期刊
NUCLEIC ACIDS RESEARCH
卷 47, 期 7, 页码 3295-3305出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz135
关键词
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资金
- National Science Foundation [CHE-1609514]
- National Institutes of Health [NIH 1R01CA236350-01A1]
- National Natural Science Foundation of China [NSFC 21728801]
- JSPS-NSF International Collaborations in Chemistry (ICC) [JSPS KAKENHI 16H06356, 15J00928]
- Basic Science and PlatformTechnology Program for Innovative Biological Medicine
- Grants-in-Aid for Scientific Research [15J00928] Funding Source: KAKEN
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 (K-d) of the conjugate can be separately evaluated from the binding of either PA or PDS. We found K-d of 0.8 nM for PA-PDS, which is much lower than PDS (K-d approximate to 450 nM) or PA (K-d approximate to 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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