September 4, 2013 Tinberg, C.E., Khare, S.D., et al. Nature. 501(7466), 212-216. (2013)
Reported on-line in Nature (Sept. 4, 2013) researchers at the Institute for Protein Design describe the use of Rosetta computer algorithms to push the envelope on protein design; crafting a protein that binds with high affinity and specificity to a small drug molecule; digoxigenin a dangerous but sometimes life saving cardiac glycoside. More information can be found here, and here.
Usually drug hunters are doing the exact opposite; designing small molecules to bind to large protein targets. Proteins are the workhorses of life, and most drugs used today are small molecules that block protein function. For example, the cocktail drug therapies used to treat HIV infection are made of a mix of small molecules which individually block important viral replication proteins, and together they do a good job of shutting down the virus. From aspirin to penicillin, small molecule drugs work by binding with specificity to a limited number of cellular protein targets, where they inhibit protein activity; like throwing a wrench in a gearbox.
Now, researchers at the Institute for Protein Design have inverted the drug design principle, by designing completely novel proteins that bind to small drug molecules.
As reported in the paper entitled “Computational design of ligand-binding proteins with high affinity and selectivity,” Dr. Christine Tinberg and a team of scientists working in Dr. David Baker’s group at the University of Washington, have designed a new protein to bind the cardiac glycoside digoxigenin, a natural steroid component of digitalis found in the flowers of foxglove plants, and often given to cardiac patients with atrial fibrillation or heart failure. This is the first report of computer-designed proteins that recognize and bind with high affinity to small molecules.
Their Nature paper is accompanied by a News & Views commentary, “Computational biology: A recipe for ligand binding proteins.” The commentator, Giovanna Ghirlanda of Arizona State University, wrote that the method developed “to design proteins with desired recognition sites could be revolutionary” because cell processes such as cell cross-talk, the production of gene products and the work of enzymes all depend on molecular recognition.
The University of Washington’s news channel ran a story “Pico-world dragnets: Computer-designed proteins recognize and bind small molecules.” Science ran a commentary entitled “Protein Designers Go Small.” The story even made news at Slashdot.
Significance
Small molecules such as drugs, vitamins, scents, flavors, and pheromones are ubiquitous participants in biological processes, pharmaceuticals, and personal care products. Molecular recognition of these compounds is a critical first step in designing novel diagnostics and therapeutics. A reliable pipeline of designed proteins with cavities that bind small molecules with exquisite specificity (e.g. digoxigenin binding sensor) will enable at-home diagnostic testing for disease state biomarkers; and such proteins may also serve as therapeutic sponges for toxic small molecules. More importantly however, this proof of concept allows the IPD to confidently pursue potentially many more lucrative applications for proteins designed to bind small molecule targets. These include diagnostics for nutrient deficiency, and quantification or therapeutic sequestration of drugs with narrow therapeutic indices requiring careful dose control.
The image here is a 3D printed model of the digoxigenin binding protein (red with yellow small molecule) was prepared by the Open3DP lab in the Department of Mechanical Engineering at UW (special thanks to Brandon Bowman, Dr. Mark Ganter, and Dr. Duane Storti for their 3D printing expertise).
This article was Authored by Dr. Lance Stewart, Sr. Director of Strategy (ljs5@uw.edu) at the Institute for Protein Design, with kind input and guidance from the researchers noted in this posting, and information from web resources linked throughout this posting.