Drug discovery is a slow, expensive, and labor-intensive process. Large sums are invested into screening compound libraries to identify initial hits and structurally optimizing these initial compounds for human therapeutic use. However, traditional medicinal chemistry often restricts itself to low structural complexity molecules that cover only a small portion of the theoretically accessible chemical space. This limitation also restricts the types of proteins that can be pursued as targets, currently leaving a significant portion of the human proteome “undruggable.”

Many organisms in nature produce defensive chemicals to enhance their fitness. Some of these products have been used clinically to treat various human diseases, including cancerous malignancies, helminthic diseases, and bacterial infections. However, these therapeutic properties in humans are largely coincidental and only indirectly evolutionarily selected. Novel, “non-natural” metabolites with structures specifically designed for human therapeutic use can enable the specific targeting of a much broader range of currently undruggable protein targets.

In the Laboratory of Drug Evolution, we employ Darwinian evolution and emulate Nature’s strategies to identify novel drug structures tailored for human use. We utilize strategies and techniques from organic chemistry and molecular biology to reroute and accelerate the drug discovery process.

Our research also explores the use of new therapeutic modalities to target intrinsically disordered proteins (IDPs), a class of proteins characterized by the absence of a stable fold. IDPs remain largely undruggable, but they play crucial roles in human diseases such as Parkinson’s disease, Alzheimer’s disease, and cancer. As new means to combat these diseases, we leverage sequence-specific proteases to reduce the intracellular levels of these disordered proteins and improve patient outcomes.