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Discovery of a Direct Ras Inhibitor by Screening a Combinatorial Library of Cell-Permeable Bicyclic Peptides.

التفاصيل البيبلوغرافية
العنوان: Discovery of a Direct Ras Inhibitor by Screening a Combinatorial Library of Cell-Permeable Bicyclic Peptides.
المؤلفون: Trinh TB; Department of Chemistry and Biochemistry, The Ohio State University , 484 West 12th Avenue, Columbus, Ohio 43210, United States., Upadhyaya P; Department of Chemistry and Biochemistry, The Ohio State University , 484 West 12th Avenue, Columbus, Ohio 43210, United States., Qian Z; Department of Chemistry and Biochemistry, The Ohio State University , 484 West 12th Avenue, Columbus, Ohio 43210, United States., Pei D; Department of Chemistry and Biochemistry, The Ohio State University , 484 West 12th Avenue, Columbus, Ohio 43210, United States.
المصدر: ACS combinatorial science [ACS Comb Sci] 2016 Jan 11; Vol. 18 (1), pp. 75-85. Date of Electronic Publication: 2015 Dec 23.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101540531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2156-8944 (Electronic) Linking ISSN: 21568944 NLM ISO Abbreviation: ACS Comb Sci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Chemical Society
مواضيع طبية MeSH: Antineoplastic Agents/*chemistry , Antineoplastic Agents/*pharmacology , Cell-Penetrating Peptides/*chemistry , Cell-Penetrating Peptides/*pharmacology , Peptides, Cyclic/*chemistry , Peptides, Cyclic/*pharmacology , ras Proteins/*antagonists & inhibitors, Antineoplastic Agents/chemical synthesis ; Cell Line, Tumor ; Cell-Penetrating Peptides/chemical synthesis ; Humans ; Lung/drug effects ; Lung/metabolism ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Peptide Library ; Peptides, Cyclic/chemical synthesis ; Point Mutation ; Signal Transduction/drug effects ; ras Proteins/genetics ; ras Proteins/metabolism
مستخلص: Cyclic peptides have great potential as therapeutic agents and research tools. However, their applications against intracellular targets have been limited, because cyclic peptides are generally impermeable to the cell membrane. It was previously shown that fusion of cyclic peptides with a cyclic cell-penetrating peptide resulted in cell-permeable bicyclic peptides that are proteolytically stable and biologically active in cellular assays. In this work, we tested the generality of the bicyclic approach by synthesizing a combinatorial library of 5.7 × 10(6) bicyclic peptides featuring a degenerate sequence in the first ring and an invariant cell-penetrating peptide in the second ring. Screening of the library against oncoprotein K-Ras G12V followed by hit optimization produced a moderately potent and cell-permeable K-Ras inhibitor, which physically blocks the Ras-effector interactions in vitro, inhibits the signaling events downstream of Ras in cancer cells, and induces apoptosis of the cancer cells. Our approach should be generally applicable to developing cell-permeable bicyclic peptide inhibitors against other intracellular proteins.
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معلومات مُعتمدة: R01 GM062820 United States GM NIGMS NIH HHS; R01 GM110208 United States GM NIGMS NIH HHS; GM062820 United States GM NIGMS NIH HHS; GM110208 United States GM NIGMS NIH HHS
فهرسة مساهمة: Keywords: Ras inhibitor; anticancer agent; bicyclic peptide; cell-penetrating peptide; peptide library
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Cell-Penetrating Peptides)
0 (Peptide Library)
0 (Peptides, Cyclic)
EC 3.6.5.2 (ras Proteins)
تواريخ الأحداث: Date Created: 20151210 Date Completed: 20161013 Latest Revision: 20181113
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC4710893
DOI: 10.1021/acscombsci.5b00164
PMID: 26645887
قاعدة البيانات: MEDLINE
الوصف
تدمد:2156-8944
DOI:10.1021/acscombsci.5b00164