Hydrophobic structure of hairpin ten-ring pyrrole-imidazole polyamides enhances tumor tissue accumulation/retention in vivo

Inoue, Takahiro; Shimozato, Osamu; Matsuo, Nina; Mori, Yusuke; Shinozaki, Yoshinao; Lin, Jason; Watanabe, Tomohiro; Takatori, Atsushi; Koshikawa, Nobuko; Ozaki, Toshinori; Nagase, Hiroki

doi:10.1016/j.bmc.2018.03.029

Cited by 13 publications

(17 citation statements)

References 41 publications

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“…This is well-corroborated with the fact that small conformational distortions are sufficient to retard RNA polymerase II [17] and potentially displace histones [44]. Evidence also suggests that lipophilicity of a PIP is associated in tumor-directed delivery in situ [22], albeit there may be some dependence on the type and origin of tumors [45]. We can thus potentially expand our synthetic repertoire to introduce novel modifications to the existing PIP design toolbox to incorporate these improvements, but there are still caveats to take note of, not to mention again that these assays may only have provided us with qualitative results.…”

Section: Defining and Evaluating "Off-target" Effectsmentioning

confidence: 69%

“…As such, by binding the minor groove, one can avoid the messiness of conventional small molecular inhibitors that work on protein surfaces. PIPs have been used in a variety of biological applications; in 2005, Beerman and colleagues successfully demonstrated the ability to cause DNA damage by conjugating 1-chloromethyl-5-hydroxy-1,2-dihydro-3H-benz(e)indole (CBI), an alkylating agent, to disrupt and inhibit SV40 DNA replication [18]; conjugation of other functional groups have also led to the rise of additional functionalities for PIPs, such as artificial nucleases [19], gene switches [20], transcriptional regulators via histone acetyltransferase activators [21] and imaging probes [22] upon the conjugation of fluorescent moieties (Figure 2a) or radioisotopes [23]. Even without those modifications, PIPs are still able to retain their high specificity, unlike mainstream DNA-damaging agents such as cisplatin [17].…”

Section: Biological Applications Of Pipsmentioning

confidence: 99%

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The Road Not Taken with Pyrrole-Imidazole Polyamides: Off-Target Effects and Genomic Binding

Lin

Nagase

2020

Biomolecules

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The high sequence specificity of minor groove-binding N-methylpyrrole-N-methylimidazole polyamides have made significant advances in cancer and disease biology, yet there have been few comprehensive reports on their off-target effects, most likely as a consequence of the lack of available tools in evaluating genomic binding, an essential aspect that has gone seriously underexplored. Compared to other N-heterocycles, the off-target effects of these polyamides and their specificity for the DNA minor groove and primary base pair recognition require the development of new analytical methods, which are missing in the field today. This review aims to highlight the current progress in deciphering the off-target effects of these N-heterocyclic molecules and suggests new ways that next-generating sequencing can be used in addressing off-target effects.

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Section: Defining and Evaluating "Off-target" Effectsmentioning

confidence: 69%

Section: Biological Applications Of Pipsmentioning

confidence: 99%

The Road Not Taken with Pyrrole-Imidazole Polyamides: Off-Target Effects and Genomic Binding

Lin

Nagase

2020

Biomolecules

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“…By evaluating candidate polyamides with expression microarrays and this systematic method can greatly improve the throughput and meaningfully shorten the initial lead selection and optimization period. We understand how changing the structure of PI polyamides may affect its binding affinity, and how these molecules’ relative hydrophobicity can have on its tumor retention [37]; yet we still know very little about how these molecules will influence the outward phenotypes, especially when binding motifs are concerned. The lack of progress in understanding the off-target effect of PI polyamides can limit the growth of PI polyamide research and the translation to bedside applications.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2019

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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.

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“…PDCs designed as anticancer agents frequently displayed the ability to alter the genetic or epigenetic state of their genomic targets, and mouse models of various human cancers also confirmed the anticancer efficacy of PDCs, simultaneously showing few adverse events 16,18‐21,58‐62 . Intriguingly, pharmacokinetic studies also suggested that PI polyamide conjugates possessed enhanced permeability and retention (EPR)‐like effects, 63 an additional advantage for PDCs to localize preferentially in tumors and the surrounding environments, as expected of well performing cancer therapeutics 64 . Several modifications to a candidate PDC could also improve its intracellular localization, for instance homing toward the mitochondria 22,59 .…”

Section: Pyrrole‐imidazole Polyamide: Synthetic Minor Groove Binders Mimicking Antibioticsmentioning

confidence: 87%

Mitochondria: Endosymbiont bacteria DNA sequence as a target against cancer

et al. 2021

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As the energy factory for the cell, the mitochondrion, through its role of adenosine triphosphate production by oxidative phosphorylation, can be regarded as the guardian of well regulated cellular metabolism; the integrity of mitochondrial functions, however, is particularly vulnerable in cancer due to the lack of superstructures such as histone and lamina folds to protect the mitochondrial genome from unintended exposure, which consequently elevates risks of mutation. In cancer, mechanisms responsible for enforcing quality control surveillance for identifying and eliminating defective mitochondria are often poorly regulated, and certain uneliminated mitochondrial DNA (mtDNA) mutations and polymorphisms can be advantageous for the proliferation, progression, and metastasis of tumor cells. Such pathogenic mtDNA aberrations are likely to increase and occasionally be homoplasmic in cancer cells and, intriguingly, in normal cells in the proximity of tumor microenvironments as well. Distinct characteristics of these abnormalities in mtDNA may provide a new path for cancer therapy. Here we discuss a promising novel therapeutic strategy, using the sequence‐specific properties of pyrrole‐imidazole polyamide‐triphenylphosphonium conjugates, against cancer for clearing abnormal mtDNA by reactivating mitochondrial quality control surveillance.

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Hydrophobic structure of hairpin ten-ring pyrrole-imidazole polyamides enhances tumor tissue accumulation/retention in vivo

Cited by 13 publications

References 41 publications

The Road Not Taken with Pyrrole-Imidazole Polyamides: Off-Target Effects and Genomic Binding

The Road Not Taken with Pyrrole-Imidazole Polyamides: Off-Target Effects and Genomic Binding

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

Mitochondria: Endosymbiont bacteria DNA sequence as a target against cancer

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