Why Some Drugs Have Side Effects
Researchers have discovered how unwanted side effects can result from how some drugs affect various membrane-spanning proteins in addition to their intended target. The findings, published in PNAS, illuminate one of the main problems of drug discovery and point to new strategies to overcome it.
Any class of drug can have side effects, but those that interact directly with cellular membranes have been especially problematic. “Those drugs tend to affect many membrane proteins, and we suspected that there’s some kind of non-specific mechanism at work,” said first author Dr Radda Rusinova, assistant professor of research in physiology and biophysics at Weill Cornell Medicine. “We wanted to see whether it could be linked to the cell membrane.”
Dr Rusinova and her colleagues used sensitive assays that allowed them to compare how different drugs affected the activities of two channel proteins that span membranes: the gramicidin ion channel and a potassium channel called KcsA. Gramicidin was used to measure the magnitude of drugs’ effect on the membrane while KcsA reflected effects these drugs could have on typical membrane proteins. They found that membrane-associated drugs can affect KcsA in at least three ways: by interacting directly with the proteins, by interfering with the proteins’ structural connections to the membrane, or by causing broad changes in membrane characteristics such as thickness or elasticity.
Changes in membrane characteristics have well-known effects on the gramicidin ion channel, an antibiotic isolated from bacteria that has long been used as a standard tool for studying such changes. “Gramicidin is a probe essentially for changes in bilayer and membrane properties, and will report on the magnitude of the changes,” said Dr. Rusinova.
“But we needed to go further to see how a more typical cell membrane protein would react,” Dr. Rusinova said. KcsA belongs to a class of proteins – potassium channels – that drive many aspects of cell physiology in everything from bacteria to humans, making it a good comparative probe.
The comparative assay results revealed a more nuanced process than the straightforward model currently used to explain how membrane-binding drugs can affect membrane-spanning proteins.
“The more data that Dr Rusinova got, the more it became apparent that this simple model did not actually cover the full spectrum of effects that we saw,” said senior author Dr Olaf Andersen, professor of physiology and biophysics.
“The investigators who are looking into molecules that can move into the cell membrane need to worry about at least three mechanisms for off-target effects,” Dr Rusinova said.
However, not all is bad news: in some cases, off-target effects at the cellular level cause no trouble to the organism, and in a few instances they can even be beneficial. Dr Rusinova points to two of the drugs her team tested as an example: amiodarone, a heart medication whose membrane-mediated effects actually boost its efficacy, and troglitazone, an anti-diabetic drug whose side effects included liver toxicity, ultimately forcing regulators to pull it from the market.
The investigators hope to develop more predictive models for such off-target effects. “We would like to determine the structural characteristics of a membrane protein that would make it more or less sensitive to bilayer effects,” Dr Rusinova said.
Source: Weill Cornell Medicine
