ד"ר Arie-Lev Gruzman
My research interests include the following topics:
1. Amyotrophic Lateral Sclerosis (ALS) it is a fatal neurodegenerative disease, characterized by progressive muscle weakness and reflective loss of upper and lower motor neurons, predominantly in the spinal cord. Our initial findings led us to working hypothesis that novel derivatives of known chemical chaperones may serve as a prototype molecule for the development of anti-ALS agents by virtue of their potential ability to increase degradation of disease related mutated proteins such as Sodium Oxide Dismutase 1 (SOD1) that prolongs cell survival.
2. Non Insulin Dependent Diabetes Mellitus (Type 2 diabetes) affects tens of millions of subjects worldwide. The search for novel antihyperglycemic compounds and drugs to treat diabetic patients is most important in diabetes research. In search for compounds that augment the rate of glucose transport in insulin-sensitive cells we have found that thiolane derivatives increase the rate of glucose transport in adipose cells and skeletal muscle cells. We, therefore, aimed at synthesized potent thiolane derivatives with favorable pharmacokinetic and pharmacodynamic parameters and testing them both, in vitro and in vivo model systems.
3. Prostate cancer.
My lab works on design and synthesis of new drugs against prostate cancer. Many aspects of prostate cancer pathogenesis remain a mystery, including the early triggers for malignant transformation and the basis for progression to androgen independence, two critical milestones in the natural history of prostate cancer.
It has been shown that prostatic acid phosphatase (PAcP) has at least two functional folding forms. First, extracellular, secreted form causes unregulated cancer growth of prostate epithelial cells, second intracellular form inhibits it. Our working hypothesis is that PAcP is the key protein which converts the differential androgen sensitive cancer cells to non differential non androgen sensitive cancer cells. We design and synthesize different compounds that prevent generation of procancer PAcP secreted isoform. These new synthetic classes of PAcP release inhibitors should bring new therapy approach against prostate cancer.
4. Catecholamine induced ventricular tachycardia is the most deadly type of
arrhythmia that leads to sudden cardiac death. A growing amount of evidence indicates the critical role of intracellular calcium in the pathogenesis of this disorder. Calcium is released from sarcoplasmic reticulum via a calcium release channel known as the ryanodine receptor. Dysfunction of this receptor leads to calcium “leak” from the sarcoplasmic reticulum and as a result to different types of arrhythmias among these catecholamine induced ventricular tachycardia. We focused on one of regulatory proteins - sorcin, that binds to ryanodine receptor and stimulates its function as a potential target for development of a new antiarrhythmic drug. Using molecular modeling we designed a small peptidomimetics that will be able to block active phosphorylation of sorcin or/and its interaction with ryanodine receptor. These compounds should normalize rhythmus of cardiac contraction.
Particular research areas (projects):
1. Synthesis of novel intracellular targeted chemical chaperones for ALS treatment
2. Design and synthesis of novel antidiabetic drugs based on an ethoxybenzo-thiazol scaffold
3. Design and synthesis of novel antidiabetic drugs based on thiolane scaffold
4. Clustered neuroligins derivatives as a potential antidiabetic drugs
5. Inhibitors of the PAcP release-the novel therapy of prostate cancer
6. Inhibitors of the sorcin phosphorylation. Development of novel antiarrhythmic drugs
7. Development of new anti-inflammatory drugs based on inhibition of a leukocyte rolling
8. Asymmetric synthesis of 4-Hydroxy-2E,6Z dodecadienal.
9. Novel metal-organic complexes as new anticancer agents
Lingappa, V.; Liu, J.; Gruzman, A. (2006). Biomarkers for Amyotrophic Lateral Sclerosis. US patent application 60/061,632.
Sasson, S.; Cerasi, E.; Gruzman, A.; Katzhendler, (2010). Development of novel anti-hyperglycemic drugs. US granted patent 7,812,142
Sasson, S.; Cerasi, E.; Gruzman, A,; Meltzer-Matz, E. (2011). Unated States patent regestration PCT61/513,802. Ethoxybenzo-thiazol derivatives as a basis for developmnet of novel oral antidiabetic drugs.