Photopharmacology: Optical Control of Activity Andrea Palazzolo Literature Seminar 06.07.14 Antibiotic Resistance Serial Inhibition Polypharmacology 06.07.14 Drug Cocktail Fischbach , M.A.; Walsh, C.T. Science 325, 1089-93 (2009). Dar, A. C.; Das, T. K.; Shokat K. M.; Cagan, R. L. Nature 486, 80-4 (2012). National Institute of Allergy and Infectious Disease. http://www.niaid.nih.gov/. 2 Ideal Solution: Reversible Control 06.07.14 Velma, W. A.; Szymanski, W.; Feringa, B. L. JACS. 136, 2178-91, (2014). 3 Light Activation in Biological Systems Restoration of Visual Response in Blind Mice Optical Control of: Neurons Kramer, R. H. et al. Neuron. 75, 271-82, (2012). Deisseroth, K., Williams, S. C. P. Nature Methods. 8, 26-90, (2011). 06.07.14 Trauner, D.; Isacoff, E. Y. et al. Nature Neuroscience. 4, 507-16, (2013). Receptors 4 The Principle of Photopharmacology Precisely targeted biological effect Deactivation of photopharmaceutical agent Light Activation of Photopharmaceutical Agents Diarylethenes Change in: Conformational Flexibility Electronic Properties Azobenzenes Change in: Geometry Dipole Moment 5 06.07.14 Velma, W. A.; Szymanski, W.; Feringa, B. L. JACS. 136, 2178-91, (2014). Designing a Photopharmaceitical Agent A photoswitch bound to a pharmacophore Prevents A photoswitch acts as a linker. binding in one state. 06.07.14 Velma, W. A.; Szymanski, W.; Feringa, B. L. JACS. 136, 2178-91, (2014). Isomerization changes the distance between the ligands 6 Designing a Photopharmaceitical Agent Quinolone Antibiotics Photoswitchable Quinolone Antibiotics 06.07.14 Velma, W. A.; van der Berg, J. P.; Hansen, M.; Szymanski, W.; Driessen, A. J. M.; Feringa, B. L. Nat. Chem. 5, 924-928, (2013). 7 Switching Between Photoisomers Ideal Conditions: No Effect Activity Threshold Saturation Saturation Point Experimentally: Velma, W. A.; Szymanski, W.; Feringa, B. L. JACS. 136, 2178-91, (2014). 06.07.14 Velma, W. A.; van der Berg, J. P.; Hansen, M.; Szymanski, W.; Driessen, A. J. M.; Feringa, B. L. Nat. Chem. 5, 924-928, (2013). 8 Photoswitching of Most Promising Candidate O O OH N N N O Before Irradiation After Irradiation at 365nm cis Wavelength (nm) 06.07.14 Absorbance at 350nm Absorbance (AU) trans Switching Switching Cycles Cycles Velma, W. A.; van der Berg, J. P.; Hansen, M.; Szymanski, W.; Driessen, A. J. M.; Feringa, B. L. Nat. Chem. 5, 924-928, (2013). 9 Binary Activity Profile O O OH N N N O Growth Curves of E. coli (CS1652) Before 06.07.14 Irradiation After Irradiation at 365nm Velma, W. A.; van der Berg, J. P.; Hansen, M.; Szymanski, W.; Driessen, A. J. M.; Feringa, B. L. Nat. Chem. 5, 924-928, (2013). 10 Binary Activity Profile After Incubation at 37oC 06.07.14 Velma, W. A.; van der Berg, J. P.; Hansen, M.; Szymanski, W.; Driessen, A. J. M.; Feringa, B. L. Nat. Chem. 5, 924-928, (2013). 11 Thermal Inactivation Thermal cis-trans isomerization Growth Curves of E. coli (37oC, 21 x 10-6M in water) 06.07.14 (40 µg/ml of inactive, non-irradiated compound 2) Velma, W. A.; Szymanski, W.; Feringa, B. L. JACS. 136, 2178-91, (2014). 12 Inactivation of Photopharmaceutical Agents A B C Inactivation via irradiation D E F G Thermal Inactivation H I J 06.07.14 Velma, W. A.; Szymanski, W.; Feringa, B. L. JACS. 136, 2178-91, (2014). 13 Ideal Conditions for Photopharmacology Will not applicable without these ideal conditions Activation with light of low cellular toxicity Ideally deep-penetrating Controlled Inactivation Additional complications with two different molecules Metabolic 06.07.14 stability, water-soluble, toxicity Velma, W. A.; Szymanski, W.; Feringa, B. L. JACS. 136, 2178-91, (2014). 14 Outlook: Are we there yet? In principal, attractive for treatment of localized diseases/infections Reduce off-target toxicity of cancer therapeutics Minimal development in the area beyond proof of concept Photoswitches must be effectively incorporated with high control of activity In Summary: No 06.07.14 Velma, W. A.; Szymanski, W.; Feringa, B. L. JACS. 136, 2178-91, (2014). 15
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