October 2002 Meeting Announcement, Delaware Valley Mass Spectrometry Discussion Group
- Topic: "High Throughput Affinity Screening Based on High Performance Mass Spectrometry: Rapid and Automated Characterization of Non-covalent Complexes Comprised of Small Molecules Bound to RNA or Protein Drug Targets"
- Speaker:Steven A. Hofstadler, Ibis Therapeutics, A Division of Isis Pharmaceuticals, Inc., Carlsbad, CA 92008
- Date: Monday, October 7, 2002. 6:30 PM
- Time: Social Hour: 6:30 PM. (Pizza and Beer)
Talk: 7:30 PM.
- Place: Widener University, Webb Room.
- Abstract: Small molecules that bind to structured regions of RNA can exhibit a significant therapeutic effect. For example, aminoglycoside antibiotics inhibit bacterial growth by disrupting essential RNA-protein and RNA-RNA interactions. Paromomycin, one of the most widely studied aminoglycosides, binds to the decoding region of the prokaryotic 16S rRNA (the A-site) and induces misreading of the genetic code during translation. Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS) is increasingly being used in the drug discovery arena as a tool to characterize macromolecules. In this presentation we describe the development of a parallel high-throughput screening (HTS) strategy to identify small molecules that bind RNA targets using FTICR as an alternative to classical high-throughput screening of compound libraries. The MASS (Multitarget Affinity/Specificity Screening) assay takes advantage of the "intrinsic mass" label of each compound and target RNA by employing high resolution, high precision mass measurements. The ability to analyze complex mixtures allows large mixtures to be screened in the presence of multiple RNA targets simultaneously. The identity of the small molecule(s) which bind, the RNA target to which it binds, the compound-specific binding affinity, and the location of the binding site on the RNA can be determined in one set of rapid experiments. The MASS assay detects noncovalent complexes with dissociation constants of < ~5 mM, with high sensitivity and is presently being employed to screen large compound collections and natural products against multiple RNA targets.
Steven A. Hofstadler received a B.S. in Chemistry from the University of New Mexico in 1988 and a Ph.D. in Analytical Chemistry from The University of Texas at Austin in 1992. Upon completing his graduate studies, he worked as a Post-Doctoral Research Fellow at Pacific Northwest National Laboratory in the laboratory of Richard Smith where he developed high performance instrumentation and methodologies based on Fourier transform ion cyclotron resonance (FTICR) mass spectrometry. Upon completion of his post-doctoral studies he remained at Pacific Northwest National Laboratory as a Senior Research Scientist for nearly 5 years during which time he continued to develop FTICR instrumentation in combination with numerous microcolumn separations. In 1997 Dr. Hofstadler relocated to Isis Pharmaceuticals, Inc. where he is presently an Executive Director in the Ibis drug discovery division. His most current research interests are centered around applications of FTICR MS for the characterization of noncovalent complexes between RNA and small drug-like molecules. He is the author/co-author over 75 peer reviewed publications and has given numerous invited talks at national and international scientific meetings.
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