Single helically folded aromatic oligoamides that mimic the charge surface of double-stranded B-DNA

Abstract

Numerous essential biomolecular processes require the recognition of DNA surface features by proteins. Molecules mimicking these features could potentially act as decoys and interfere with pharmacologically or therapeutically relevant protein-DNA interactions. Although naturally occurring DNA-mimicking proteins have been described, synthetic tunable molecules that mimic the charge surface of double-stranded DNA are not known. Here, we report the design, synthesis and structural characterization of aromatic oligoamides that fold into single helical conformations and display a double helical array of negatively charged residues in positions that match the phosphate moieties in B-DNA. These molecules were able to inhibit several enzymes possessing non-sequence-selective DNA-binding properties, including topoisomerase 1 and HIV-1 integrase, presumably through specific foldamer-protein interactions, whereas sequence-selective enzymes were not inhibited. Such modular and synthetically accessible DNA mimics provide a versatile platform to design novel inhibitors of protein-DNA interactions.

Crystal structure and Hirshfeld surface analysis of dichlorido(methanol-κO)bis(2-methylpyridine-κN)copper(II)

“…Both organic (from simple molecules to peptides and proteins) and inorganic complexes have been known for more than a century and are central to modern chemistry because of their fascinating, aesthetic architectures and multiple applications (Gan et al, 2011;Gellman, 1998;Thorat et al, 2013;Vijayadas et al, 2013;Ziach et al, 2018). Recently, coordination compounds have been reported that find applications in fields such as catalysis, gas storage, separation technology and molecular sensing (Mueller et al, 2006;Wan et al, 2006;Fé rey et al, 2003;James, 2003;Eddaoudi et al, 2002;Ruben et al, 2005, Kitagawa et al, 2004.…”

Targeting Uracil-DNA Glycosylases for Therapeutic Outcomes Using Insights from Virus Evolution

“…This could yet be a peptidic molecule, however new approaches in effecting DNA mimicry for protein interaction using aromatic oligoamides, might also offer an alternative [116].…”

Structure Elucidation of Helical Aromatic Foldamer–Protein Complexes with Large Contact Surface Areas

“…Some possess antibiotic activity . Both linear and helical foldamers have been developed and varied targets have been identified, including h DM2 and B‐cell lymphoma‐2 (Bcl‐2) regulator proteins, protein precursors of amyloids,– G‐quadruplex DNA and some DNA‐binding enzymes . Advantages of aromatic foldamers include their ease of synthesis, for example through solid‐phase methodologies, and the predictability and stability of their folded conformations in both protic and aprotic solvents .…”

“…Because relatively large and well‐defined folded objects can be produced using aromatic amide backbones, it may be envisaged to cover large surface areas of proteins and nucleic acids. For example, we recently reported protein binding using a 9.2 kDa foldamer mimicking a 16 base–pair DNA duplex . Nevertheless, designing objects that can recognize large surface areas of proteins is difficult: which side chains are to be selected and where should they be located?…”

“…Nevertheless, designing objects that can recognize large surface areas of proteins is difficult: which side chains are to be selected and where should they be located? Some of the published work concerned mimetics of α‐helices, B‐DNA, or natural products . Other approaches use screening through directed evolution methods .…”