University of California
675 Nelson Rising Lane, 3rd Floor
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University of California
The DeGrado Research Group focuses on small molecule and protein design as an approach to understanding macromolecule structure and function. The DeGrado group's primary research interest is in the de novo design, in which one designs proteins beginning from first principles. This approach critically tests our understanding of protein folding and function, while also laying the groundwork for the design of proteins and biomimetic polymers with properties unprecedented in nature. The de novo design of proteins has proven to be a useful approach for understanding the features in a protein sequence that cause them to fold into their unique three-dimensional structures. In addition, it has been possible to design functionally interesting proteins, which bind redox-active cofactors, DNA, and transition metals. Finally, this approach has been extended to the design of membrane-active proteins, including ion channels, antibiotics and fusogenic agents.
The DeGrado Research Group also studies the structure and function of a number of pharmacologically interesting systems. The DeGrado group is determining the structure of the M2 proton channel from influenza A virus, and its mode of inhibition by various channel-blocking drugs. In collaboration with Joel Bennett (Department of Medicine), we study the mechanism of signal transduction of integrins such as ?II?b3, with a particular focus on the role played by the membrane-spanning regions of this protein. We have developed small molecule mimics of integrins and the platelet collagen receptor, gpVI. Finally, the DeGrado group developed a number of small molecule mimics of antimicrobial host defense proteins, which show considerable promise for treating antibiotic-resistant infections.
Dr. Benet, Professor and former Chairman (1978-1998) of Bioengineering and Therapeutic Sciences, UCSF, received his AB, BS and MS from the University of Michigan, and PhD from UCSF. He has received 7 honorary doctorates including Uppsala University (1987), Leiden University (1995), University of Athens (2005) and Catholic University of Leuven (2010).
His recent studies have led to the development of the Biopharmaceutics Drug Disposition Classification System, which allows prediction of the relevance of enzymes and transporters (including their genetic variants) for new molecular entities and drug-drug interactions for drugs on the market.
Dr. Benet served as President of the Academy of Pharmaceutical Sciences (1985) and in 1986 was a founder and first President of the American Association of Pharmaceutical Scientists (AAPS). In 1987 he was elected to membership in the Institute of Medicine of the US National Academy of Sciences. In 1993-4 he served as President of the American Association of Colleges of Pharmacy (AACP) and from 1996-2000 as Chair of the International Pharmaceutical Federation (FIP) Board of Pharmaceutical Sciences.
In 1989 he received the AAPS Distinguished Pharmaceutical Scientist Award; in 1991, the AACP Volwiler Research Achievement Award; in 1995, the American Society for Clinical Pharmacology and Therapeutics (ASCPT) Rawls-Palmer Progress in Medicine Award; in 2000, the American Pharmacists Association Higuchi Research Prize and the AAPS Wurster Award in Pharmaceutics; in 2001 the FIP Høst-Madsen Medal; and in 2004 the FIP Pharmaceutical Sciences World Congress Research Achievement Award and the Controlled Release Society’s Career Achievement in Oral Drug Delivery Award. In 2007, he was the Distinguished Clinical Research Lecturer at UCSF. In 2010, he received the ASCPT Hunter Award in Therapeutics.
Dr. Benet has published over 500 scientific articles and book chapters, holds 11 patents and served as editor of seven books. He is listed among the most highly cited pharmacologists worldwide.
Professor, Department of Pharmaceutical Chemistry
Dr. Wells received a BA degree in biochemistry from the University of California, Berkeley, and a PhD degree in biochemistry from Washington State University. His postdoctoral studies were done at Stanford University Medical School, Department of Biochemistry. Dr. Wells was the founding member of the Protein Engineering Department at Genentech, Inc where he worked for 16 years. His research focused on designing new functional properties into enzymes and hormones and developing new technologies for engineering proteins. In 1998, Dr. Wells founded Sunesis Pharmaceuticals where he served as President and Chief Scientific Officer and developed a novel fragment discovery technology known as disulfide trapping or Tethering. In 2005, Dr. Wells joined UCSF as the Harry W. and Diana Hind Distinguished Professor in Pharmaceutical Sciences. He is a joint Professor in the Departments of Cellular & Molecular Pharmacology, and Pharmaceutical Chemistry.
We are interested in the discovery and design of small molecules that trigger or modulate cellular processes in inflammation and cancer. Our research spans the multiple disciplines of biophysics, cell biology, molecular biology, biochemistry and chemistry. We are interested in the allosteric “circuitry” in proteins, i.e., how two distant functional sites communicate through a protein. In particular, we are focused on the signaling circuitry in pathways involved in cell death and cellular inflammation. We are developing specific cell active enzyme inhibitors or activators by using a novel disulfide trapping technology which allows us to target specific sites on proteins and determine their role in driving cellular signaling processes. This technology allows us to trap allosteric states so that they may be studied by biophysical and mutational means. We are using this approach to determine the role of specific inflammatory caspases via selective inhibitors and study activation of proteins in proliferation and apoptotic pathways via allosteric activators. This approach will identify “orphan allosteric sites’ which may have natural binding partners and pose new targets for drug discovery. In addition, we are developing methods for tagging N-termini of proteins using engineered enzymes so we can follow proteolytic cascades especially those in apoptosis and cellular inflammation.
