target for hepatocellular carcinoma (HCC) and colon cancer. In a previous study, we demonstrated the prophylactic and therapeutic effects of a TM4SF5-specific peptide vaccine and monoclonal antibody in HCC and colon cancer in a mouse model. Here, we designed a cyclic peptide targeting TM4SF5. Cyclic peptide-specific antibodies were produced in mice after immunization with a complex of the peptide, CpG-DNA, and liposomes. Intravenous injection of the CT-26 mouse colon cancer cell line into mice induced tumors in the lung. Immunization with the peptide vaccine improved the survival rate and reduced the growth of lung tumors. We established a monoclonal antibody specific to the cyclic TM4SF5-based peptide and humanized the antibody sequence by complementarity determining region-grafting. The humanized antibody was reactive to the cyclic peptide and TM4SF5 protein. Treatment of CT-26 cells with the humanized antibody reduced cell motility in vitro. Furthermore, direct injection of the humanized anti-TM4SF5 antibody in vivo reduced growth of lung tumors in mouse metastasis model. Therefore, we conclude that the immunization with the cyclic peptide vaccine and injection of the TM4SF5-specifc humanized antibody have an anti-metastatic effect against colon cancer in mice. Importantly, the humanized antibody may serve as a starting platform for further development and application in clinical settings.

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Section: Discussionmentioning

confidence: 99%

Anti-metastatic effect of the TM4SF5-specific peptide vaccine and humanized monoclonal antibody on colon cancer in a mouse lung metastasis model

Kim

et al. 2016

Oncotarget

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“…Some cyclic peptides with phytotoxic activity show potential applications such as herbicides against weeds [ 217 ]. Biological analysis revealed a pro-apoptotic effect for most of the cyclic peptides that indicated that the cyclic peptides could be developed as the pro-apoptotic agents [ 218 ].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Structural Diversity and Biological Activities of Fungal Cyclic Peptides, Excluding Cyclodipeptides

Wang

Lin

et al. 2017

Molecules

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Cyclic peptides are cyclic compounds formed mainly by the amide bonds between either proteinogenic or non-proteinogenic amino acids. This review highlights the occurrence, structures and biological activities of fungal cyclic peptides (excluding cyclodipeptides, and peptides containing ester bonds in the core ring) reported until August 2017. About 293 cyclic peptides belonging to the groups of cyclic tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, tetradeca-, and octadecapeptides as well as cyclic peptides containing ether bonds in the core ring have been isolated from fungi. They were mainly isolated from the genera Aspergillus, Penicillium, Fusarium, Acremonium and Amanita. Some of them were screened to have antimicrobial, antiviral, cytotoxic, phytotoxic, insecticidal, nematicidal, immunosuppressive and enzyme-inhibitory activities to show their potential applications. Some fungal cyclic peptides such as the echinocandins, pneumocandins and cyclosporin A have been developed as pharmaceuticals.

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“…This latter mechanism could contribute to their anticancer activity [12][13][14][15]. Following our interest in the field [16][17][18], in this scenario, pyrrolo-1,5-benzoxazepines, typified by the 4acetoxy-5-(1-naphthyl) naphtho [2,3-b]pyrrolo [2,1-d] [1,4]oxazepine (PNOX, Table 1) [17,[19][20][21][22][23][24][25][26]. With the aim of further improving the class of benzoxazepine anticancers (antitumor potency and drug-like properties) and to fully elucidate their mechanism of action, we extended our studies by further decorating and/or modifying the original scaffold at different levels [27].…”

Section: Accepted Manuscriptmentioning

confidence: 95%

Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents

Brindisi

Ulivieri

Alfano

et al. 2019

European Journal of Medicinal Chemistry

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Microtubule-targeting agents (MTAs) are a class of clinically successful anti-cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j, one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors.

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Development of novel cyclic peptides as pro-apoptotic agents

Cited by 23 publications

References 50 publications

Anti-metastatic effect of the TM4SF5-specific peptide vaccine and humanized monoclonal antibody on colon cancer in a mouse lung metastasis model

Anti-metastatic effect of the TM4SF5-specific peptide vaccine and humanized monoclonal antibody on colon cancer in a mouse lung metastasis model

Structural Diversity and Biological Activities of Fungal Cyclic Peptides, Excluding Cyclodipeptides

Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents

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