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A new way to discover drugs
Nevan Krogan, Professor of Cellular Molecular Pharmacology and Director of the Quantitative Biosciences Institute, University of California, San Francisco, explains:
Proteins are the molecular machines that make your cells function. When proteins malfunction or are hijacked by a pathogen, you often get disease. Most drugs work by disrupting the action of one or several of these malfunctioning or hijacked proteins. So a logical way to look for new drugs to treat a specific disease is to study individual genes and proteins that are directly affected by that disease. For example, researchers know that the BRCA gene – a gene that protects your DNA from being damaged – is closely related to the development of breast and ovarian cancer. So a lot of work has focused on finding drugs that affect the function of the BRCA protein.
However, single proteins working in isolation are usually not solely responsible for disease. Genes and the proteins they encode are part of complicated networks – the BRCA protein interacts with tens to hundreds of other proteins that help it perform its cellular functions. My colleagues and I are part of a small but growing field of researchers who study these connections and interactions among proteins – what we call protein networks.
For a few years now, my colleagues and I have been exploring the potential of these networks to find more ways drugs could ameliorate disease. When the coronavirus pandemic hit, we knew we had to try this approach and see if it could be used to rapidly find a treatment for this emerging threat. We immediately started mapping the extensive network of human proteins that SARS-CoV-2 hijacks so it can replicate.
Once we built this map, we pinpointed human proteins in the network that drugs could easily target. We found 69 compounds that influence the proteins in the coronavirus network. 29 of them are already FDA-approved treatments for other illnesses. On Jan. 25 we published a paper showing that one of the drugs, Aplidin (Plitidepsin), currently being used to treat cancer, is 27.5 times more potent than remdesivir in treating COVID-19, including one of the new variants. The drug has been approved for phase 3 clinical trials in 12 countries as a treatment for the new coronavirus.
But this idea of mapping the protein interactions of diseases to look for novel drug targets doesn’t apply just to the coronavirus. We have now used this approach on other pathogens as well as other diseases including cancer, neurodegenerative and psychiatric disorders.
These maps are allowing us to connect the dots among many seemingly disparate aspects of single diseases and discover new ways drugs could treat them. We hope this approach will allow us and researchers in other areas of medicine to discover new therapeutic strategies and also see whether any old drugs might be repurposed to treat other conditions.
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