Howard Hughes Investigator, Department of Cellular & Molecular Pharmacology
To ensure proper folding, cells have evolved a sophisticated and essential machinery of proteins called molecular chaperones that assists the folding of newly made polypeptides and disposes of misfolded proteins. The importance of proper protein folding is underscored by the fact that a number of diseases, including Alzheimer's and those involving infectious proteins (prions), result from protein-misfolding events. My research focuses on identifying and understanding the machinery necessary for efficient folding, as well as studying the mechanism and consequences of protein misfolding especially as it relates to prion-based inheritance. We are also developing experimental and analytical approaches for exploring the organizational principles of complex biological systems as well as tools for globally monitoring protein translation with sub-codon resolution.
Dr. Laurence Tecott's laboratory uses molecular genetic approaches to examine the contributions of serotonin (5-HT) receptors to the actions of neuropsychiatric drugs and to the genetic determination of complex behavioral traits. For example, the serotonergic control of feeding is being examined in studies of 5-HT receptor mutant mice. Animals lacking the 5-HT2C receptor subtype display chronically elevated food intake, leading to "middle-age" obesity and type 2 diabetes mellitus.
These mice display reduced sensitivity to the appetite suppressant fenfluramine, further implicating this receptor as a target for antiobesity drug development. The genetic control of neural systems underlying anxiety and depression is another focus of investigation. Animals devoid of 5-HT1A receptors exhibit enhanced anxiety-like responses in a variety of behavioral assays and robust antidepressant-like responses in an animal model of depression. These animals exhibit markedly enhanced sensitivity to the effects of antidepressants such as fluoxetine (Prozac).
Recent advances in gene targeting and gene expression technologies will facilitate studies of the mechanisms through which serotonin receptors modulate behavior and the actions of neuropsychiatric drugs.
Brian Shoichet received a BSc in Chemistry and a BSc in History in 1985 from MIT. He received his PhD for work with Tack Kuntz on molecular docking in 1991, from UCSF. Shoichet's postdoctoral research was largely experimental, focusing on protein structure and stability with Brian Matthews at the Institute of Molecular Biology in Eugene, Oregon, as a Damon Runyon Fellow. Shoichet joined the faculty at Northwestern University in the Dept. of Molecular Pharmacology & Biological Chemistry as an Assistant Professor in 1996. He was promoted to a tenured Associate Professor in 2002. Around that time he was recruited back to UCSF, where he is now a Professor in the Department of Pharmaceutical Chemistry. Research in the Shoichet Lab uses computational and experimental techniques to investigate enzyme structure, function, stability and inhibition, and the links among them. It is supported by the NIH.
Dr. Seeley received his MD from the UCSF School of Medicine. He then completed an internship in Internal Medicine at UCSF and a residency in Neurology at the Massachusetts General and Brigham and Women's Hospitals in Boston. He is currently an Assistant Professor of Neurology at the UCSF Memory and Aging Center, where he participates in patient evaluation and management. He also directs the MAC Autopsy Program and the Neuropathology Core.
Dr. Seeley's research concerns regional vulnerability in dementia, that is, why particular dementias target specific neuronal populations. Dr. Seeley addresses this question through behavioral, functional imaging and neuropathology studies. The goal of his research is to determine what makes brain tissues susceptible or resistant to degeneration, with an eye toward ultimately translating these findings into novel treatment approaches.
My research projects involve studying the therapeutic effects of quinacrine and new therapeutic agents in patients afflicted with Creutzfeldt-Jakob disease, and another project is developing diagnostic tests on extra CNS tissues for prion diseases. I instruct residents, post-sophomore fellows, and rotating medical students in the field of autopsy pathology.
I am actively involved in teaching and curriculum design in the schools of dentistry, medicine and pharmacy.
Andrej Sali received his BSc degree in chemistry from the University of Ljubljana, Slovenia, in 1987. He was awarded the Research Council of Slovenia Scholarship, the Overseas Research Students Award, and the Merck Sharpe and Dohm Academic Scholarship at Birkbeck College, University of London, where he received his PhD in biophysics in 1991, under the supervision of Prof. Tom L. Blundell. He focused on development of methods for comparative modeling of protein three-dimensional structure and their implementation in the program MODELLER. He then went to the Department of Chemistry at Harvard University as a Jane Coffin Childs Memorial Fund post-doctoral fellow with Prof. Martin Karplus, where he continued to develop comparative modeling methods and also studied simple lattice Monte Carlo models of protein folding. From 1995 to 2002, Dr. Sali was first an Assistant Professor and then an Associate Professor at The Rockefeller University.
In 2003, he moved to University of California at San Francisco as a Professor of Computational Biology in the Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, and California Institute for Quantitative Biosciences (QB3). He was a Sinsheimer Scholar (1996), an Alfred P. Sloan Research Fellow (1998), and an Irma T. Hirschl Trust Career Scientist (2000), and the recipient of the Zois Award of Science Ambassador of Republic of Slovenia (2007). Dr. Sali is an Editor of Structure and a Founder of Prospect Genomix that merged with Structural Genomix, finally acquired by E. Lilly & Co. He is currently the Director of QB3 at UCSF.
Dr. Sali is interested in using computation grounded in the laws of physics and the theory of evolution to study the structure and function of proteins. He is aiming to improve and apply methods for (i) predicting the structures of proteins; (ii) determining the structures of macromolecular assemblies; and (iii) annotating the functions of proteins using their structures.