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Science 21 April 2006:
Vol. 312. no. 5772, pp. 443 - 446
DOI: 10.1126/science.1120378
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Reports

Differential Targeting of Gß{gamma}-Subunit Signaling with Small Molecules

Tabetha M. Bonacci,1 Jennifer L. Mathews,1 Chujun Yuan,2 David M. Lehmann,1 Sundeep Malik,1 Dianqing Wu,3 Jose L. Font,1 Jean M. Bidlack,1 Alan V. Smrcka1,2*

G protein ß{gamma} subunits have potential as a target for therapeutic treatment of a number of diseases. We performed virtual docking of a small-molecule library to a site on Gß{gamma} subunits that mediates protein interactions. We hypothesized that differential targeting of this surface could allow for selective modulation of Gß{gamma} subunit functions. Several compounds bound to Gß{gamma} subunits with affinities from 0.1 to 60 µM and selectively modulated functional Gß{gamma}-protein-protein interactions in vitro, chemotactic peptide signaling pathways in HL-60 leukocytes, and opioid receptor–dependent analgesia in vivo. These data demonstrate an approach for modulation of G protein–coupled receptor signaling that may represent an important therapeutic strategy.

1 Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
2 Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
3 Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.

* To whom correspondence should be addressed. E-mail: Alan_Smrcka{at}URMC.rochester.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)