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Editor-in-Chief | Axonal degeneration is one of the early lesions of many neurodegenerative diseases
.
SARM1 (sterile alpha and Toll/interleukin-1 receptor motif-containing 1) protein is an important executive molecule in the process of axon degeneration, and itself has an enzyme that hydrolyzes nicotinamide adenine dinucleotide (NAD+), an important metabolic molecule in the human body.
catalytic activity
.
In the absence of SARM1 protein or its enzymatic catalytic activity, axons can be better protected in a variety of neurodegenerative diseases
.
Therefore, small chemical molecules that can bind to SARM1 protein and inhibit the enzymatic activity of SARM1 have the potential to become new drugs for the treatment of various neurodegenerative diseases
.
The structure of SARM1 protein contains four domains, namely ARM domain, SAM1 domain, SAM2 domain, and TIR domain
.
Previously, the team of Dr.
Thomas Ve from Griffith University, Australia, and the team of Professor Bostjan Kobe from the University of Queensland, Australia, have solved the crystal structures of SAM1-SAM2 domains and TIR domains [1] and Cryo-EM structure of full-length SARM1 protein in inactive state [2]
.
They elucidated that the TIR domain that forms the double-stranded structure has the enzymatic function of hydrolyzing NAD+, the SAM1-SAM2 domain forms an octameric ring structure, and the ARM domain senses intracellular nicotinamide mononucleotide (NMN) An increase in the ratio of NAD+ activates the enzymatic activity of the TIR domain
.
On March 24, 2022, Dr.
Thomas Ve's team collaborated with Disarm Therapeutics (a wholly-owned subsidiary of Eli Lilly), an American biotechnology company, to publish a paper entitled Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules online in Molecular Cell The paper [3], for the first time analyzed the crystal structure of the SARM1 enzyme active site combined with chemical small molecules and the cryo-electron microscope structure of the SARM1 protein in the active state, and revealed the first batch of neuroprotective activities.
Inhibitory mechanism of SARM1 protein by anti-axonal degeneration small molecules
.
Dr.
Yun Shi of Griffith University is the first author of this article
.
In this paper, a class of small molecule inhibitors of SARM1 based on isoquinoline structure was firstly studied.
Among them, compound No.
1 has a very strong inhibitory effect on SARM1 enzymatic activity, with an IC50 value of 75 nanomolar (nM), and was proved to protect Injured nerve cell axons prevent their damage from getting worse
.
However, Shi Yun et al.
noted that compound 1 is very small, consisting of only 11 heavy atoms, and is unlikely to bind strongly to protein molecules with high affinity on the order of nanomolar
.
So this paper uses nuclear magnetic resonance (NMR) and other experimental methods to find that compound No.
1 is actually a pro-drug
.
Under physiological conditions, compound No.
1 will be converted by its target protein SARM1, and undergo an exchange reaction with the nicotinamide (NAM) moiety in the NAD+ structure of SARM1's natural substrate to generate a new compound 1AD, which is the real strong SARM1.
effective inhibitor
.
Based on this exchange reaction mechanism, Shi Yun et al.
studied a series of nicotinamide (NAM) derivatives and a NAD+ analog, araF-NAD+, and used this mechanism to obtain the first small molecule inhibitor that binds to the TIR domain.
The first substrate bound to the TIR domain, and the crystal structure of the first chemical molecule covalently bound to the TIR domain
.
These three-dimensional structures reveal for the first time that the enzymatically active site (orthosteric site) of SARM1 protein is located at the interface between the two TIR domains, and reveal that the enzymatic reaction of SARM1 occurs in a double displacement mechanism
.
Then, using the small molecule inhibitor 1AD as a tool, this paper used its high affinity to aggregate the TIR domains of the full-length SARM1 protein in the activated state, and successfully captured the cryo-electron microscope structure of the full-length SARM1 in the activated state for the first time.
.
Compared with previously reported structures in the inactive state, the ARM domain in the activated state undergoes a dramatic conformational change, allowing the eight TIR domains that were originally locked in the loop to be released and brought together
.
