Figure 1. Current model for colloid
formation, protein adsorption, & inhibition.
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.