Dr. Avraham Samson

Research Highlights  

In the past years, our team identified and tested several new drug candidates for treating Alzheimer’s disease, hypertension, and cancer. A number of exciting outcomes were achieved which will be translated into medical applications.  Some of research projects are highlighted in the following paragraphs.   

Arginase as aNew Target in the Treatment of Alzheimer’s Disease 

The precise cause of Alzheimer`s disease remains a mystery despite decades of intensive investigation, and one reason that no long-term effective drug has been developed is the shortage of pharmaceutical targets in the brain. In this study, we proposes a new pharmaceutical target, namely arginase which is the central enzyme of the urea cycle. Arginase is associated with the development of neurodegenerative diseases, and too much of it has been shown to contribute to Alzheimer's disease. Remarkably, targeting arginase and blocking its action reverses the development of Alzheimer`s disease in rodent models. Consequently, the new target represents a promising direction for clinical development. To read more, please click here http://odem.md.biu.ac.il/nrr.pdf 

Norvaline: A novel Alzheimer's Disease-modifying agent. 

Alzheimer’s disease is a slowly progressive, neurodegenerative disorder that is characterized by severe decline in memory, thinking and reasoning skills. Recently, we developed a new drug that targets arginase, namely norvaline, and showed it reverses memory decline and brain tissue loss in a mouse model of Alzheimer’s disease. Furthermore, norvaline restores the blood brain barrier integrity in a mouse model of Alzheimer’s Disease. As such, norvaline is a new therapeutic agent against Alzheimer's disease, and clinical trials have begun to test the efficacy in human patients. To read more, click here: http://odem.md.biu.ac.il/ijms.pdf 

Reduction of High Blood Pressure with Norvaline.  

Growing evidence suggests that increased arginase activity affects vital processes in various systems such as blood pressure and diabetes. Remarkably, we showed that norvaline also reduces blood pressure and promotes urine formation in rats with high blood pressure.  The same drug did not affect the blood pressure of mice with normal blood pressure. As such, norvaline is a potential new therapeutic agent against high blood pressure. To read more, click here: http://odem.md.biu.ac.il/bmri.pdf 

 Invasion and Metastasis: The Elusive Hallmark of Cancer. 

Hallmarks of cancer are essential abilities that are acquired by human cancer.  The hallmarks include survival, resistance, evasion, immortality, and invasion and metastasis. In this study, we showed that invasion and metastasis is the most important hallmark, as it alone is the leading cause of mortality even following surgical removal of the main tumor, if possible. Interestingly, most scientific effort is funneled towards the development of drugs that target other hallmarks.  Little and not enough effort is invested towards finding drugs against invasion and metastasis. Consequently, we recommends focusing more research around invasion and metastasis, and develop new drugs that target this important hallmark. To read more, click here: http://odem.md.biu.ac.il/onogene.pdf 

A new protein motif: κ-helix. 

Proteins are essential building blocks of cells, and consist of well-defined 3D folds.  Protein folds, in turn, are responsible for their function and interaction.   Recently, we uncovered a new protein motif, and named it κ-helix.  The κ -helix, adopts a 3-fold rotational symmetry, and is responsible for the lock-and-key interaction of proteins involved in cellular communication, such as SH3, WW, profilin, MHC-II, EVH1 and GYF domains.  Based on a geometric analysis of 255 proteins, we found that κ-helices are characterized by a distinctive rotations and vary between different orientations, expand the current molecular understanding of the cellular communication in disease and health. To read more, click here: http://odem.md.biu.ac.il/bioinformatics3.pdf 

 Understanding the onset of Alzheimer’s disease. 

Over the past decade, several studies showed that toxic amyloid-peptides produced in Alzheimer`s disease bind to brain receptors and block signal transmission. To better understand the onset of Alzheimer's diseases, we deciphered the 3D structure of solubilized amyloid-peptides before they form β-structures, and aggregate in the brain of Alzheimer's patients. We found that water soluble amyloid-peptides adopt a helical structure which is very different from the β-sheet like structure  found in the brain of affected subjects affected.  The conversion from α to β structure is driven by a kink at position K28. The structure sheds light on the structural changes of proteins that characterize Alzheimer’s disease. To read more, click here: http://odem.md.biu.ac.il/fonar.pdf 

 Molecular motion of nerve channel is blocked by scorpion and spider toxins. 

To better understand the function of nerve channels receptors, we calculated their molecular motion using powerful computers equipped with hundreds of processors. The calculations revealed a paddle motion responsible for channel function.  Strikingly, the paddle motion was not observed for the channels upon binding of scorpion and spider toxins.  These toxins prevent the molecular motion and block channel activation.  These results shed light on the activation mechanism of nerve channels, and their blocking by scorpion and spider venom. To read more, click here: http://odem.md.biu.ac.il/greenberger.pdf 

 Molecular motion is essential for drug action.  

About 70% of drugs used in medicine bind to a family of receptors named the G-protein-coupled receptors (GPCR).  To better understand drug binding and receptor activation, we calculated the motion of several receptors of this family involved in blood pressure regulation, inflammation, etc. The calculation revealed that drug binding and contraction on one side of the receptor lead to dilation and cavity formation on the other side.  Furthermore, electric-charge calculations revealed that the binding site acts like a magnet to attract specific drugs. Altogether, these results illustrate how drug binding induces motion which in turn initiates action. To read more, click here: http://odem.md.biu.ac.il/kolan.pdf 

What is a protein fold? 

Together with Prof. Michael Levitt, the 2013 Nobel Laureate of Chemistry, we wrote a review in the prestigious journal "Annual Review of Biophysics" in collaboration with Prof. Rachel Kolodny of Haifa University, and Dr. Leonid Pereyeslavets a postdoc in the Levitt lab.  The review is titled:  "On the universe of protein folds", and discusses the physical rules governing protein structure and defines the term protein fold as a the structure adopted by a family of proteins. Notably, the definition of a fold is subjective to classification, and a fold lies in the eye of the beholder. To read more, click here: http://odem.md.biu.ac.il/kolodny.pdf