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 2009 Press Release

Small Molecules Show Potential for Development of Therapeutic Drugs


MIAMI, FL (September 2009) - In another DRI first, Peter Buchwald, Ph.D., head of the drug discovery initiative at the Diabetes Research Institute, has demonstrated that small molecules can be effective inhibitors of the CD40-CD154 interaction, a pathway that has now emerged as one of the most important therapeutic targets to prevent immune attack on transplanted islet cells and allow for islet engraftment and long-term survival of transplanted cells. 

These findings were recently published online in Wiley InterScience: 2009/Journal of Molecular Recognition and in the Journal of Molecular Science.

Researchers have been investigating this particular pathway, known as the CD40-CD154 pathway, to determine if they can interfere with the cascade of events that lead to transplant rejection by the recipient's immune system. 

DRI scientists previously demonstrated that treatment of diabetic pre-clinical models with an antibody to the CD154 molecule led to long-term islet survival and function, with only one monthly injection and without side effects.  These results have not been duplicated with any other agent.  However, the unfortunate occurrence of blood clots in 10% of patients treated with this drug led to its removal from clinical development.  

Dr. Buchwald and his team have made significant progress in analyzing small molecules that might block the same CD40-CD154 pathway that the antibody targeted, but without the blood clot side effects of the large antibody protein.  This is but a first step toward the ultimate goal of the program – a clinically useful drug candidate, but it is an important one. 

It proves that it might be possible to replace biotechnology tools that have harmful side effects with traditional drug-like small molecules.  The benefits being that they could be easier to develop, more convenient to administer and might avoid the problematic side effects due to their different chemical nature (small molecule vs. large protein).   

One of the challenges that remain before a widespread cure for diabetes can be offered to all people living with the disease is the prevention of immune system attack on insulin-producing islet cells.  While new drugs have been developed and are in use, they still cause unwanted side effects and are toxic to the organs, tissues and cells.  

The DRI’s Drug Discovery initiative was launched in 2007 to address this and other issues.  Dr. Buchwald was selected to serve as director of the program and is also assistant professor in the Department of Molecular and Cellular Pharmacology at the University of Miami Miller School of Medicine.  


Financial support by the Diabetes Research Institute Foundation, Future Leadership Foundation, Inc., Rowland and Sylvia Schaefer Family Foundation and Martin Granowitz is gratefully acknowledged.  


Small-molecule costimulatory blockade: organic dye inhibitors of the CD40-CD154 interaction
>>View this paper published in the Journal of Molecular Science 




Computer models predict newly identified small molecules bind to specific regions (zones) on the surface of the CD154 molecule (blue corresponds to more positively charged- and red to more negatively charged portions) known to be critical in activating the immune response and, as a result, can block this response that would otherwise initiate a cascade of events leading to rejection.

 


Dr. Buchwald (right) in the DRI's Drug Discovery Lab

    Learn more
  • Read about the DRI's Drug Discovery Program and watch a video interview with Peter Buchwald, Ph.D.
 

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