Estimating genome-wide off-target effects for pyrrole-imidazole polyamide binding by a pathway-based expression profiling approach

Jason Lin, Sakthisri Krishnamurthy, Hiroyuki Yoda, Yoshinao Shinozaki, Takayoshi Watanabe, Nobuko Koshikawa, Atsushi Takatori, Brice Horton Ii Paul, Hiroki Nagase

Research output: Contribution to journalArticle

Abstract

In the search for new pharmaceutical leads, especially with DNA-binding molecules or genome editing methods, the issue of side and off-target effects have always been thorny in nature. A particular case is the investigation into the off-target effects of N-methylpyrrole-N-methylimidazole polyamides, a naturally inspired class of DNA binders with strong affinity to the minor-groove and sequence specificity, but at < 20 bases, their relatively short motifs also insinuate the possibility of non-unique genomic binding. Binding at non-intended loci potentially lead to the rise of off-target effects, issues that very few approaches are able to address to-date. We here report an analytical method to infer off-target binding, via expression profiling, based on probing the relative impact to various biochemical pathways; we also proposed an accompanying side effect prediction engine for the systematic screening of candidate polyamides. This method marks the first attempt in PI polyamide research to identify elements in biochemical pathways that are sensitive to the treatment of a candidate polyamide as an approach to infer possible off-target effects. Expression changes were then considered to assess possible outward phenotypic changes, manifested as side effects, should the same PI polyamide candidate be administered clinically. We validated some of these effects with a series of animal experiments, and found agreeable corroboration in certain side effects, such as changes in aspartate transaminase levels in ICR and nude mice post-administration.

Original languageEnglish
Article numbere0215247
JournalPloS one
Volume14
Issue number4
DOIs
Publication statusPublished - 2019 Apr 1

Fingerprint

pyrroles
Pyrroles
imidazoles
Nylons
Genes
Genome
genome
adverse effects
biochemical pathways
Inbred ICR Mouse
new drugs
animal experimentation
DNA
engines
Aspartate Aminotransferases
Nude Mice
aspartate transaminase
Binders
analytical methods
Screening

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Lin, J., Krishnamurthy, S., Yoda, H., Shinozaki, Y., Watanabe, T., Koshikawa, N., ... Nagase, H. (2019). Estimating genome-wide off-target effects for pyrrole-imidazole polyamide binding by a pathway-based expression profiling approach. PloS one, 14(4), [e0215247]. https://doi.org/10.1371/journal.pone.0215247
Lin, Jason ; Krishnamurthy, Sakthisri ; Yoda, Hiroyuki ; Shinozaki, Yoshinao ; Watanabe, Takayoshi ; Koshikawa, Nobuko ; Takatori, Atsushi ; Paul, Brice Horton Ii ; Nagase, Hiroki. / Estimating genome-wide off-target effects for pyrrole-imidazole polyamide binding by a pathway-based expression profiling approach. In: PloS one. 2019 ; Vol. 14, No. 4.
@article{f705956fb5ba4c2bb19cc50578d99162,
title = "Estimating genome-wide off-target effects for pyrrole-imidazole polyamide binding by a pathway-based expression profiling approach",
abstract = "In the search for new pharmaceutical leads, especially with DNA-binding molecules or genome editing methods, the issue of side and off-target effects have always been thorny in nature. A particular case is the investigation into the off-target effects of N-methylpyrrole-N-methylimidazole polyamides, a naturally inspired class of DNA binders with strong affinity to the minor-groove and sequence specificity, but at < 20 bases, their relatively short motifs also insinuate the possibility of non-unique genomic binding. Binding at non-intended loci potentially lead to the rise of off-target effects, issues that very few approaches are able to address to-date. We here report an analytical method to infer off-target binding, via expression profiling, based on probing the relative impact to various biochemical pathways; we also proposed an accompanying side effect prediction engine for the systematic screening of candidate polyamides. This method marks the first attempt in PI polyamide research to identify elements in biochemical pathways that are sensitive to the treatment of a candidate polyamide as an approach to infer possible off-target effects. Expression changes were then considered to assess possible outward phenotypic changes, manifested as side effects, should the same PI polyamide candidate be administered clinically. We validated some of these effects with a series of animal experiments, and found agreeable corroboration in certain side effects, such as changes in aspartate transaminase levels in ICR and nude mice post-administration.",
author = "Jason Lin and Sakthisri Krishnamurthy and Hiroyuki Yoda and Yoshinao Shinozaki and Takayoshi Watanabe and Nobuko Koshikawa and Atsushi Takatori and Paul, {Brice Horton Ii} and Hiroki Nagase",
year = "2019",
month = "4",
day = "1",
doi = "10.1371/journal.pone.0215247",
language = "English",
volume = "14",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

