Devising a successful project in Photopharmacology:
For detailed guidelines and a personal account, see: Acc. Chem. Res. 2015, 48, 1947–1960
The following steps summarize the current “best-practice” workflow of a typical photopharmacology project:
1. Define your target: The biological target should meet the criteria for photodruggability.
2. The biological target: Are there crystal structures available? How does the active site look like?
3. Existing Agonists/Antagonists/Blockers: Find suitable biologically active substances that interact with the chosen target.
4. Study Structure-Activity-Relationships (SAR): What changes in the structure are tolerated?
5. Photoswitch strategy:
1. Modification of the pharmacophore vs. appended photoswitches
2. Photoswitchable linker of multivalent drugs (diarylethenes)
3. Azologation (ACS Chem. Neurosci. 2014, 5, 514−518)
6. Choice of the photoswitch : Guided by SAR, photoswitch strategy, synthetic accessibility and required photoswitching properties.
7. Synthesis of the photoswitchable drug candidate: Devise a synthetic route that allows for facile structural modification (for later SAR studies)
8. Photochemical characterization: Absorption spectra, photoswitching, thermal stability of the isomers, fatigue resistance, resistance to metabolism (e.g. reduction of azobenzenes: GSH-assay, ChemBioChem 2007, 8, 591 – 594).
9. Initial enzymatic testing: Dose-response curves, initial SAR studies.
10. Adjust the properties of the photoswitch:
1. T- vs. P-type photoswitch
2. Thermal half-life of the thermally unstable isomer
5. Absorption maximum
6. Photochemical characteristics (extinction coefficients ε, photochemical quantum yield φ)
11. Advanced biological tests/Choice of Light-Delivery: e.g. mouse model, brain slices, etc.
12. Toxicological studies
An approach that has been underdeveloped so far includes deliberate screening of large compound libraries. This approach can lead to successful results (Nat. Chem. Biol. 2013, 9, 257–263), but generally the screening assay needs to be strategically planned:
• Dose-response curves read out must not interfere with the photoswitch
• Behavioural vs. enzymatic screen
• Global target vs. specific target
• How to generate a photoswitch library? A recent successful example uses phage-display photoswitch optimization (J. Am. Chem. Soc., 2014, 136, 5880–5883).
© 2017 Michael M. Lerch |