Phosphorothioate analogs of m7GTP are enzymatically stable inhibitors of cap-dependent translation.
We report synthesis and properties of a pair of new potent inhibitors of translation, namely two diastereomers of 7-methylguanosine 5'-(1-thiotriphosphate). These new analogs of mRNA 5'cap (referred to as m(7)GTPalphaS (D1) and (D2)) are recognized by translational factor eIF4E with high affinity and are not susceptible to hydrolysis by Decapping Scavenger pyrophosphatase (DcpS). The more potent of diastereomers, m(7)GTPalphaS (D1), inhibited cap-dependent translation in rabbit reticulocyte lysate approximately 8-fold and approximately 15-fold more efficiently than m(7)GTP and m(7)GpppG, respectively. Both analogs were also significantly more stable in RRL than unmodified ones.
Kowalska
Joanna
J
Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 02-089 Warsaw, Poland.
Lukaszewicz
Maciej
M
Zuberek
Joanna
J
Ziemniak
Marcin
M
Darzynkiewicz
Edward
E
Jemielity
Jacek
J
D000818:Animals; D004722:Endoribonucleases / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012314:RNA Cap Analogs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012315:RNA Caps / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013237:Stereoisomerism; D013873:Thionucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C541278:7-methylguanosine 5'-(1-thiotriphosphate); D039561:Eukaryotic Initiation Factor-4E; D011500:Protein Synthesis Inhibitors; D012314:RNA Cap Analogs; D012315:RNA Caps; D012333:RNA, Messenger; D013873:Thionucleotides; C017516:7-methylguanosine triphosphate; D006160:Guanosine Triphosphate; D004722:Endoribonucleases; C485332:DcpS protein, human