When developing new drug treatments for disease, researchers look to yeast. With its rapid cell cycle and the ease with which its genes can be tweaked, yeast is a flexible tool used to test how a particular drug, chemical or enzyme affects unicellular organisms (e.g. bacteria).
Like human cells, yeast has a eukaryotic structure (nucleus, cytoplasm and mitochondria). It also shares many genes with human cells; yeast cells can be used to investigate how a particular drug affects a certain human gene.
Although it identifies whether a new drug binds to what it’s supposed to, it does not offer insight into whether the drug binds to anything else in human cells. For example, researchers can screen a new cancer drug for potentially dangerous interactions (e.g. unexpected cell death) prior to clinical trials. However, they can only look at these off-target interactions one at a time.
A new paper by University of Washington (UW) electrical engineers and biochemists retools yeast’s mating habits, so researchers can test hundreds of drugs against thousands of potential targets. The paper, entitled “High-throughput characterization of protein-protein interactions by reprogramming yeast mating,” identifies how researchers used flourescent genetic markers to track yeast’s natural mating types and subsequently build new “sexes” for yeast to bind to.
The blue and red fluorescent markers that dot the yeast’s cell surface indicate whether the microorganism has been mated (purple) or unmated (blue and red). The team played around with numerous proteins and recorded their interactions. Through tracking the mating efficiency, researchers could tell how strongly any two protein molecules interact. They then built new sexes based on the strongest protein interactions.
The team put the results to the test. For the emerging cancer drug XCD07, researchers were able to identify the versions of the drug that only bound to the intended target.
The researchers’ goal is to share the tool for large-scale scientific research. The team has given the engineered yeast strains to several institutions, including Yale University, Stanford University and the University of California, Los Angeles (UCLA).
For lead author David Younger, a UW electrical engineering postdoctoral researcher, he wants the research to enable a “comprehensive preclinical drug screening, rather than the current practice of screening a very small subset of possible off-target interactions.”
Additional authors on the paper include UW biochemistry postdoctoral fellow Stephanie Berger, UW biochemistry Professor David Baker and UW electrical engineering Professor Eric Klavins.