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 language | English |
|---|---|
| Article number | e0215247 |
| Journal | PloS one |
| Volume | 14 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2019 Apr |
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All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
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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; Horton, Paul; Nagase, Hiroki.
In: PloS one, Vol. 14, No. 4, e0215247, 04.2019.Research output: Contribution to journal › Article
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 - Horton, Paul
AU - Nagase, Hiroki
PY - 2019/4
Y1 - 2019/4
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
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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 -