Constrained peptides mimic a viral suppressor of RNA silencing
| Autor: | Arne Kuepper, Niall M McLoughlin, Saskia Neubacher, Alejandro Yeste-Vázquez, Estel Collado Camps, Chandran Nithin, Sunandan Mukherjee, Lucas Bethge, Janusz M Bujnicki, Roland Brock, Stefan Heinrichs, Tom N Grossmann |
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| Přispěvatelé: | Organic Chemistry, Chemistry and Pharmaceutical Sciences, AIMMS |
| Rok vydání: | 2021 |
| Předmět: |
Cell Membrane Permeability
AcademicSubjects/SCI00010 Medizin 010402 general chemistry Cucumovirus 01 natural sciences Viral Proteins 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center Chemical Biology and Nucleic Acid Chemistry RNA Precursors Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] Genetics Humans RNA Small Interfering RNA Double-Stranded 030304 developmental biology 0303 health sciences Molecular Mimicry RNA-Binding Proteins 0104 chemical sciences MicroRNAs RNA Interference Endopeptidase K K562 Cells Peptides Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] |
| Zdroj: | Nucleic acids research, 49(22), 12622-12633. Oxford University Press Nucleic Acids Research, 49, 22, pp. 12622-12633 Nucleic Acids Research, 49, 12622-12633 Nucleic Acids Research Kuepper, A, McLoughlin, N M, Neubacher, S, Yeste-Vázquez, A, Collado Camps, E, Nithin, C, Mukherjee, S, Bethge, L, Bujnicki, J M, Brock, R, Heinrichs, S & Grossmann, T N 2021, ' Constrained peptides mimic a viral suppressor of RNA silencing ', Nucleic acids research, vol. 49, no. 22, pp. 12622-12633 . https://doi.org/10.1093/nar/gkab1149 |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | The design of high-affinity, RNA-binding ligands has proven very challenging. This is due to the unique structural properties of RNA, often characterized by polar surfaces and high flexibility. In addition, the frequent lack of well-defined binding pockets complicates the development of small molecule binders. This has triggered the search for alternative scaffolds of intermediate size. Among these, peptide-derived molecules represent appealing entities as they can mimic structural features also present in RNA-binding proteins. However, the application of peptidic RNA-targeting ligands is hampered by a lack of design principles and their inherently low bio-stability. Here, the structure-based design of constrained α-helical peptides derived from the viral suppressor of RNA silencing, TAV2b, is described. We observe that the introduction of two inter-side chain crosslinks provides peptides with increased α-helicity and protease stability. One of these modified peptides (B3) shows high affinity for double-stranded RNA structures including a palindromic siRNA as well as microRNA-21 and its precursor pre-miR-21. Notably, B3 binding to pre-miR-21 inhibits Dicer processing in a biochemical assay. As a further characteristic this peptide also exhibits cellular entry. Our findings show that constrained peptides can efficiently mimic RNA-binding proteins rendering them potentially useful for the design of bioactive RNA-targeting ligands. |
| Databáze: | OpenAIRE |
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