Finding cortisone alternatives with fewer side effects
DNA binding is essential for effectiveness of steroids

Date:
September 2, 2020
Source:
Technical University of Munich (TUM)
Summary:
Researchers are examining the beneficial effects of cortisone in
order to lay the groundwork for the development of similar drugs
with fewer side effects.



FULL STORY ==========================================================================
Many people use cortisone of a regular basis. It is used for treating rheumatism, asthma, multiple sclerosis, or even COVID-19. Steroidal
medication such as cortisone is highly effective but also possesses
severe side effects.

Henriette Uhlenhaut, professor at Technical University of Munich (TUM),
and her team are examining the beneficial effects of cortisone in order
to lay the groundwork for the development of similar drugs with fewer
side effects.


==========================================================================
The work group around Henriette Uhlenhaut, Professor for Metabolic
Programming at TUM School of Life Sciences in Freising-Weihenstephan and researcher in the field of Molecular Endocrinology at Helmholtz Zentrum Mu"nchen is working with so-called glucocorticoids. These are steroidal hormones such as cortisone, which are released by the adrenal glands every
day before waking up or whenever a person is subjected to stress. These steroids are bound to their glucocorticoid receptor and control not only
our body's immune reaction but also our sugar and fat metabolism.

As glucocorticoid receptors are so efficient at disabling immune
reactions, synthetic steroid medication is among the most prescribed
drugs overall and it has been for decades.

The goal: Finding molecules with anti-inflammatory effects "Unfortunately,
this useful property leads to severe side effects as one hormone or
drug causes different effects in other non-immune cells," explained the professor. Among these effects are the reduction of muscle mass or the deposition of fat.

"We still don't fully understand the effects of steroid compounds," said Uhlenhaut. With her team, she wants to discover the molecular mechanisms
that steroids such as cortisone utilize to stop inflammatory reactions.



==========================================================================
As soon as researchers know how cortisone works, so how it mutes
inflammation genes in immune system cells, they can begin looking for
molecules that possess the same anti-inflammatory properties as cortisone,
but with fewer side effects.

Common theory refuted Until recently, scientists believed that the
steroids' anti-inflammatory effect was based on protein-to-protein
interaction. It was assumed that the glucocorticoid receptor -- in other
words, the protein that binds these drugs or hormones -- would connect
to other inflammation inducing proteins without any DNA contact.

Using a new preclinical model, the team of researchers could now
demonstrate that DNA binding is required for these drugs to have
an effect; for years, scientists had assumed that this was not the
case. Without the glucocorticoid receptor (the protein that binds these
drugs or hormones) enabling DNA binding to chromosomes, chromatin or
genes, there is no biological effect.

A milestone for drug development "Now we know that DNA binding plays a
major role, yet we have not found a way to separate side effects from
the desired effects," explained Prof. Uhlenhaut.

Regarding COVID-19, researchers do not have a clear answer either as to
why these kinds of treatments are successful. Further research in this
area is required.

Until now, various approaches focused on protein-to-protein contact,
which might explain why these have not been successful. As this basic
approach can now be discarded, further research regarding drug development
of cortisone alternatives can now focus on the DNA.


========================================================================== Story Source: Materials provided by
Technical_University_of_Munich_(TUM). Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Nina Henriette Uhlenhaut, Michael Wierer, Fabiana Quagliarini,
Franziska
Greulich, Laura Escoter-Torres. Anti-inflammatory functions of the
glucocorticoid receptor require DNA binding. Nucleic Acids Research,
2020; DOI: 10.1093/nar/gkaa565 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200902095120.htm

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