This structure demonstrates for the first time that the TIR domain in the full-length SARM1 protein aggregates into a double-stranded structure with a certain radian and forms a complete active site to catalyze the NAD+ hydrolysis reaction, which eventually leads to axonal degeneration
.
In summary, this study not only revealed the mechanism of a number of anti-axon degeneration inhibitors at the molecular level, but also demonstrated a number of high-precision protein-ligand three-dimensional structures, which are the basis for the next generation of anti-axon degeneration small molecules.
The design of structure and mechanism provides a variety of ideas
.
Original link: https:// Publisher: Eleven References 1.
Horsefield, S.
; Burdett, H.
; Zhang, X .
; Manik, MK; Shi, Y.
; Chen, J.
; Qi, T.
; Gilley, J.
; Lai, J.
-S.
; Rank, MX; et al.
NAD+ Cleavage Activity by Animal and Plant TIR Domains in Cell Death Pathways.
Science 2019, 365, 793–799, doi:10.
1126/science.
aax1911.
2.
Figley, MD; Gu, W.
; Nanson, JD; Shi, Y.
; Sasaki, Y.
; Cunnea, K .
; Malde, AK; Jia, X.
; Luo, Z.
; Saikot, FK; et al.
SARM1 Is a Metabolic Sensor Activated by an Increased NMN/NAD+ Ratio to Trigger Axon Degeneration.
Neuron 2021, doi:10.
1016/j.
neuron.
2021.
02.
009.
3.
Shi, Y.
; Kerry, PS; Nanson, JD; Bosanac, T.
; Sasaki, Y.
; Krauss, R.
; Saikot, FK; Adams, SE; Mosaiab, T.
; Masic, V .
; et al.
Structural Basis of SARM1 Activation, Substrate Recognition, and Inhibition by Small Molecules.
Mol.
Cell 2022, 82,1–17, doi: 10.
1016/j.
molcel.
2022.
03.
007.
Reprint notice [Non-original article] The copyright of this article belongs to the author of the article.
Personal reposting and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights.
Violators must study
.
.
SARM1 (sterile alpha and Toll/interleukin-1 receptor motif-containing 1) protein is an important executive molecule in the process of axon degeneration, and itself has an enzyme that hydrolyzes nicotinamide adenine dinucleotide (NAD+), an important metabolic molecule in the human body.
catalytic activity
.
In the absence of SARM1 protein or its enzymatic catalytic activity, axons can be better protected in a variety of neurodegenerative diseases
.
Therefore, small chemical molecules that can bind to SARM1 protein and inhibit the enzymatic activity of SARM1 have the potential to become new drugs for the treatment of various neurodegenerative diseases
.
The structure of SARM1 protein contains four domains, namely ARM domain, SAM1 domain, SAM2 domain, and TIR domain
.
Previously, the team of Dr.
Thomas Ve from Griffith University, Australia, and the team of Professor Bostjan Kobe from the University of Queensland, Australia, have solved the crystal structures of SAM1-SAM2 domains and TIR domains [1] and Cryo-EM structure of full-length SARM1 protein in inactive state [2]
.
They elucidated that the TIR domain that forms the double-stranded structure has the enzymatic function of hydrolyzing NAD+, the SAM1-SAM2 domain forms an octameric ring structure, and the ARM domain senses intracellular nicotinamide mononucleotide (NMN) An increase in the ratio of NAD+ activates the enzymatic activity of the TIR domain
.
On March 24, 2022, Dr.
Thomas Ve's team collaborated with Disarm Therapeutics (a wholly-owned subsidiary of Eli Lilly), an American biotechnology company, to publish a paper entitled Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules online in Molecular Cell The paper [3], for the first time analyzed the crystal structure of the SARM1 enzyme active site combined with chemical small molecules and the cryo-electron microscope structure of the SARM1 protein in the active state, and revealed the first batch of neuroprotective activities.
Inhibitory mechanism of SARM1 protein by anti-axonal degeneration small molecules
.
Dr.
