ORGN 455 |
| This talk will provide an overview of our group's work on the design of molecules that interact with membranes and membrane proteins. Topics will include: 1) Design and characterization of foldamers and small molecule mimics of antimicrobial peptides. We have designed a number of small molecules that mimic the activities of antimicrobial peptides. These molecules show good activity in vivo, as assessed from models for MRSA and other bacterial infections. Their biophysical characterization will be discussed, as will their impact on bacterial signaling pathways. 2) The role of transmembrane helix-helix interactions in mediating protein-protein interactions in membranes. We have developed computational methods to predict helix-helix interactions in membranes. These programs have now been extended to allow design of peptides that target TM domains of complex membrane proteins in much the same way that antibodies target water-soluble regions of proteins. This approach has been used to probe the mechanisms by which integrins are activated to adhere to extracellular ligands. 3) Structural basis for the function and pharmaceutical inhibition of influenza virus proton channels. The M2 proton channel mediates acidification of the interior of endosomally entrapped virus in a step that is required for replication of the virus. M2 is the target of the anti-influenza drug amantadine, which was used for three decades until recent years when resistance to this and related drugs reached over 90%. We have determined the crystal structure of the channel-forming region of the protein in the presence and absence of the channel-blocking drug amantadine. The structure provides insight into the function of the channel, and it is proving to be a useful starting point for the design of small molecules that address the problem of resistance to M2 channel blockers. |
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Ralph F. Hirschmann Award in Peptide Chemistry: Symposium in Honor of William F. DeGrado
9:00 AM-12:00 PM, Wednesday, April 9, 2008 Morial Convention Center -- La Nouvelle, Blrm. C, Oral
Division of Organic Chemistry |