Lin, J, Krishnamurthy, S, Yoda, H, Shinozaki, Y, Watanabe, T, Koshikawa, N, Takatori, A, Paul, BHI & Nagase, H 2019, 'Estimating genome-wide off-target effects for pyrrole-imidazole polyamide binding by a pathway-based expression profiling approach', PloS one, vol. 14, no. 4, e0215247. https://doi.org/10.1371/journal.pone.0215247

Estimating genome-wide off-target effects for pyrrole-imidazole polyamide binding by a pathway-based expression profiling approach. / Lin, Jason; Krishnamurthy, Sakthisri; Yoda, Hiroyuki; Shinozaki, Yoshinao; Watanabe, Takayoshi; Koshikawa, Nobuko; Takatori, Atsushi; Paul, Brice Horton Ii; Nagase, Hiroki.

In: PloS one, Vol. 14, No. 4, e0215247, 01.04.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Estimating genome-wide off-target effects for pyrrole-imidazole polyamide binding by a pathway-based expression profiling approach

AU - Lin, Jason

AU - Krishnamurthy, Sakthisri

AU - Yoda, Hiroyuki

AU - Shinozaki, Yoshinao

AU - Watanabe, Takayoshi

AU - Koshikawa, Nobuko

AU - Takatori, Atsushi

AU - Paul, Brice Horton Ii

AU - Nagase, Hiroki

PY - 2019/4/1

Y1 - 2019/4/1

N2 - In the search for new pharmaceutical leads, especially with DNA-binding molecules or genome editing methods, the issue of side and off-target effects have always been thorny in nature. A particular case is the investigation into the off-target effects of N-methylpyrrole-N-methylimidazole polyamides, a naturally inspired class of DNA binders with strong affinity to the minor-groove and sequence specificity, but at < 20 bases, their relatively short motifs also insinuate the possibility of non-unique genomic binding. Binding at non-intended loci potentially lead to the rise of off-target effects, issues that very few approaches are able to address to-date. We here report an analytical method to infer off-target binding, via expression profiling, based on probing the relative impact to various biochemical pathways; we also proposed an accompanying side effect prediction engine for the systematic screening of candidate polyamides. This method marks the first attempt in PI polyamide research to identify elements in biochemical pathways that are sensitive to the treatment of a candidate polyamide as an approach to infer possible off-target effects. Expression changes were then considered to assess possible outward phenotypic changes, manifested as side effects, should the same PI polyamide candidate be administered clinically. We validated some of these effects with a series of animal experiments, and found agreeable corroboration in certain side effects, such as changes in aspartate transaminase levels in ICR and nude mice post-administration.

AB - In the search for new pharmaceutical leads, especially with DNA-binding molecules or genome editing methods, the issue of side and off-target effects have always been thorny in nature. A particular case is the investigation into the off-target effects of N-methylpyrrole-N-methylimidazole polyamides, a naturally inspired class of DNA binders with strong affinity to the minor-groove and sequence specificity, but at < 20 bases, their relatively short motifs also insinuate the possibility of non-unique genomic binding. Binding at non-intended loci potentially lead to the rise of off-target effects, issues that very few approaches are able to address to-date. We here report an analytical method to infer off-target binding, via expression profiling, based on probing the relative impact to various biochemical pathways; we also proposed an accompanying side effect prediction engine for the systematic screening of candidate polyamides. This method marks the first attempt in PI polyamide research to identify elements in biochemical pathways that are sensitive to the treatment of a candidate polyamide as an approach to infer possible off-target effects. Expression changes were then considered to assess possible outward phenotypic changes, manifested as side effects, should the same PI polyamide candidate be administered clinically. We validated some of these effects with a series of animal experiments, and found agreeable corroboration in certain side effects, such as changes in aspartate transaminase levels in ICR and nude mice post-administration.

UR - http://www.scopus.com/inward/record.url?scp=85064089235&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064089235&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0215247

DO - 10.1371/journal.pone.0215247

M3 - Article

C2 - 30964912

AN - SCOPUS:85064089235

VL - 14

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e0215247

ER -