Pyrrole–Imidazole Polyamides – A Frontrunner in Nucleic Acid‐Based Small Molecule Drugs

Abstract

The remarkable success of messenger RNA vaccines against the ongoing coronavirus-2019 (COVID-19) pandemic renews attention toward nucleic acid therapeutics. While nucleic acid therapy using unmodified DNA or RNA is the primary focus in disease treatment, there is growing need to develop nucleic acid-based small molecules owing to their potential clinical benefits as drugs in terms of cost and scalability. While small molecules targeting protein-protein interactions are known to alter the transcriptional status of a cell, they can result in a transient effect and variation of bio-efficacy among patients. Small molecules targeting DNA and/or RNA are in demand in the precision medicine approach as they have consistent bioactivity among patients. This review details the progress of sequence-specific DNA-binding pyrrole-imidazole polyamides (PIPs) in modulating the transcriptional status of target gene(s) without altering the underlying DNA sequence. Here, the different versions of PIPs are listed, and also, how conjugating them with DNA alkylating agents, epigenetic modulators, and other drugs can improve their clinical utility as targeted transcription therapeutics. Owing to their specificity, functional diversity, and limited toxicity, PIP technology holds enormous promise as frontrunner in small-molecule-based nucleic acid drugs to precisely regulate therapeutically important genes on demand and treat intractable diseases.

Domain-Selective BET Ligands Yield Next-Generation Synthetic Genome Readers/Regulators with Nonidentical Cellular Functions

“…Among these, pyrrole-imidazole polyamides have emerged as a versatile class of molecules that can be rationally designed to target nearly every permutation of the DNA sequence observed in the human genome . Not only does this class of synthetic DNA-binding molecules display sequence selectivity and affinity properties that are comparable to mammalian DNA-binding transcription factors (TFs), but they can also access binding sites in nucleosomes and heterochromatin. ,− Moreover, polyamides retain their sequence specificity when further conjugated to other small molecules or peptides. ,− Based on the modular architecture of eukaryotic TFs, we and others have developed synthetic transcription factors by tethering DNA-binding polyamides to different ligands that bind the transcriptional machinery. − These heterobifunctional molecules, much like their natural counterparts, leverage the principle of induced proximity , to “recruit” specific cellular machinery to targeted genomic loci. This form of chemically induced proximity enables the recruited proteins to perform targeted genomic transactions.…”

Nucleic acid‐based small molecules as targeted transcription therapeutics for immunoregulation

“…Accordingly, the approach called "Transcription Therapy" with agents designed to target the transcription factors for therapeutic purposes is one of the emerging areas in disease treatment. 3,4 In particular, the rational design of agents capable of directly recruiting and assembling the factors for precisely regulating the previously "undruggable" gene target(s) associated with the immune response is urgently needed. This is because the transcriptional alteration of the dynamic immune system could be a double-edged sword and may lead to autoimmune disorders.…”