The majority of drugs either affect, produce, or eliminate proteins. Many are, themselves, proteins. To that end, proteomics is making important contributions to drug discovery, whether it’s deconvoluting targets or elucidating mechanism of actions. Now, a new method, decryptE, takes a proteome-wide approach to measure the dose–response characteristics of drug-induced protein expression changes.
Researchers at the Technical University of Munich (TUM) assayed 144 clinical drugs and research compounds against 8,000 proteins. The study produced more than one million dose–response curves. The results—which are available to the research community in the ProteomicsDB database and the associated app—could help to identify previously unknown potential benefits of existing drugs.
This work is published in Nature Biotechnology in the paper, “Decrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomics.”
“Many drugs can do more than we think,” said Bernhard Küster, PhD, professor of proteomics and bioanalytics at the TUM School of Life Sciences. “A familiar example is aspirin. Its effectiveness as a painkiller was well established. But observations showed that the effective ingredient, acetylsalicylic acid (ASA), also has a blood thinning effect. Nowadays it is routinely given to patients who suffer a stroke or heart attack. We believe that many widely used drugs will also have effects of which we are still unaware. One of the goals of our research is to systematically seek them out without having to wait for such accidental discoveries.”
The researchers treated cells with various doses of 144 active substances over an 18-hour period. Most of the drugs are currently used in cancer treatment or are in the clinical approval stage. After being extracted, the proteins were analyzed using mass spectrometry allowing for cell reactions to be further investigated.
Cancer is a prime example of why uncovering a detailed understanding of cellular phenotypes is so important: Different cancers have very different processes going on at the molecular level. Analysis of the team’s data provided molecular explanations for known phenotypic drug effects and uncovered new aspects of the MoA of human medicines. With the data, the team was able to show, for example, that the immune system can be weakened by HDAC inhibitors. More specifically, they showed that “histone deacetylase inhibitors potently and strongly down-regulated the T cell receptor complex resulting in impaired human T cell activation in vitro and ex vivo.” This finding can affect the treatment of tumors that leverage the immune system. It can also, the authors wrote, offer “a rational explanation for the efficacy of histone deacetylase inhibitors in certain lymphomas and autoimmune diseases and explains their poor performance in treating solid tumors.”
The team is hoping that the results, and decryptE in general, will harbor insights into previously undiscovered effects of widely used drugs.
