ISRIB (
integrated stress response
The integrated stress response is a cellular stress response evolutionary conservation, conserved in eukaryotic cell (biology), cells that downregulates protein synthesis and upregulates specific genes in response to internal or environmental stres ...
inhibitor) is an experimental drug that reverses the effects of
eIF2α phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
with an
IC50 of 5
nM. It was discovered in the laboratory of
Peter Walter
Peter Walter (born December 5, 1954) is a German-American molecular biologist and biochemist and is Director of the Bay Area Institute of Science at Altos Labs, Professor at the University of California, San Francisco (UCSF). He was a Howard H ...
at
University of California, San Francisco
The University of California, San Francisco (UCSF) is a public land-grant research university in San Francisco, California. It is part of the University of California system and is dedicated entirely to health science and life science. It cond ...
(UCSF) through a semi-automated screening of a large library of small molecules by Carmela Sidrauski, who decided to pursue research on it.
[Piore, Adam, ]
The miracle molecule that could treat brain injuries and boost your fading memory
', MIT Technology Review, August 25, 2021 (Carmela Sidrauski interview) It has been shown to inhibit eIF2α phosphorylation-induced
stress granule
Stress granules are dense aggregations in the cytosol composed of proteins and RNAs that appear when the cell is under stress. The RNA molecules stored are stalled translation pre-initiation complexes: failed attempts to make protein from mRNA. St ...
(SG) formation. Since eIF2α phosphorylation is known to be involved in memory formation, ISRIB was tested to see whether it would be active ''in vivo'', and was found to readily cross the
blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
, with a half-life of eight hours.
Subsequent testing in 2013 found ISRIB to produce significant
nootropic
Nootropics ( , or ) (colloquial: smart drugs and cognitive enhancers, similar to adaptogens) are a wide range of natural or synthetic supplements or drugs and other substances that are claimed to improve cognitive function or to promote re ...
effects in mice, as measured by enhancement of spatial and fear-associated learning in standard
water-maze and conditioned environment tests.
The technology was licensed to
Calico
Calico (; in British usage since 1505) is a heavy plain-woven textile made from unbleached, and often not fully processed, cotton. It may also contain unseparated husk parts. The fabric is far coarser than muslin, but less coarse and thick than ...
in 2015 and Sidrauski was hired to help find possible drugs based on ISRIB.
She heads the laboratory in which it is being studied.
Testing in 2017 indicated the experimental drug improved the ability of brain-injured mice to learn and form memories on memory tests, thus appearing to reverse impairments from traumatic brain injury.
ISRIB treatment also corrects spatial memory deficits and improves working memory in aged mice.
Further research on the drug by Sidrauski has shown that the molecule restored memory formation in mice months after traumatic brain injuries. It also has shown potential in treating neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Lou Gehrig’s disease (also known as amyotrophic lateral sclerosis, or ALS). In mice, it has reduced age-related cognitive decline and given healthy mice improved memory.
Research on ISRIB by Sidrauski continues at Calico.
See also
*
Meclofenoxate
Meclofenoxate (International Nonproprietary Name, INN, British Approved Name, BAN; brand name Lucidril, also known as centrophenoxine) is a cholinergic nootropic used as a dietary supplement. It is an ester of dimethylethanolamine (DMAE) and 4-Ch ...
*
Salubrinal
Salubrinal is a drug which acts as a specific inhibitor of eIF2α phosphatase enzymes and is primarily used experimentally, to study stress responses in eukaryotic cells associated with the action of eIF2. Salubrinal indirectly inhibits eIF2 as a ...
References
{{reflist
External links
DEC 1, 2020:Drug reverses age-related cognitive decline within days, by University of California, San Francisco
Chloroarenes
Cyclohexanes
CategorY:Carboxamides