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Chemogenetics

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Chemogenetics

The term chemogenetics has been used to describe the processes by which macromolecules can be engineered to interact with previously unrecognized small molecules. Chemogenetics as a term was originally coined to describe the observed effects of mutations on chalcone isomerase activity on substrate specificities in the flowers of Dianthus caryophyllus.[1] Such engineered macromolecules include nucleic acid hybrids,[2] kinases [3] a variety of metabolic enzymes,[4][5] and G-protein coupled receptors (GPCRs) such as DREADDs.[6][7][8][9][10][11]

Uses

GPCRs are the target for some of the most widely used pharmaceuticals to treat diseases that involve virtually all tissues of the body. Viral expression of DREADD proteins, both in-vivo enhancers and inhibitors of neuronal function, have been used to bidirectionally control behaviors in mice (e.g odor discimination).[12]

References

  1. ^ Forkmann G, Dangelmayr B. 1980. Genetic control of chalcone isomerase activity in flowers of Dianthus caryophyllus. Biochem Genet 18: 519-27
  2. ^ Strobel SA, Ortoleva-Donnelly L, Ryder SP, Cate JH, Moncoeur E. 1998. Complementary sets of noncanonical base pairs mediate RNA helix packing in the group I intron active site. Nat Struct Biol 5: 60-
  3. ^ Bishop AC, Shah K, Liu Y, Witucki L, Kung C, Shokat KM. 1998. Design of allele-specific inhibitors to probe protein kinase signaling. Curr Biol 8: 257-66
  4. ^ Collot J, Gradinaru J, Humbert N, Skander M, Zocchi A, Ward TR. 2003. Artificial metalloenzymes for enantioselective catalysis based on biotin-avidin. J Am Chem Soc 125: 9030-1
  5. ^ Haring D, Distefano MD. 2001. Enzymes by design: chemogenetic assembly of transamination active sites containing lysine residues for covalent catalysis. Bioconjug Chem 12: 385-90
  6. ^ Strader CD, Gaffney T, Sugg EE, Candelore MR, Keys R, et al. 1991. Allele-specific activation of genetically engineered receptors. J Biol Chem 266: 5-8
  7. ^ Coward P, Wada HG, Falk MS, Chan SD, Meng F, et al. 1998. Controlling signaling with a specifically designed Gi-coupled receptor. Proc Natl Acad Sci U S A 95: 352-7
  8. ^ Westkaemper R, Glennon R, Hyde E, Choudhary M, Khan N, Roth B. 1999. Engineering in a region of bulk tolerance into the 5-HT2A receptor. Eur J Med Chem 34: 441-47
  9. ^ Jacobson KA, Gao ZG, Chen A, Barak D, Kim SA, et al. 2001. Neoceptor concept based on molecular complementarity in GPCRs: a mutant adenosine A(3) receptor with selectively enhanced affinity for amine-modified nucleosides. J Med Chem 44: 4125-36
  10. ^ Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL. 2007. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci U S A 104: 5163-8
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