Modulating DNA by polyamides to regulate transcription factor PU.1-DNA binding interactions

Epigallocatechin gallate regulates the myeloid-specific transcription factor PU.1 in macrophages

“…Structural organization of PU.1 protein is illustrated in Fig 1C for reference. DB2313 is a commercially available, heterocyclic diamidine that specifically disrupts binding of PU.1 to chromatin through interaction with the DNA bases in minor groove similar to Distamycin [ 25 , 28 ], illustrated in Fig 1D . Human and Mouse PU.1 proteins show high degree of sequence homology, conserved amino acids in the DNA binding and dimerization domains, possibly indicating a similar mode of inhibition of PU.1 in mouse and human cells ( S1 Fig ).…”

“…Small molecule inhibitors of PU.1 protein developed by Munde et al, have been shown to interact with PU.1 ETS/DNA binding [ 25 , 26 ]. Subsequent studies have confirmed the heterocyclic di-amidines and heterocyclic di-cations as small molecule inhibitors that bind with AT rich DNA minor grooves, thereby inhibit PU.1-DNA binding [ 27 , 28 ]. The small molecule inhibitors disrupt the interaction of PU.1 with target gene promoters and downregulate expression of PU.1 transcriptional targets.…”

“…heterocyclic di-amidines and heterocyclic di-cations as small molecule inhibitors that bind with AT rich DNA minor grooves, thereby inhibit PU.1-DNA binding [27,28]. The small molecule inhibitors disrupt the interaction of PU.1 with target gene promoters and downregulate expression of PU.1 transcriptional targets.…”

“…Heterocyclic di-amidines and di-cations were designed that act as small molecule inhibitors of PU.1 DNA binding [ 25 , 26 ]. Based on the mechanism of action, the heterocyclic di- amides and di-cations bind to genome-wide minor groove DNA, which in turn inhibits the binding of PU.1 to DNA [ 27 , 28 ]. In the current study, we used a molecular docking approach and demonstrated that EGCG acts like a small molecule structural inhibitor that binds to PU.1 protein.…”

Site-Specific Arrangement and Structure Determination of Minor Groove Binding Molecules in Self-Assembled Three-Dimensional DNA Crystals

“…The synthesis of small molecules that can mimic the sequence-specific binding of certain proteins to DNA has been an attractive pursuit for decades, especially to design artificial transcription factors for therapeutics. − Dervan and colleagues proposed that polyamide molecules could preferentially bind to DNA sequences within the minor groove (MG) of DNA, and differentiate between G·C/C·G and A·T/T·A pairs. − This was first accomplished with the crystal structure of netropsin, which is a polyamide molecule known to have antibiotic and antiviral activity, containing two aromatic N -methylpyrrole (Py) rings bound to an AATT sequence in the MG of the duplex. , Netropsin belongs to a larger family of small molecules that bind to A/T-rich regions of the MG, including cell staining dyes such as 4′,6-diamidino-2-phenylindole (DAPI) and Hoechst 33342 and 33258 …”