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N1-Propargylguanosine Modified mRNA Cap Analogs: Synthesis, Reactivity, and Applications to the Study of Cap-Binding Proteins

1
College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland
2
Centre of New Technologies, University of Warsaw; S. Banacha 2c, 02-097 Warsaw, Poland
3
Faculty of Physics, University of Warsaw; L. Pasteura 5, 02-093 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(10), 1899; https://doi.org/10.3390/molecules24101899
Received: 23 April 2019 / Revised: 14 May 2019 / Accepted: 15 May 2019 / Published: 17 May 2019
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Abstract

The mRNA 5′ cap consists of N7-methylguanosine bound by a 5′,5′-triphosphate bridge to the first nucleotide of the transcript. The cap interacts with various specific proteins and participates in all key mRNA-related processes, which may be of therapeutic relevance. There is a growing demand for new biophysical and biochemical methods to study cap–protein interactions and identify the factors which inhibit them. The development of such methods can be aided by the use of properly designed fluorescent molecular probes. Herein, we synthesized a new class of m7Gp3G cap derivatives modified with an alkyne handle at the N1-position of guanosine and, using alkyne-azide cycloaddition, we functionalized them with fluorescent tags to obtain potential probes. The cap derivatives and probes were evaluated in the context of two cap-binding proteins, eukaryotic translation initiation factor (eIF4E) and decapping scavenger (DcpS). Biochemical and biophysical studies revealed that N1-propargyl moiety did not significantly disturb cap–protein interaction. The fluorescent properties of the probes turned out to be in line with microscale thermophoresis (MST)-based binding assays. View Full-Text
Keywords: mRNA cap; 7-methylguanosine; DcpS; eIF4E; fluorescent probes; MST mRNA cap; 7-methylguanosine; DcpS; eIF4E; fluorescent probes; MST
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Kopcial, M.; Wojtczak, B.A.; Kasprzyk, R.; Kowalska, J.; Jemielity, J. N1-Propargylguanosine Modified mRNA Cap Analogs: Synthesis, Reactivity, and Applications to the Study of Cap-Binding Proteins. Molecules 2019, 24, 1899.

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