N-Methylpyrrole (Py)-N-methylimidazole-(Im) polyamides are sequence-specific DNA-binding modules that are widely used for gene regulation, as synthetic transcriptional factors and as sequence-specific DNA alkylating agents. Recently, Py-Im polyamides have been conjugated with fluorophores, resulting in conjugates that are useful for the detection of specific DNA sequences. A Förster resonance energy transfer has been observed between Cy3- and Cy5-conjugated Py-Im polyamides on the nucleosome, indicating that fluorescence-conjugated Py-Im polyamides could possibly be used to characterise protein-DNA complexes. In this minireview, we discuss recent reports regarding fluorescence-conjugated Py-Im polyamides and their future application in the characterization of protein-DNA complex formation.
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http://dx.doi.org/10.1039/c5bm00214a | DOI Listing |
ACS Med Chem Lett
November 2022
Research Center for Chemical Biology and Omics Analysis, Department of Chemistry and Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, 1088 Xueyuan Boulevard, Shenzhen, Guangdong 518055, P. R. China.
To optimize the pharmacological properties of an anticancer pyrrole-imidazole (Py-Im) polyamide (), we characterized the acid dissociation constants of , three other structurally related hairpin-shaped polyamides, and a cyclic polyamide bearing the same core sequence as via potentiometric titration. The acidities of the carboxylic acid at the C-terminus and the tertiary amine in the triamine linker remained very similar among the polyamides tested, whereas the p of the -methylimidazole (Im) moieties varied with the peptide sequence and molecular architecture. A nearly 0.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2022
Division of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093;
Elongating RNA polymerase II (Pol II) can be paused or arrested by a variety of obstacles. These obstacles include DNA lesions, DNA-binding proteins, and small molecules. Hairpin pyrrole-imidazole (Py-Im) polyamides bind to the minor groove of DNA in a sequence-specific manner and induce strong transcriptional arrest.
View Article and Find Full Text PDFJ Med Chem
May 2021
Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China.
In recent years, PD-1 immune checkpoint inhibitors based on monoclonal antibodies have revolutionized cancer therapy, but there still exist unresolved issues, such as the high cost, the relatively low response rates, and so on, compared with small-molecule drugs. Herein a type of pyrrole-imidazole (Py-Im) polyamide as a small-molecule DNA binder was designed and synthesized, which could competitively bind to the same double-stranded DNA stretch in the PD-L1 promoter region as the STAT3 binding site and thus downregulate PD-L1 expression. It was demonstrated that the Py-Im polyamides directly caused apoptosis in tumor cells and retarded cell migration in the absence of T cells through inhibiting the Akt/caspase-3 pathway.
View Article and Find Full Text PDFPLoS One
February 2021
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.
Pyrrole-imidazole (Py-Im) polyamides are synthetic molecules that can be rationally designed to target specific DNA sequences to both disrupt and recruit transcriptional machinery. While in vitro binding has been extensively studied, in vivo effects are often difficult to predict using current models of DNA binding. Determining the impact of genomic architecture and the local chromatin landscape on polyamide-DNA sequence specificity remains an unresolved question that impedes their effective deployment in vivo.
View Article and Find Full Text PDFChembiochem
October 2020
Department of Chemical & Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117585, Singapore.
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