An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site.
Aminoacyl-transfer RNA (tRNA) synthetases, which catalyze the attachment of the correct amino acid to its corresponding tRNA during translation of the genetic code, are proven antimicrobial drug targets. We show that the broad-spectrum antifungal 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), in development for the treatment of onychomycosis, inhibits yeast cytoplasmic leucyl-tRNA synthetase by formation of a stable tRNA(Leu)-AN2690 adduct in the editing site of the enzyme. Adduct formation is mediated through the boron atom of AN2690 and the 2'- and 3'-oxygen atoms of tRNA's3'-terminal adenosine. The trapping of enzyme-bound tRNA(Leu) in the editing site prevents catalytic turnover, thus inhibiting synthesis of leucyl-tRNA(Leu) and consequentially blocking protein synthesis. This result establishes the editing site as a bona fide target for aminoacyl-tRNA synthetase inhibitors.
Rock
Fernando L
FL
Anacor Pharmaceuticals, Incorporated, 1060 East Meadow Circle, Palo Alto, CA 94303, USA.
Mao
Weimin
W
Yaremchuk
Anya
A
Tukalo
Mikhail
M
Crépin
Thibaut
T
Zhou
Huchen
H
Zhang
Yong-Kang
YK
Hernandez
Vincent
V
Akama
Tsutomu
T
Baker
Stephen J
SJ
Plattner
Jacob J
JJ
Shapiro
Lucy
L
Martinis
Susan A
SA
Benkovic
Stephen J
SJ
Cusack
Stephen
S
Alley
M R K
MR
D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001895:Boron / Q000737:chemistry; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D025141:Drug Resistance, Fungal / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007935:Leucine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011500:Protein Synthesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017393:RNA Editing / Q000187:drug effects; D012356:RNA, Transfer, Leu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics
D000935:Antifungal Agents; D001896:Boron Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; D012356:RNA, Transfer, Leu; D007935:Leucine-tRNA Ligase; C512998:tavaborole; D001895:Boron