Submolecular dissection reveals strong and specific binding of polyamide-pyridostatin conjugates to human telomere interface

Nucleic Acids Research
Shankar MandalHanbin Mao

Abstract

To modulate biological functions, G-quadruplexes in genome are often non-specifically targeted by small molecules. Here, specificity is increased by targeting both G-quadruplex and its flanking duplex DNA in a naturally occurring dsDNA-ssDNA telomere interface using polyamide (PA) and pyridostatin (PDS) conjugates (PA-PDS). We innovated a single-molecule assay in which dissociation constant (Kd) of the conjugate can be separately evaluated from the binding of either PA or PDS. We found Kd of 0.8 nM for PA-PDS, which is much lower than PDS (Kd ∼ 450 nM) or PA (Kd ∼ 35 nM). Functional assays further indicated that the PA-PDS conjugate stopped the replication of a DNA polymerase more efficiently than PA or PDS. Our results not only established a new method to dissect multivalent binding into actions of individual monovalent components, they also demonstrated a strong and specific G-quadruplex targeting strategy by conjugating highly specific duplex-binding molecules with potent quadruplex ligands.

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Citations

Jul 29, 2020·Organic & Biomolecular Chemistry·Vladimir B TsvetkovAndrey V Aralov
Sep 23, 2020·Nucleic Acids Research·Thi Quynh Ngoc NguyenAnh Tuân Phan
Sep 26, 2020·Nucleic Acids Research·Derrick J Y TanAnh Tuân Phan
Dec 22, 2020·Nucleic Acids Research·Xu LiZhongbo Yu
Apr 15, 2021·Chemistry : a European Journal·Raj PaulJyotirmayee Dash

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Methods Mentioned

BETA
optical tweezers
electrophoresis
PCR
chip
dissection
dissections

Software Mentioned

BIAevaluation
LabView

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