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Analyzing Telomeric Protein-DNA Interactions Using Single-Molecule Magnetic Tweezers
Published on: August 30, 2024
A chiral wedge molecule inhibits telomerase activity
Ken-ichi Shinohara1, Yuta Sannohe, Shuji Kaieda
1Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku Kyoto 606-8502, Japan.
Journal of the American Chemical Society
|March 3, 2010
Summary
Researchers discovered a chiral cyclic helicene that can recognize G-quadruplex DNA structures. This compound shows potent telomerase inhibition, offering a new strategy for targeting telomeres.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Secondary DNA structures, beyond the Watson-Crick double helix, are crucial in biological processes.
- G-quadruplexes, found at chromosome ends, inhibit telomerase activity by blocking telomere access.
- These structures are emerging as targets for novel DNA-interactive therapeutic compounds.
Purpose of the Study:
- To report the first instance of enantioselective recognition of quadruplex DNA by a chiral cyclic helicene.
- To investigate the potential of cyclic helicenes as telomerase inhibitors.
Main Methods:
- Synthesis and characterization of a chiral cyclic helicene (M1).
- Investigation of M1's interaction with telomeric human G-quadruplex DNA.
- Assay of M1's inhibitory activity against telomerase.
Main Results:
- The cyclic helicene M1 demonstrated enantioselective recognition of quadruplex DNA.
- A novel ligand-binding cleft between two telomeric human G-quadruplexes, linked by a TTA linker, was identified.
- Compound M1 exhibited potent inhibition of telomerase activity.
Conclusions:
- Chiral cyclic helicenes represent a new class of molecules capable of targeting G-quadruplex DNA.
- The identified binding site and potent inhibitory activity suggest M1 as a promising candidate for telomere-targeted therapies.
- This study opens new avenues for developing G-quadruplex-interacting drugs.
Related Concept Videos
02:41Telomeres and Telomerase
In eukaryotic DNA replication, a single-stranded DNA fragment remains at the end of a chromosome after the removal of the final primer. This section of DNA cannot be replicated in the same manner as the rest of the strand because there is no 3’ end to which the newly synthesized DNA can attach. This non-replicated fragment results in gradual loss of the chromosomal DNA during each cell duplication. Additionally, it can induce a DNA damage response by enzymes that recognize single-stranded DNA.
02:41Telomeres and Telomerase
In eukaryotic DNA replication, a single-stranded DNA fragment remains at the end of a chromosome after the removal of the final primer. This section of DNA cannot be replicated in the same manner as the rest of the strand because there is no 3’ end to which the newly synthesized DNA can attach. This non-replicated fragment results in gradual loss of the chromosomal DNA during each cell duplication. Additionally, it can induce a DNA damage response by enzymes that recognize single-stranded DNA.
02:34Inhibition of CDK Activity
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
02:34Inhibition of Cdk Activity
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
01:52Eukaryotic Transcription Inhibitors
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA...
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA...
02:25Chirality
Chirality is a term that describes the lack of mirror symmetry in an object. In other words, chiral objects cannot be superposed on their mirror images. For example, our feet are chiral, as the mirror image of the left foot, the right foot, cannot be superposed on the left foot.
Chiral objects exhibit a sense of handedness when they interact with another chiral object. For example, our left foot can only fit in the left shoe and not in the right shoe. Achiral objects — objects that have...
Chiral objects exhibit a sense of handedness when they interact with another chiral object. For example, our left foot can only fit in the left shoe and not in the right shoe. Achiral objects — objects that have...