Mechanisms of drug side effects uncovered

Date:
November 10, 2021
Source:
Weill Cornell Medicine
Summary:
Researchers have discovered how drugs can affect various membrane-
spanning proteins in addition to their intended target, potentially
causing unwanted side effects. The results illuminate one of the
central problems of drug discovery and point to new strategies
for solving it.



FULL STORY ========================================================================== Researchers at Weill Cornell Medicine have discovered how drugs can affect various membrane-spanning proteins in addition to their intended target, potentially causing unwanted side effects. The results illuminate one
of the central problems of drug discovery and point to new strategies
for solving 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."
In the study, published Nov. 9 in PNAS, 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.

Results from the comparative assays revealed a more nuanced process
than the straightforward model currently in use for explaining 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 Dr. Olaf Andersen, professor of physiology and biophysics
and senior author on the study.

"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.

The news isn't all bad, though. In some cases, off-target effects at
the cellular level cause no trouble to the organism, while in a few
instances they can even be beneficial. To highlight the diversity of
possible outcomes, Dr.

Rusinova points to two of the drugs her team tested: 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 extend their work by developing 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.

========================================================================== Story Source: Materials provided by Weill_Cornell_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Radda Rusinova, Changhao He, Olaf S. Andersen. Mechanisms underlying
drug-mediated regulation of membrane protein function. Proceedings
of the National Academy of Sciences, 2021; 118 (46): e2113229118
DOI: 10.1073/ pnas.2113229118 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211110131518.htm

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