In a pair of related studies, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown their drug candidates can target biological pathways involved in the destruction of brain cells in Parkinson's disease.
The studies, published in the Journal of Medicinal Chemistry and Scientific Reports, suggest that it is possible to design highly effective and highly selective (targeted) drug candidates that can protect the function of mitochondria, which provide the cell with energy, ultimately preventing brain cell death.
These drug candidates act on what are known as the JNK (pronounced "junk") kinases—JNK1, JNK2 and JNK3—each an enzyme with a unique biological function. JNK is linked to many of the hallmark components of Parkinson's disease, such as oxidative stress and programmed cell death.
"These are the first isoform selective JNK 2/3 inhibitors that can penetrate the brain and the first shown to be active in functional cell-based tests that measure mitochondrial dysfunction," said Philip LoGrasso, a TSRI professor who led both studies. "In terms of their potential use as therapeutics, they've been optimized in every way but one—their oral bioavailability. That's what we're working on now."
The new studies raise the hope that such a therapy could prevent the gradual degeneration of brain cells in Parkinson's disease and halt these patients' decline.
"Some of these compounds had a level of selectivity that ranged as high as 20,000-fold against competing targets and were extremely effective against oxidative stress and mitochondrial dysfunction—both potent cell killers," added HaJeung Park, director of Scripps Florida's X-ray Crystallography Core Facility and the first author of the Scientific Reports study.
The scientists found that within JNK3, a single amino acid—L144—was primarily responsible for the high level of JNK3 selectivity. Isoform selectivity can help to limit potential side effects of a drug.
Intriguingly, some recent studies have shown that JNK3 not only plays a central role in brain cell death in Parkinson's disease, but also in Alzheimer's disease. LoGrasso and his colleagues also believe their JNK3 drug candidates have potential for treating ALS (Lou Gehrig's disease).
More information: Scientific Reports, "Structural Basis and Biological Consequences for JNK2/3 Isoform Selective Aminopyrazoles," http://ift.tt/PUevwq
Journal of Medicinal Chemistry, "Design and Synthesis of Highly Potent and Isoform Selective JNK32 Inhibitors: SAR Studies on Aminopyrazole Derivatives," http://ift.tt/1Bu129A
Medical Xpress on facebook
Related Stories
Scientists uncover potential drug target to block cell death in Parkinson's disease
Jan 10, 2013
Oxidative stress is a primary villain in a host of diseases that range from cancer and heart failure to Alzheimer's disease, Amyotrophic Lateral Sclerosis and Parkinson's disease. Now, scientists from the Florida campus of ...
Scientists design a potential drug compound that attacks Parkinson's disease on two fronts
Jun 20, 2013
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have found a compound that could counter Parkinson's disease in two ways at once.
Key protein interactions involved in neurodegenerative disease revealed
Nov 08, 2012
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have defined the molecular structure of an enzyme as it interacts with several proteins involved in outcomes that can influence neurodegenerative ...
Scientists find way to block stress-related cell death
Jun 02, 2011
Scientists from the Florida campus of The Scripps Research Institute have uncovered a potentially important new therapeutic target that could prevent stress-related cell death, a characteristic of neurodegenerative diseases ...
Compound developed by scientists protects heart cells during and after attack
Feb 07, 2013
Using two different compounds they developed, scientists from the Florida campus of The Scripps Research Institute (TSRI) have been able to show in animal models that inhibiting a specific enzyme protects heart cells and ...
Recommended for you
Antiangiogenesis drugs could make major improvement in tuberculosis treatment
14 hours ago
Use of the same antiangiogenesis drugs that have improved treatment of some cancers could also help surmount persistent difficulties in treating tuberculosis (TB). In their PNAS Early Edition report, invest ...
Collagen fibres not only passively support bone, tendons and ligaments, but also actively contract
16 hours ago
The bodies of humans and animals owe their strength especially to a fibrous structural protein called collagen. Collagen is abundant in bones, tendons, ligaments and skin. Water, a substance that is not often ...
Possible therapeutic target for common, but mysterious brain blood vessel disorder
17 hours ago
Tens of millions of people around the world have abnormal, leak-prone sproutings of blood vessels in the brain called cerebral cavernous malformations (CCMs). These abnormal growths can lead to seizures, ...
Scientists discover a new blood platelet formation mechanism
17 hours ago
Thrombocytopenia is a disease characterised by a lower platelet level than normal. Platelets are tiny cells that participate in the coagulation of blood. Patients usually suffer uncontrolled bleeding that ...
Cochlear implant users can hear, feel the beat in music
18 hours ago
People who use cochlear implants for profound hearing loss do respond to certain aspects of music, contrary to common beliefs and limited scientific research, says a research team headed by an investigator at Georgetown University ...
Hemin improves adipocyte morphology and function by enhancing proteins of regeneration
19 hours ago
Scientists at the University of Saskatchewan College of Medicine, Department of Physiology, Saskatoon, Canada, led by Dr. Joseph Fomusi Ndisang have determined that upregulating heme-oxygenase with hemin improves pericardial ...
User comments
Please sign in to add a comment. Registration is free, and takes less than a minute. Read more
Click here to reset your password.
Sign in to get notified via email when new comments are made.
