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Prof. Adegboyega Oyelere, Georgia Tech
Histone Deacetylase, Ribosome and Macrolides â" A Story of Two Tunnels and One Tunnel Blocker
School Colloquium
Proteins and RNAs adopt compact structural folds and interact with a variety of ligands including small molecules, lipid bilayers, other proteins and nucleic acids. Crucial to the structure and function of proteins and RNAs are driving forces which should operate obeying similar physical principles in either molecule. In this presentation, I will present evidence that histone deacetylases (HDACs) and ribosome, two biomacromolecules with hydrophobic tunnels designed to interact with a wide array of peptide sequence, have a common ligand in a class of glycosylated polyketide antibiotics called macrolides. In the first half of the presentation, I will discuss the discovery of new ribosome binding peptide-ketolide compounds (peptolides). I will present evidence on the application of peptolides in deciphering molecular âgymnasticsâ crucial to the proper functioning of the ribosome and in the design of new generation of ribosome inhibitors. In the second half, I will discuss the discovery and SAR studies of a new class of macrocyclic HDAC inhibitors based on the macrolide antibiotics skeletons. HDAC inhibitors hold great promise in cancer therapy due to their demonstrated ability to arrest proliferation of nearly all transformed cell types. However, most of these agents are non-selective inhibitors of many HDAC isoforms; and a large number of the identified HDAC inhibitors have not progressed beyond preclinical characterizations. I will also present preliminary evidence for lung selective accumulation of selected examples of this new class of macrocyclic HDAC inhibitors. This aspect of our research raises the prospect of tissue-selective HDAC inhibition as a particularly enticing alternative to isoform selective HDAC inhibition which as been so far elusive and could lead to the identification of new chemotherapeutic agents with broad application in targeted cancer therapy. Toward the end of my talk, I will discuss the prospect of macrolides and other small molecules in targeted delivery of nanoparticles.
Acknowledgement: This work is financially supported by Georgia Institute of Technology, by the Blanchard fellowship, by NASA Grant R9867 and by NIH Grant R01CA131217.
For more information contact Prof. Charles Liotta (404-894-8222).
