Ronald F. Borne Lecture
An annual event honoring Emeritus Professor Ron Borne
|Dr. Ronald F. Borne||Dr. Kenneth A. Jacobson|
2012-2013 Ronald F. Borne Lecture
Tuesday, April 30, 2013, 11 am: TCRC 2066
Dr. Kenneth A. Jacobson, Ph.D., Chief, Laboratory of Bioorganic Chemistry & Molecular Recognition Section, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health
"Topic: Structure-Based Discovery of Novel Ligands of GPCRs: Focus on Adenosine and P2Y Receptors"
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Borne Lecturer Info:
Dr. Jacobson got his Ph.D. at the University of California, San Diego, in 1981, after getting his B.A. at Reed College. Here is a summary of his research interests:
Dr. Jacobson is a medicinal chemist with interests in the structure and pharmacology of receptors and in developing drugs that act as agonists or antagonists of G protein-coupled receptors (GPCRs). The current focus is on receptors for purines, encompassing both adenosine receptors and P2 receptors, which are activated by ATP and UTP. Dr. Jacobson has taken an interdisciplinary approach to studying the chemical and biological aspects of these receptors. He has developed a "functionalized congener approach" to drug design. Novel ligands (small molecules) for these receptors are developed using classical synthetic approaches and also by semi-rational methods based on molecular modeling and template design. Receptors are computer-modeled by homology to rhodopsin, and the models for ligand recognition are tested and refined using site-directed mutagenesis of the receptor proteins. Recently, the involvement of extracellular loops of GPCRs have been implicated in the receptor binding of small molecules, as demonstrated through the mutagenesis and modeling of P2Y1 receptors.
Substances developed as potent and selective agents acting through adenosine and P2 receptors have proven useful as pharmacological probes and have potential for treating diseases of the central nervous system, immune system, and cardiovascular system. Recent accomplishments include the design and synthesis of the first A3 adenosine receptor agonists and antagonists, using a combination of library screening and optimization of known adenosine receptor ligands. These substances have been shown to be effective in models of treatment of glaucoma, cancer, stroke, and cardiac ischemia. A selective A3 adenosine receptor agonist developed in our laboratory is currently in clinical trials for colon carcinoma and rheumatoid arthritis. We have synthesized the first P2Y1 receptor-selective antagonists, through functionalization of adenine nucleotides. The antagonists were optimized with the aid of receptor homology modeling. These substances have been shown to be effective in models of antithrombotic treatment, due to blockade of the proaggregatory effects of ADP. The pharmacological probes designed in our section have been used to demonstrate the connection between purine receptors and apoptosis (programmed cell death). A3 adenosine receptor agonists at low concentrations and P2Y6 receptor agonists have antiapoptotic effects.
Another potential means of using the protective effects of AR activation was achieved through receptor engineering. Constitutively active mutant A3 adenosine receptors, in principle, could be delivered by tissue-targeted vectors for gene therapy. In addition, we have introduced the approach of “neoceptors”, also intended for eventual use in gene therapy, in which the putative agonist binding site is redesigned to accept only agonist molecules altered in a complementary fashion. Insight into the recognition of agonist by the receptors may be gained using site-directed mutagenesis and molecular modeling. We are exploring this approach conceptually with tailor-made agonist ligands (“neoligands” that are selective for the neoceptor and not the native receptor) in combination with receptor mutagenesis. The neoceptor concept has so far been applied to A2A and A3 adenosine receptors.