Yeast: bridging the gap between phenotypic and biochemical assays for high-throughput screening

ABSTRACT

Introduction: Both in vitro biochemical and phenotypic assay platforms have clear limitations in high throughput screening (HTS) for drug discovery. The use of genetically tractable model yeast as a vehicle for target-based HTS overcomes many of these by allowing the identification of on-target compounds that function within a eukaryotic cellular context.

Areas covered: In this special report, the use of yeast-based assays in HTS is discussed with reference to the various platforms that have been utilized over the past 20 years. The specific issues considered are the necessity to employ counter and secondary screening approaches to ensure the on-target activity of hits, and the recent developments in detection systems that have facilitated miniaturization and ultra-HTS.

Expert opinion: It is difficult at present to predict the future. That being said, the demonstrable possibilities of optimizing yeast-based HTS, coupled with the demonstration of utility in an industrial setting, shows that these platforms have the potential to bridge the gap between phenotypic and biochemical assays for HTS.

KEYWORDS:

• Yeast
• eukaryotic
• high throughput screening
• drug discovery

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Article highlights

• Yeast-based screening has the potential to bridge the gap between phenotypic and biochemical assays for HTS

• Lethal expression, transactivation and substitution yeast-based assays have all been effectively employed in HTS, including ultra HTS

• Exploiting the genetic tractability of yeast to overcome platform limitations is possible, e.g. deletion of efflux pumps and use of fluorescent markers for multiplexing

• Recent developments, including the identification of a clinical candidate for Parkinson’s disease, have shown that yeast-based HTS can take its place amongst the currently utilized drug discovery platforms

• Whilst the future is difficult to predict, yeast-based platforms are well positioned to take their place in the armory of drug discovery techniques in coming years

This box summarizes key points contained in the article.

Additional information

Funding

The authors are supported by the Medical Research Council via grant MR/P027989/1 and Biotechnology and Biological Sciences Research Council (BBSRC) via grant BB/M024156/1.