A General Strategy for Targeting Drugs to Bone.

Area of Science:

• Pharmacology
• Drug Delivery
• Biochemistry

Background:

• Targeting drugs to specific sites enhances safety and efficacy.
• Bisphosphonates are bone-targeting drugs but have strong bone affinity and poor oral bioavailability.
• Farnesyl pyrophosphate synthase (FPPS) is an enzyme targeted by these drugs.

Purpose of the Study:

• To develop novel FPPS inhibitors with tunable bone affinity and improved oral bioavailability.
• To evaluate the relationship between drug structure and bone affinity.
• To establish a new strategy for bone-targeted drug delivery.

Main Methods:

• Development of FPPS inhibitors utilizing a monophosphonate bone-affinity tag.
• Utilizing NMR-based bone-binding assays to evaluate drug-bone interactions.
• Structure-activity relationship studies for bone affinity.

Main Results:

• Monophosphonate tag confers moderate, tunable bone affinity.
• Achieved improved oral bioavailability compared to bisphosphonates.
• Demonstrated a clear relationship between structure and bone affinity.

Conclusions:

• Novel FPPS inhibitors offer a promising approach for bone-targeted drug delivery.
• Tunable moderate bone affinity and enhanced oral bioavailability represent significant advancements.
• This strategy has broad implications for developing other bone-targeting therapeutics.