Yun Shi of Griffith University is the first author of this article
.
In this paper, a class of small molecule inhibitors of SARM1 based on isoquinoline structure was firstly studied.
Among them, compound No.
1 has a very strong inhibitory effect on SARM1 enzymatic activity, with an IC50 value of 75 nanomolar (nM), and was proved to protect Injured nerve cell axons prevent their damage from getting worse
.
However, Shi Yun et al.
noted that compound 1 is very small, consisting of only 11 heavy atoms, and is unlikely to bind strongly to protein molecules with high affinity on the order of nanomolar
.
So this paper uses nuclear magnetic resonance (NMR) and other experimental methods to find that compound No.
1 is actually a pro-drug
.
Under physiological conditions, compound No.
1 will be converted by its target protein SARM1, and undergo an exchange reaction with the nicotinamide (NAM) moiety in the NAD+ structure of SARM1's natural substrate to generate a new compound 1AD, which is the real strong SARM1.
effective inhibitor
.
Based on this exchange reaction mechanism, Shi Yun et al.
studied a series of nicotinamide (NAM) derivatives and a NAD+ analog, araF-NAD+, and used this mechanism to obtain the first small molecule inhibitor that binds to the TIR domain.
The first substrate bound to the TIR domain, and the crystal structure of the first chemical molecule covalently bound to the TIR domain
.
These three-dimensional structures reveal for the first time that the enzymatically active site (orthosteric site) of SARM1 protein is located at the interface between the two TIR domains, and reveal that the enzymatic reaction of SARM1 occurs in a double displacement mechanism
.
Then, using the small molecule inhibitor 1AD as a tool, this paper used its high affinity to aggregate the TIR domains of the full-length SARM1 protein in the activated state, and successfully captured the cryo-electron microscope structure of the full-length SARM1 in the activated state for the first time.
.
Compared with previously reported structures in the inactive state, the ARM domain in the activated state undergoes a dramatic conformational change, allowing the eight TIR domains that were originally locked in the loop to be released and brought together
.
This structure demonstrates for the first time that the TIR domain in the full-length SARM1 protein aggregates into a double-stranded structure with a certain radian and forms a complete active site to catalyze the NAD+ hydrolysis reaction, which eventually leads to axonal degeneration
.
In summary, this study not only revealed the mechanism of a number of anti-axon degeneration inhibitors at the molecular level, but also demonstrated a number of high-precision protein-ligand three-dimensional structures, which are the basis for the next generation of anti-axon degeneration small molecules.
The design of structure and mechanism provides a variety of ideas
.
Original link: https:// Publisher: Eleven References 1.
Horsefield, S.
; Burdett, H.
; Zhang, X .
; Manik, MK; Shi, Y.
; Chen, J.
; Qi, T.
; Gilley, J.
; Lai, J.
-S.
; Rank, MX; et al.
NAD+ Cleavage Activity by Animal and Plant TIR Domains in Cell Death Pathways.
Science 2019, 365, 793–799, doi:10.
1126/science.
aax1911.
2.
Figley, MD; Gu, W.
; Nanson, JD; Shi, Y.
; Sasaki, Y.
; Cunnea, K .
; Malde, AK; Jia, X.
; Luo, Z.
; Saikot, FK; et al.
SARM1 Is a Metabolic Sensor Activated by an Increased NMN/NAD+ Ratio to Trigger Axon Degeneration.
Neuron 2021, doi:10.
1016/j.
neuron.
2021.
02.
009.
3.
Shi, Y.
; Kerry, PS; Nanson, JD; Bosanac, T.
; Sasaki, Y.
; Krauss, R.
; Saikot, FK; Adams, SE; Mosaiab, T.
; Masic, V .
; et al.
Structural Basis of SARM1 Activation, Substrate Recognition, and Inhibition by Small Molecules.
Mol.
Cell 2022, 82,1–17, doi: 10.
1016/j.
molcel.
2022.
03.
007.
Reprint notice [Non-original article] The copyright of this article belongs to the author of the article.
Personal reposting and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights.
Violators must study
.