© Medical Xpress 2011-2014, Science X network
In a pair of related studies, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown their drug candidates can target biological pathways involved in the destruction of brain cells in Parkinson's disease.
The studies, published in the Journal of Medicinal Chemistry and Scientific Reports, suggest that it is possible to design highly effective and highly selective (targeted) drug candidates that can protect the function of mitochondria, which provide the cell with energy, ultimately preventing brain cell death.
These drug candidates act on what are known as the JNK (pronounced "junk") kinases—JNK1, JNK2 and JNK3—each an enzyme with a unique biological function. JNK is linked to many of the hallmark components of Parkinson's disease, such as oxidative stress and programmed cell death.
"These are the first isoform selective JNK 2/3 inhibitors that can penetrate the brain and the first shown to be active in functional cell-based tests that measure mitochondrial dysfunction," said Philip LoGrasso, a TSRI professor who led both studies. "In terms of their potential use as therapeutics, they've been optimized in every way but one—their oral bioavailability. That's what we're working on now."
The new studies raise the hope that such a therapy could prevent the gradual degeneration of brain cells in Parkinson's disease and halt these patients' decline.
"Some of these compounds had a level of selectivity that ranged as high as 20,000-fold against competing targets and were extremely effective against oxidative stress and mitochondrial dysfunction—both potent cell killers," added HaJeung Park, director of Scripps Florida's X-ray Crystallography Core Facility and the first author of the Scientific Reports study.
The scientists found that within JNK3, a single amino acid—L144—was primarily responsible for the high level of JNK3 selectivity. Isoform selectivity can help to limit potential side effects of a drug.
Intriguingly, some recent studies have shown that JNK3 not only plays a central role in brain cell death in Parkinson's disease, but also in Alzheimer's disease. LoGrasso and his colleagues also believe their JNK3 drug candidates have potential for treating ALS (Lou Gehrig's disease).
More information: Scientific Reports, "Structural Basis and Biological Consequences for JNK2/3 Isoform Selective Aminopyrazoles," http://ift.tt/PUevwq
Journal of Medicinal Chemistry, "Design and Synthesis of Highly Potent and Isoform Selective JNK32 Inhibitors: SAR Studies on Aminopyrazole Derivatives," http://ift.tt/1Bu129A
Medical Xpress on facebook
Related Stories
Scientists uncover potential drug target to block cell death in Parkinson's disease
Jan 10, 2013
Oxidative stress is a primary villain in a host of diseases that range from cancer and heart failure to Alzheimer's disease, Amyotrophic Lateral Sclerosis and Parkinson's disease. Now, scientists from the Florida campus of ...
Scientists design a potential drug compound that attacks Parkinson's disease on two fronts
Jun 20, 2013
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have found a compound that could counter Parkinson's disease in two ways at once.
Key protein interactions involved in neurodegenerative disease revealed
Nov 08, 2012
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have defined the molecular structure of an enzyme as it interacts with several proteins involved in outcomes that can influence neurodegenerative ...
Scientists find way to block stress-related cell death
Jun 02, 2011
Scientists from the Florida campus of The Scripps Research Institute have uncovered a potentially important new therapeutic target that could prevent stress-related cell death, a characteristic of neurodegenerative diseases ...
Compound developed by scientists protects heart cells during and after attack
Feb 07, 2013
Using two different compounds they developed, scientists from the Florida campus of The Scripps Research Institute (TSRI) have been able to show in animal models that inhibiting a specific enzyme protects heart cells and ...
Recommended for you
Antiangiogenesis drugs could make major improvement in tuberculosis treatment
14 hours ago
Use of the same antiangiogenesis drugs that have improved treatment of some cancers could also help surmount persistent difficulties in treating tuberculosis (TB). In their PNAS Early Edition report, invest ...
Collagen fibres not only passively support bone, tendons and ligaments, but also actively contract
16 hours ago
The bodies of humans and animals owe their strength especially to a fibrous structural protein called collagen. Collagen is abundant in bones, tendons, ligaments and skin. Water, a substance that is not often ...
Possible therapeutic target for common, but mysterious brain blood vessel disorder
17 hours ago
Tens of millions of people around the world have abnormal, leak-prone sproutings of blood vessels in the brain called cerebral cavernous malformations (CCMs). These abnormal growths can lead to seizures, ...
Scientists discover a new blood platelet formation mechanism
17 hours ago
Thrombocytopenia is a disease characterised by a lower platelet level than normal. Platelets are tiny cells that participate in the coagulation of blood. Patients usually suffer uncontrolled bleeding that ...
Cochlear implant users can hear, feel the beat in music
18 hours ago
People who use cochlear implants for profound hearing loss do respond to certain aspects of music, contrary to common beliefs and limited scientific research, says a research team headed by an investigator at Georgetown University ...
Hemin improves adipocyte morphology and function by enhancing proteins of regeneration
19 hours ago
Scientists at the University of Saskatchewan College of Medicine, Department of Physiology, Saskatoon, Canada, led by Dr. Joseph Fomusi Ndisang have determined that upregulating heme-oxygenase with hemin improves pericardial ...
User comments
Please sign in to add a comment. Registration is free, and takes less than a minute. Read more
Click here
to reset your password.
Sign in to get notified via email when new comments are made.
© Medical Xpress 2011-2014, Science X network
0 comments:
Post a Comment