Sensor dimer disruption as a new mode of action to block the IRE1-mediated unfolded protein response

• The unfolded protein response (UPR) is activated to cope with an accumulation of improperly folded proteins in the Endoplasmic reticulum (ER). The Inositol requiring enzyme 1 alpha (IRE1 alpha) is the most evolutionary conserved transducer of the UPR. Activated IRE1 forms 'back-to-back'-dimers that enables the unconventional splicing of X-box Binding Protein 1 (XBP1) mRNA. The spliced XBP1 (XBP1s) mRNA is translated into a transcription factor controlling the expression of UPR target genes. Herein, we report a detailed in silico screening specifically targeting for the first time the dimer interface at the IRE1 RNase region. Using the database of FDA approved drugs, we identified four compounds (neomycin, pemetrexed, quercitrin and rutin) that were able to bind to and distort IRE1 RNase cavity. The activity of the compounds on IRE1 phosphorylation was evaluated in HEK293T cells and on IRE1 RNase activity using an in vitro fluorescence assay. These analyzes revealed sub-micromolar IC50 values. The current study reveals a new and unique mode of action to target and block the IRE1-mediated UPR signaling, whereby we may avoid problems associated with selectivity occurring when targeting the IRE1 kinase pocket as well as the inherent reactivity of covalent inhibitors targeting the RNase pocket. (C)& nbsp;2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.& nbsp;

Subject headings

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology (hsv//eng)

Keyword

IRE1 alpha

UPR

Peptide docking

Dimer disruptor

FDA approved

drugs

MD simulations

potential functions

accurate docking

force-field

ire1-alpha

inhibition

pathway

phase

glide

activation

prediction

Biochemistry & Molecular Biology

Biotechnology & Applied Microbiology

Publication and Content Type

ref (subject category)

art (subject category)