Towards Selective Binding to the GLUT5 Transporter: Synthesis, Molecular Dynamics and In Vitro Evaluation of Novel...

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Cancer cells exhibit altered energy metabolism, with glucose transporters (GLUTs) playing a crucial role in hexose uptake.
• While GLUT1 is often elevated, some breast cancers utilize fructose via the GLUT5 transporter, presenting an alternative metabolic pathway.
• Elevated GLUT5 mRNA in human breast cancer suggests its potential as a biomarker for early detection.

Purpose of the Study:

• To design and synthesize novel fructose mimics targeting the GLUT5 transporter.
• To investigate the binding pocket requirements of GLUT5 for selective ligand interaction.
• To lay the groundwork for developing high-affinity molecular imaging probes for GLUT5-expressing cancers.

Main Methods:

• Synthesis and screening of a new class of fructose mimics based on the 2,5-anhydromannitol scaffold.
• In vitro testing of compound inhibition against a known ¹⁸F-labeled fructose probe (6-FDF) in EMT6 breast cancer cells.
• Molecular docking and molecular dynamics simulations to analyze hexose-GLUT interactions and ligand specificity.

Main Results:

• Several synthesized fructose mimics demonstrated low millimolar IC₅₀ values against the 6-FDF probe in cancer cells.
• Molecular modeling provided insights into the binding interactions governing GLUT5 selectivity over other GLUTs.
• The study identified promising compounds for further development as GLUT5-targeting agents.

Conclusions:

• Novel fructose mimics based on the 2,5-anhydromannitol scaffold show potential for targeting GLUT5.
• These compounds exhibit inhibitory activity and selective binding to GLUT5, offering a basis for new imaging probes.
• This research advances the development of diagnostic tools for breast cancers that rely on fructose metabolism via GLUT5.