A team of UCLA researchers led by Professor Keriann Backus and graduate students Ashley R. Julio and Flowreen Shikwana has shed new light on the functional consequences of cysteine-reactive compounds in cells. Their discovery that compounds commonly used in screening studies can cause electrophile stress is highly significant  for understanding cellular responses to stress and for advancing both current and future efforts  in covalent drug discovery.

Using cutting-edge mass spectrometry-based chemoproteomic techniques, the researchers first mapped potential druggable cysteine residues within proteins. Their findings reveal how a particular small molecule can degrade the SARS-CoV-2 nonstructural protein 14 (nsp14) by modifying cysteines in both the virus and host proteins.

Notably, this degradation is amplified by a broader cellular response that promotes the degradation of multiple proteins, leading to the formation of stress granules and aggresomes—two cellular structures that help cells manage stress. The study sheds light on the complex ways these cysteine-targeting compounds can influence cellular processes, providing an important technical foundation for future therapeutic discovery efforts.

They recently reported their research in a paper titled “Delineating cysteine-reactive compound modulation of cellular proteostasis processes” in the journal Nature Chemical Biology.

Co-authors on the paper include Backus group members Cindy Truong, Nikolas R. Burton, Emil R. Dominguez III, Alexandra C. Turmon, and former postdoc Dr. Jian Cao, now a researcher at Novartis in San Diego, CA .