Solution structure of a thrombin binding aptamer complex with a non-planar platinum(ii) compound

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Biochemistry

Background:

• Thrombin binding aptamer (TBA) is a G-quadruplex DNA that inhibits human alpha-thrombin.
• Platinum(II) compounds are explored for their therapeutic potential.

Purpose of the Study:

• To synthesize and characterize a novel platinum(II) compound with selective affinity for TBA.
• To investigate the binding mechanism and structural consequences of the platinum(II)-TBA interaction.
• To assess the functional impact of the platinum(II) compound on TBA's inhibitory activity.

Main Methods:

• Synthesis of a quasi-cross-shaped platinum(II) compound (L'2LPt).
• Nuclear Magnetic Resonance (NMR) spectroscopy to solve the 1:1 L'2LPt-TBA complex structure.
• Fibrinogen clotting assay to evaluate TBA's inhibitory activity.

Main Results:

• L'2LPt selectively binds to the TBA G-quadruplex.
• L'2LPt abrogates the inhibitory activity of TBA against thrombin.
• NMR structure reveals a unique self-adaptive binding mode where L'2LPt forms a 'wall-mounted' structure, with the platinum atom outside the G-tetrad.

Conclusions:

• The study elucidates a novel binding mode of a self-adaptive platinum(II) compound to an antiparallel G-quadruplex.
• The findings provide insights for designing selective G-quadruplex-targeting molecules.
• This work contributes to understanding DNA-metal interactions for potential therapeutic applications.