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

Abstract

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.

Engineering CRISPR/Cas9 therapeutics for cancer precision medicine

“…The other methods that have been employed over time include zinc finger nucleases, TAL effector nucleases, peptide nucleic acids, and polyamides for efficient DNA cleavage and inducing a change in DNA sequence ( Good and Nielsen, 1999 ; Nielsen and Egholm, 1999 ; Cathomen and Joung, 2008 ; Simon et al, 2008 ; Christian et al, 2010 ; Li and Yang, 2013 ; Koeller et al, 2014 ; Gaj et al, 2016 ; Yu et al, 2019 ). However, these methods have their own limitations, such as complex designing, inefficient delivery, potential toxicity, expensive, and possible off-target effects ( Gaj et al, 2016 ; Montazersaheb et al, 2018 ; Lin and Nagase, 2020 ; Gonzalez Castro et al, 2021 ). CRISPRs were first described by Ishino et al, in 1987 as short interspersed sequences in the genome of Escherichia coli while investigating the gene "alkaline phosphatase” ( Ishino et al, 1987 ).…”

Synthetic Peptides: Promising Modalities for the Targeting of Disease‐Related Nucleic Acids

“…[10] However, the advancement towards therapeutic use has remained limited. [11] RNA can fold to several more or less defined three-dimensional structures. [12] Compared to proteins these motifs are less defined and structurally more flexible, but, nevertheless, targeting these motifs with small molecules has recently shown intriguing potential.…”

Application of Artificial Intelligence for Medical Research

“…Ai et al analyzed microarray gene expression data using weighted gene co-expression network analysis and a variational autoencoder to predict colorectal cancer with high accuracy [ 24 ]. In their review, Lin et al proposed the use of machine learning to improve the off-target properties of N -methylpyrrole- N -methylimidazole polyamides (pyrrole-imidazole polyamides (PIPs)) [ 25 ].…”