New & Noteworthy
May 15, 2014
Imagine you are in a band and the only instruments you have are guitars. Yes, you can play some beautiful music, but there will be a whole lot of music that your band won’t be able to play.
In some ways, finding chemical leads to develop into drugs is similar to an all guitar band. The compounds in available libraries all tend to have a lot in common. They are like a vast array of subtly different guitars.
In a new study, Klein and coworkers use synthetic biology to have the yeast Saccharomyces cerevisiae make more varied libraries on its own. As an added bonus, the authors also use the yeast to assay the new leads. Not only have they expanded the range of instruments available to your band, but they’ve also made it so you can play all the instruments. You are now a one man band!
The first step in all of this is to have an assay that can easily pick out the important leads. Klein and coworkers use a galactose inducible Brome Mosaic Virus (BMV) system they had previously developed.
In this system, if one of the viral genes is on, then it produces a fusion protein that includes the Ura3 protein. When the URA3 gene is expressed, yeast die in the presence of 5-fluoroorotic acid (5-FOA). So any yeast that can make a compound that can inhibit viral expression will survive in 5-FOA.
The next step in creating these in vivo libraries was to randomly assemble various biochemical pathways into yeast artificial chromosomes (YACs) and to transform them into yeast. These pathways were chosen because they have yielded important compounds before or because they come from medically important beasts. This work was described in detail in a previous paper.
Specifically, Klein and coworkers randomly combined cDNA genes from eight biochemical pathways into YACs and transformed them into the BMV replication yeast strain. They found 74 compounds that allowed the yeast to survive in the presence of 5-FOA. Of these, 28 had activity in a secondary BMV assay.
A close look at the 74 compounds showed that by and large, most had characteristics that put them in the right ballpark to be useful leads. They had low molecular weight and the right hydrophobicity, and were chemically complex. In addition, many could easily be improved chemically (this last point is called optimizability). Most importantly, they were pretty unique from a drug lead point of view.
Over 75% of the compounds resembled nothing in known libraries. And the compounds were not similar to one another. Klein and coworkers had created a wide range of instruments other than guitars.
Of course, keeping a yeast strain alive is hardly reason to look for a new drug. But that isn’t all these compounds can do. At least some of these leads show excellent activity against two viruses related to BMV, Dengue and hepatitis C, and one looks particularly promising.
With a random combination of genes from a variety of biochemical pathways, yeast has been coaxed into synthesizing chemical leads that can target two medically relevant viruses. Scientists should be able to use a similar approach to tackle other diseases. All they need is a yeast strain with the right assay.
Yeast can make our bread rise, get us drunk, and now maybe cure us of disease. Is there anything yeast can’t do? Well, they still can’t play a guitar.
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics