A molecular system with potential to target DNA structures associated with cancer

During DNA replication, the classic double helix can temporarily rearrange into an alternative structure known as a DNA three-way junction (3WJ). These configurations form a well-defined central cavity capable of hosting molecules with specific shapes and properties. Because of their role in cellular processes linked to cancer, 3WJs are gaining attention as promising molecular targets for next-generation therapeutic approaches.

Now, a research team at CiQUS has designed a new molecule that self-assembles into fibrous materials, remaining inactive until exposed to cobalt ions. Upon stimulation, the molecule undergoes a structural transformation into a well-defined 3D arrangement that fits precisely into the central cavity of the DNA junction. Led by CiQUS group leader and USC Professor Miguel Vázquez López, the study introduces a new paradigm in selective recognition of noncanonical DNA structures from dormant molecular precursors. The research, featured this week on the cover of JACS, was carried out at the CiQUS laboratories—an institution recognized as a CIGUS center of excellence by the Xunta de Galicia and supported by EU funding through the Galicia FEDER Program 2021–2027.

At the heart of this system is a small peptide-based molecule called BTMA-1, which spontaneously self-organizes under physiological conditions into supramolecular helical fibers. When exposed to metal ions such as cobalt, these fibers disassemble and generate biologically active peptide helicates—molecular complexes capable of selectively binding to DNA three-way junctions. This controlled transformation represents a key advance toward the development of responsive functional materials that can be activated by external stimuli to carry out specific biological tasks.

One of the most innovative aspects of the study is the behavior of these helical fibers as inactive precursors: stable, temporary assemblies that release the active helicate units only upon chemical activation. This dynamic behavior, previously unobserved in such supramolecular polymers, opens new opportunities to design molecular systems capable of storing their biological function until needed—an idea with broad implications in complex cellular environments.

Although its biomedical applications remain at an early stage, this research lays the groundwork for a new molecular strategy that is both adaptable and environmentally responsive. In the future, such systems could offer spatiotemporal control over DNA recognition in targeted anticancer therapies. The findings broaden the landscape at the interface between chemical biology and molecular materials, and reinforce the potential of supramolecular chemistry as a powerful tool for designing programmable molecular systems.

The study also involved researchers from the Center for Research in Nanomaterials and Biomedicine (CINBIO) at the University of Vigo, and received support from the CiQUS-Synergy program, which fosters collaborations across research groups and disciplines within the center.