Moleküler Biyoloji ve Genetik Seminerleri: Prof. Richard B. Silverman
Moleküler Biyoloji ve Genetik Bölümümüzün organize ettiği seminer serisinin yeni konuğu, Northwestern University’den Prof. Richard B. Silverman olacak.
Dr. Silverman’ın “Inhibition of Protein Aggregation and the Development of NU-9 for Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases” başlıklı konuşmasını 13 Nisan Perşembe saat 16:00’dan itibaren Zoom üzerinden takip edebilirsiniz.
Etkinlik İngilizcedir.
Zoom ID: 885 1468 3830
Özet: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which the motor neuron circuitry progressively degenerates, affecting mostly motor neurons in the brain (upper motor neurons) and spinal cord (lower motor neurons). There are no effective cures, although three drugs, riluzole, edaravone, and AMX0035, have been FDA approved, but with limited improvement in patients. Death generally occurs within 2-5 years from disease diagnosis. About 10% of patients have familial ALS (hereditary; fALS) and the remainder have sporadic ALS (sALS) with no known genetic cause. Greater than 150 gene mutations have been identified in fALS.
Protein aggregation is a hallmark of all neurodegenerative diseases. We carried out a phenotypic high-throughput screen to identify compounds that inhibited protein aggregation caused by mutation of the sod1 gene, which leads to ALS in about 2% of ALS patients. Screen hits were filtered computationally, and three hit series were optimized.
In this lecture, I will discuss the development of two of these lead series, leading to two advanced compounds, for which one we have identified its target and the other, called NU-9, has been subjected to numerous preclinical studies related to efficacy, pharmacokinetics, and toxicology. The standard mouse model is used to show life extension by compound treatment; however, there is no translation from success in this mouse model and in patients. Therefore, we have taken a different approach, one that interogates the effectiveness of compounds to improve the health of the upper motor neurons in mouse models, which we anticipate should translate to patient efficacy. Preclinical results with NU-9 toward the treatment of ALS and Alzheimer’s disease will be presented.
Konuşmacı Hakkında: Prof Richard B. Silverman, known for the discovery of pregabalin, which is marketed by Pfizer under the brand name Lyrica, is the Patrick G. Ryan/Aon Professor in the Department of Chemistry with courtesy appointments in the Department of Molecular Biosciences (Weinberg College of Arts and Sciences) and Department of Pharmacology (Feinberg School of Medicine). Prof Silverman received his B.S. in chemistry from Pennsylvania State University in 1968. He spent one semester at Harvard University before being drafted and serving as a United States Army Physical Sciences Assistant at the Walter Reed Army Institute of Research from January 1969 until his honorable discharge in January 1971. In June 1974, he received his Ph.D. from Harvard University in organic chemistry with advisor David Dolphin. He then spent two years as a postdoctoral fellow with Robert Abeles in biochemistry at Brandeis University. His research is focused on the design, synthesis, and evaluation of small molecules that inhibit enzymes, cancer, and protein aggregation. Target enzymes include GABA aminotransferase for the treatment of epilepsy and addiction, ornithine aminotransferase for the treatment of hepatocellular carcinoma, and neuronal nitric oxide synthase for the treatment of neurodegenerative diseases and melanoma. Protein aggregation inhibitors are targeted for the treatment of neurodegenerative diseases, including ALS. Inactivation mechanisms for molecules designed as irreversible inhibitors are investigated with the use of several mass spectral techniques, X-ray crystallography, and computer modeling. The ultimate goal is to bring small molecules into clinical trials. His research is supported primarily by NIH.