Colloidal aggregation in drug discovery & drug formulation

Aggregation Model
Figure 1. Current model for colloid formation, protein adsorption, & inhibition.
Unstabilized fulvestrant colloids Stabilized fulvestrant colloids
Figure 2. Transmission EM of unstabilized (left) & stabilized (right) fulvestrant colloids after four hours in 10% serum.

Many organic molecules form colloidal aggregates at micromolar and sub-micromolar concentrations. The colloids are a state intermediate between true solution and precipitate, with properties different from both. They inhibit both soluble and membrane proteins without specificity but with a shared mechanism: direct association and binding followed by partial denaturation. About 2% of compound libraries aggregate at micromolar concentrations, making them the dominant artifact in early drug discovery and chemical biology. Recent work suggests that they are stable in multiple biological media, including cell culture, serum, and simulated intestinal fluid.

In ongoing projects, we are investigating their physical structures and mechanisms of action, and their effects in early discovery, SAR progression, efficacy in cell-culture, and in formulation and delivery. A recent project focuses on opportunities to exploit the unique properties that colloidal aggregates possess, such as the ability to specifically and reversibly sequester folded proteins over DNA and peptides.

Recent papers include:

Supported by NIGMS GM71630.