新しいスクリーニング技術で、がん治療薬の探索を飛躍的にスピードアップ(New screening technique will radically speed up hunt for cancer-fighting drugs)

バース大学の科学者たちは、がんを引き起こすことが知られているタンパク質を遮断する薬の発見を加速させるための新しい技術を開発しました。 Scientists at the University of Bath have developed a new technique to accelerate the discovery of drugs that shut down proteins known to cause cancer.

2022-04-08 バース大学

<関連情報>

• https://www.bath.ac.uk/announcements/new-screening-technique-will-radically-speed-up-hunt-for-cancer-fighting-drugs/
• https://pubs.acs.org/doi/10.1021/jacsau.2c00105

転写因子活性を阻害する機能性ペプチド誘導体へのアプローチ An Approach to Derive Functional Peptide Inhibitors of Transcription Factor Activity

Andrew Brennan, James T. Leech, Neil M. Kad, and Jody M. Mason*
JACSAu　Publication Date:April 6, 2022
https://doi.org/10.1021/jacsau.2c00105

Abstract

We report the development of a high-throughput, intracellular “transcription block survival” (TBS) screening platform to derive functional transcription factor antagonists. TBS is demonstrated using the oncogenic transcriptional regulator cJun, with the development of antagonists that bind cJun and prevent both dimerization and, more importantly, DNA binding remaining a primary challenge. In TBS, cognate TRE sites are introduced into the coding region of the essential gene, dihydrofolate reductase (DHFR). Introduction of cJun leads to TRE binding, preventing DHFR expression by directly blocking RNA polymerase gene transcription to abrogate cell proliferation. Peptide library screening identified a sequence that both binds cJun and antagonizes function by preventing DNA binding, as demonstrated by restored cell viability and subsequent in vitro hit validation. TBS is an entirely tag-free genotype-to-phenotype approach, selecting desirable attributes such as high solubility, target specificity, and low toxicity within a complex cellular environment. TBS facilitates rapid library screening to accelerate the identification of therapeutically valuable sequences.