Navigation Links
New class of compounds discovered for potential Alzheimer's disease drug
Date:8/10/2009

PHILADELPHIA A new class of molecules capable of blocking the formation of specific protein clumps that are believed to contribute to Alzheimer's disease pathology has been discovered by researchers at the University of Pennsylvania School of Medicine. By assaying close to 300,000 compounds, they have identified drug-like inhibitors of AD tau protein clumping, as reported in the journal Biochemistry.

Co-authors Alex Crowe, Research Specialist; Kurt R. Brunden, PhD, Director of Drug Discovery at Penn's Center for Neurodegenerative Disease Research (CNDR); Virginia M.-Y. Lee, PhD, and John Q. Trojanowski, MD, PhD, CNDR Co-Directors, and colleagues conducted the screen to find small molecules that prevent the formation of the tau protein fibrils. These fibrils, a hallmark pathological feature of AD, have been a holy grail for investigators hoping to better treat AD and related neurodegenerative diseases.

Tau fibrils accumulate as insoluble deposits in brain nerve cells of patients with a host of debilitating neurodegenerative diseases, the most prevalent of which is AD. Since these tau aggregates are found in several neurodegenerative disorders and are thought to contribute to disease pathology, it is hoped that drugs that prevent these deposits might prove to be effective therapeutic agents for AD and related disorders. This is the largest drug screen completed to date using the compound repository housed at the National Institutes of Health (NIH) Chemical Genomics Center.

Small molecules that prevent or reverse tau clumping might have therapeutic value, explains Brunden. Examples of such compounds have been described previously but nearly all have properties, such as chemical reactivity, poor absorption by the gut, or poor brain penetration, that render them unsuitable as drug candidates.

The test-tube-based assay used to screen the large NIH library was designed by Dr. Lee to see if each compound could block fibril formation in a sample of purified tau protein. Fluorescent tags embedded in the tau protein signal fibril formation as well as intermediary protein structures on the way to becoming fully formed fibrils. Fibril formation was also monitored with a specific dye that can bind to tau fibrils but not normal tau.

The team found a total of 285 compounds that were of potential interest, and of these they focused on a specific chemical series called ATPZs that effectively block fibril formation. The ATPZs fit most of the criteria for potential drug candidacy such as proper size, desirable chemical properties, specificity for the tau protein, and a predicted likelihood of crossing the blood-brain barrier. "This led us to further explore this unique chemical series," says Brunden.

They and NIH colleagues made or obtained 21 ATPZ analogue compounds, each with a similar core structure but having different chemical side-chains. "Think of this as variations on a theme," says Brunden "Certain variations will lead to improved compound potency compared to others and we measured this by how well each ATPZ analogue inhibited tau fibril formation."

By comparing how various side-chain changes affect the properties of the ATPZs, knowledge is gained on how to better improve compounds. Although increasing the potency of compounds is an important part of the process of developing a drug candidate, other aspects of compounds such as residence time in the body, the ability to be absorbed after oral administration, brain penetration and overall safety must all be considered during this optimization process.

"While we are excited about the discovery of this new series of tau fibril inhibitors, we are still a long ways from turning these early lead compounds into drugs," Brunden cautions. "However, we believe that certain of our ATPZ compounds will be very useful in allowing us to gain a better understanding of the consequences of inhibiting tau fibril formation in transgenic mouse models of Alzheimer's disease."


'/>"/>

Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

Related medicine news :

1. Allscripts Notified of Purported Class Action Lawsuit
2. Chindex International, Inc. Launches World-Class Cancer Treatment Center
3. Hagens Berman Sobol Shapiro: Vytorin and Zetia Makers Settle Class-Action Suit With Proposed $41.5 Million
4. Class Action Notice for Minnesota Light Cigarette Litigation From Lommen, Abdo, Cole, King & Stageberg, P.A.
5. More Than One in Five 12 to 17-Year-Olds Have Trouble Seeing in Class
6. Gym Class Injuries Up 150 Percent
7. New national study finds increase in P.E. class-related injuries
8. Post-Recession Incomes Will Be Hit Hard by Health Care Spending for Middle Class Working Families, PENN Analysis Shows
9. American Academy of Dermatology Commends Reclassification of Tanning Beds as Carcinogenic
10. Birdies for Breast Cancer Announces Fifth Annual Charity Golf Classic Hosted by Top Womens Golfer, Cristie Kerr
11. The CLASS Act: Retirement In-Security
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
New class of compounds discovered for potential Alzheimer's disease drug
(Date:5/27/2016)... ... May 27, 2016 , ... ... is bolstered by inspiring human-interest stories, courtesy of awareness-driven celebrities and thought leaders. ... from leading advocates, associations and industry leaders such as Bioness. , As ...
(Date:5/27/2016)... ... May 27, 2016 , ... Aimed at ... inspiring human interest stories, courtesy of leaders in the nursing and health care ... industry, from leading advocates and associations—namely Jones & Bartlett Learning. , Jones & ...
(Date:5/27/2016)... ... May 27, 2016 , ... ... in the pharmaceutical, medical and food industries. Aside from its GMP accreditation, Validation ... providing proof of successfully certified products, services and staff. , Validation Center is ...
(Date:5/26/2016)... (PRWEB) , ... May 26, 2016 , ... W.S. ... products, has been honored with a 2016 When Work Works Award for its use ... part of the national When Work Works project administered by the Families and Work ...
(Date:5/26/2016)... ... 26, 2016 , ... Georgia State University College of Law ... , Answering to the increasing demand for curricular specializations, the Certificate in Intellectual ... and land use law. ,  , “The demand for lawyers with specific knowledge ...
Breaking Medicine News(10 mins):
(Date:5/25/2016)... May 25, 2016  Zymo Research Corp. announced ... new reference materials that help researchers obtain the ... to analyses. The rapid growth of the study ... to have standard methods to improve the reproducibility ... inherently exist at every step of the measurement ...
(Date:5/25/2016)... , May 25, 2016 Digital Health ... to it by the US Patent and Trademark ... technology includes proprietary processes for electronic opt-­in and ... and wellness programs, HIPAA compliance and otherwise. ... "Our technology allows for ...
(Date:5/24/2016)... , May 24, 2016 Cirujanos ... para ayudar a los médicos a compartir sus mejores ... a escala mundial. Profesionales médicos de Europa, África, ... han apuntado a la aplicación, que combina la transmisión ... entorno totalmente seguro. Educación   "Imagine ...
Breaking Medicine Technology: