Scientists identify promising new ALS drug candidates
Novel Selenium-based compounds shown to have therapeutic potential

Date:
September 1, 2020
Source:
University of Liverpool
Summary:
Scientists have taken a significant step forward in the search to
find effective new drug candidates for the treatment of Amyotrophic
lateral sclerosis (ALS), also known as motor neuron disease.



FULL STORY ========================================================================== Scientists have taken a significant step forward in the search to find effective new drug candidates for the treatment of motor neuron disease.


========================================================================== Researchers from the Universities of Liverpool (UK) and Nagoya (Japan)
have shown that a Selenium-based drug-molecule called ebselen and a
number of other novel compounds developed at Liverpool can change many
of the toxic characteristics of a protein, superoxide dismutase (SOD1),
which causes some cases of Amyotrophic lateral sclerosis (ALS), also
known as motor neuron disease.

The study is published in the journal EBioMedicine.

ALS is a neurodegenerative disease which affects motor neurons and the
neuronal links between our brain and our muscles. Over the course of
the disease these nerve links die, and the patient becomes paralysed,
with the majority dying within 2 to 5 years of diagnosis. Around 20%
of the familial ALS cases arise from dominant mutations in the sod1
gene. Aggregation of mutant SOD1 protein in familial cases and of
wild-type SOD1 in at least some sporadic ALS cases is one of the known
causes of the disease. Riluzole, approved in 1995 and edaravone in 2017
remain the only drugs with limited therapeutic benefits.

Stabilisation of the original SOD structure is seen as a key
strategy to avoid aggregation. The team have developed a number of ebselen-based compounds with improvements in SOD1 stabilisation and
in vitro therapeutic effects with significantly better potency than
edaravone. Structure-activity relationship of hits has been guided by
high resolution structures of ligand-bound A4V SOD1, a mutant which causes
the most severe disease. They were also able to show clear disease onset
delay of ebselen in a transgenic ALS model mouse, holding encouraging
promise for potential therapeutic compounds.

Professor Samar Hasnain, who led the international team of
interdisciplinary experts said: "The fact that this new generation of organo-selenium compounds have better in vitro neuroprotective activity
than edaravone holds a significance promise for the potential of this
class of compounds as an alternative therapeutic agent for ALS treatment.

"The ability of these compounds to target cysteine 111 in SOD may
have wider therapeutic applications targeting cysteines of enzymes
involved in pathogenic and viral diseases including the main protease of SARS-Cov-2 (COVID-19)." Professor Paul O'Neill, who lead the medicinal chemistry programme said: "Our medicinal chemistry approach, guided
by protein-ligand crystallography studies, focused on the design of
ebselen based analogues that have improved in vitro potency coupled with excellent predicted CNS exposure and improved solubility and metabolic stability characteristics. By employing this multi-parameter optimisation approach to drug design, the next key stage will be to screen our next generation compounds in appropriate disease models." Professor Koji
Yamanaka, a physician-neuroscientist at Nagoya University, said: "It
is very encouraging that a number of these novel Selenium compounds
exhibited better in vitro neuroprotection in mouse neuronal cells than edaravone. In vivo disease onset delay by ebselen has been demonstrated
for the first time in ALS mouse model and further improvement can be
expected from the new novel compounds in view of their improved in vitro protection. Choices are very limited for a current ALS therapy, therefore,
we are excited to take a significant step forward for developing a new
class of drug candidate for ALS."

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


========================================================================== Journal Reference:
1. Kangsa Amporndanai, Michael Rogers, Seiji Watanabe, Koji Yamanaka,
Paul
M. O'Neill, S. Samar Hasnain. Novel Selenium-based compounds with
therapeutic potential for SOD1-linked amyotrophic lateral sclerosis.

EBioMedicine, 2020; 59: 102980 DOI: 10.1016/j.ebiom.2020.102980 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200901125911.htm

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