Bisphosphonate Inhibitors of Mammalian Glycolytic Aldolase

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Glycolytic enzyme aldolase is a drug target for diseases like cancer and protozoan infections.
• These diseases rely on high glycolysis for energy and biomass production.
• Structural data for aldolase with phosphate inhibitors was previously unavailable.

Purpose of the Study:

• Determine the crystal structure of mammalian aldolase with a phosphate-derived inhibitor.
• Use this structure to design novel bisphosphonate-based inhibitors.
• Evaluate the inhibitory potential of designed compounds against cancer cells.

Main Methods:

• Determined the crystal structure of mammalian aldolase complexed with naphthalene 2,6-bisphosphate.
• Designed and synthesized bisphosphonate analogs based on the crystal structure.
• Assessed inhibitor binding kinetics and anti-proliferative effects on cancer and normal cells.

Main Results:

• Obtained crystal structures of aldolase with phosphate-derived inhibitors.
• Identified 2-phosphate-naphthalene 6-bisphosphonate (compound 2) as a potent inhibitor (Ki ~38 nM).
• Compound 2 selectively inhibited HeLa cancer cell proliferation but not normal HEK293 cells.

Conclusions:

• The crystal structures provide a template for high-affinity phosphate-derived inhibitor design.
• Bisphosphonate inhibitors targeting aldolase show potential for developing new anti-cancer and anti-parasitic therapies.
• Further development could lead to prophylactic agents against relevant diseases.