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Yeast techniques for modeling drugs targeting Bcl-2 and caspase family members
T E Beaumont1, T M Shekhar, L Kaur
1Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
Abstract:
Development of drugs targeting Bcl-2 relatives and caspases, for treating diseases including cancer and inflammatory disorders, often involves measuring interactions with recombinant target molecules, and/or monitoring cancer cell killing in vitro. Here, we present yeast-based methods for evaluating drug-mediated inhibition of Bcl-2 relatives or caspases. Active Bax and caspases kill Saccharomyces cerevisiae, and pro-survival Bcl-2 proteins can inhibit Bax-induced yeast death. By measuring the growth or adenosine triphosphate content of transformants co-expressing Bax with pro-survival Bcl-2 relatives, we found that the Bcl-2 antagonist drugs ABT-737 or ABT-263 abolished Bcl-2 or Bcl-xL function and reduced Bcl-w activity, but failed to inhibit Mcl-1, A1 or the poxvirus orthologs DPV022 and SPPV14. Using this technique, we also demonstrated that adenoviral E1B19K was resistant to these agents. The caspase inhibitor Q-VD-OPh suppressed yeast death induced by caspases 1 and 3. Yeast engineered to express human apoptotic regulators enable simple, automatable assessment of the activity and specificity of candidate drugs targeting Bcl-2 relatives or caspases.
Insights
This study introduces a novel yeast-based system to screen drugs targeting Bcl-2 proteins and caspases. This method efficiently assesses drug efficacy against cancer and inflammatory disease targets.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Drug development for cancer and inflammatory diseases often targets Bcl-2 family proteins and caspases.
- Current methods involve recombinant molecule interactions or in vitro cancer cell killing assays.
- A need exists for simpler, automatable screening methods for these drug targets.
Purpose of the Study:
- To develop and validate yeast-based assays for evaluating drug-mediated inhibition of Bcl-2 relatives and caspases.
- To assess the activity and specificity of known Bcl-2 antagonist drugs and caspase inhibitors using this system.
Main Methods:
- Engineered Saccharomyces cerevisiae expressing human apoptotic regulators (Bcl-2 family proteins, Bax, caspases).
- Assessed drug effects by measuring yeast growth and adenosine triphosphate (ATP) content.
- Evaluated inhibition of Bax-induced yeast death by pro-survival Bcl-2 proteins and caspase-induced yeast death.
Main Results:
- Bcl-2 antagonist drugs ABT-737 and ABT-263 inhibited Bcl-2, Bcl-xL, and Bcl-w, but not Mcl-1, A1, or viral orthologs (DPV022, SPPV14).
- Adenoviral E1B19K protein was resistant to these Bcl-2 antagonists.
- Caspase inhibitor Q-VD-OPh effectively suppressed yeast death induced by caspases 1 and 3.
Conclusions:
- Yeast engineered with human apoptotic regulators provide a simple, automatable platform for assessing drug activity and specificity.
- This system is effective for screening candidate drugs targeting Bcl-2 relatives and caspases.
- The findings highlight the differential sensitivity of various Bcl-2 family members and viral inhibitors to tested drugs.
