Our laboratory employs an interdisciplinary approach to study protein-protein interactions (PPIs), combining synthetic organic chemistry with biochemistry and molecular biology. We are interested in developing small molecules that can be used to probe or inhibit PPIs. These small molecules would be used to understand the structure and function of multi-protein complexes as well as to develop new leads for drug discovery. Due to the urgent need for new drugs, we are particularly interested in developing chemical tools and therapeutic agents for protein aggregation (a type of PPIs) diseases such as Alzheimer’s disease and Transthyretin Amyloidosis.

Our group recently developed AG10, a small molecule that prevents amyloidosis of the plasma protein Transthyretin (TTR). Currently, AG10 is being developed by Eidos Therapeutics (co-founded by Dr. Alhamadsheh and Dr. Isabella Graef) as treatment for TTR Amyloid Cardiomyopathy.

Publication: AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin

Crystal structure of TTR – AG10 complex

Another active area of research in our lab, is developing novel technologies to enhance the in vivo half-life of therapeutic agents. These technologies would decrease the production cost of therapeutic agents and increase the clinical success rate. This is a collaborative project with Dr. Miki Park and Dr. William Chan at Pacific.

(a) Peptides have short half-life due to proteolytic degradation and rapid clearance by the kidneys. (b) Current approach for enhancing the in vivo half-life of peptides are based on conjugation to macromolecules such as albumin and PEG. However, these approaches typically decreases the potency of the peptide. (c,d) We developed a novel approach (TTR ligands for half-life Extension, TLHE) to extend the in vivo half-life of peptides without compromising its potency. For more information, please see
Penchala et al. Nature Chemical Biology, 2015.