ISRIB (short for "
integrated stress response
The integrated stress response is a cellular stress response conserved in eukaryotic cells that downregulates protein synthesis and upregulates specific genes in response to internal or environmental stresses.
Background
The integrated stres ...
inhibitor") is an experimental drug that reverses the effects of
eIF2α
Eukaryotic translation initiation factor 2 subunit 1 (eIF2α) is a protein that in humans is encoded by the ''EIF2S1'' gene.
Function
The protein encoded by this gene is the alpha (α) subunit of the translation initiation factor eIF2 prote ...
phosphorylation
In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:
:
This equation can be writ ...
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. He is currently the Director of the Bay Area Institute of Science at Altos Labs and an emeritus professor at the Department of Biochemistry and Biop ...
at
University of California, San Francisco
The University of California, San Francisco (UCSF) is a Public university, public Land-grant university, land-grant research university in San Francisco, California, United States. It is part of the University of California system and is dedic ...
(UCSF) through a semi-automated screening of a large library of small molecules by Carmela Sidrauski, who decided to pursue research on it.
It has been shown to inhibit eIF2α phosphorylation-induced
stress granule
In cellular biology, stress granules are biomolecular condensates in the cytosol composed of proteins and RNA that assemble into 0.1–2 μm membraneless organelles when the cell is under stress. The mRNA molecules found in stress granules a ...
(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 regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...
, with a half-life of eight hours.
Drug development
Subsequent testing in 2013 found ISRIB to produce significant
nootropic
Nootropics ( or ) (colloquially brain supplements, smart drugs, cognitive enhancers, memory enhancers, or brain boosters) are chemical substances which purportedly improve cognitive functions, such as attention, memory, wakefulness, and self ...
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.
Mechanism of action
Cryo-EM structures of ISRIB bound to eIF2B indicates that ISRIB staples together two tetrameric eIF2B (βγδε) subcomplexes into a 8-meric complex (βγδε)
2, which is more amenable to binding EIF2B alpha subunits. As a result, ISRIB accelerates the assembly of EIF2B into an active 10-meric form, thereby increasing the amount of active EIF2B. Because phosphorylation of eIF2α exerts its effects by depleting the stock of active EIF2B, increasing the EIF2B supply would reverse its effects. ISRIB does not increase the total supply of EIF2B, so in cell cultures with very high levels of stress, the ISR can still proceed after the inactivating the cell's entire stock of EIF2B.
See also
*
Meclofenoxate
Meclofenoxate ( INN, 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-chlorophenoxyacetic acid (pCPA).
In elderly patients, me ...
*
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
4-Chlorophenyl compounds
Cyclohexanes
Carboxamides