Conceptual Photopharmacology Research
Photoswitches can be reversibly E⇆Z photoisomerised with excellent spatiotemporal precision. This generally recommends reagents that incorporate photoswitches (photopharmaceuticals) as tools for studying the biology of protein targets that play different roles in different places within cells or organisms, or proteins with rapid temporal responses e.g. signal integration/filtering and transmission systems.
We and many others are convinced that photopharmaceuticals can be invaluable tools for basic research, if properly designed and optimised. Our group stands out however, for our focus on critically re-evaluating the implicit customs for "good design" as well as for "appropriate optimisation" that the field has followed over the last two decades. This is what we call our conceptual research program.
(1) We emphasise the need for tool robustness, including the ease of transfer of a reagent from cellular to in vivo systems. Repeatability of compound action (i.e. it can be easily switched off when unwanted) and reagent solubility are obvious needs; but we feel that a general re-write of how to even design photoswitchable tools in the first place is needed in order to avoid them "failing late" upon translation to in vivo. We thus promote to design for what we term ideal efficacy switches for protein chromocontrol (BioRxiv 2024), rather than the ubiquitous current design paradigm of affinity switches created through e.g. azologisation that deliver conflated photocontrol.
(2) Another conceptual requirement for in vivo use that has remained a negative salient for some decades, is to discover viable methods for easy and noninvasive in vivo photoswitching. This essentially requires efficient and biocompatible single-photon photoswitching in both E→Z and Z→E directions, at two different wavelengths in the biotransparent NIR region. We are pioneering methods that finally succeed in this, by escaping the usual energy restrictions of direct photoswitching, and instead entering the realms of singlet manifold photoredox (ChemRxiv 2023) or conditional intersystem crossing (ChemRxiv 2024).
(3) Even on the more basic level of "tools for cell culture", the standards in the field leave much room for improvement. For example, creating photopharmaceutical tools with sufficient biochemical specificity and potency is a challenge that has long been clear to the whole field (and, it can be addressed in a target-by-target fashion based on ligand binding sites, by classical med chem approaches). Yet, we consider that several other key factors are needed to generate high quality photoswitchable probes (Angewandte 2024), e.g. explicit maximisation of the practical potency differential (between photogenerated E*-PSS and Z*-PSS populations; ChemSci 2024), explicit testing to confirm a lack of specific off-targets (usually, closely-related proteins), and explicit testing to confirm a lack of nonspecific effects at appropriate working concentrations (e.g. polypharmacological effects; cellular dysregulation driven by partitioning (Nat Commun 2022) and polarity (OBC 2022); chromophore-localised phototoxicity [CALI]; etc): which requires much more stringent assay designs as well as the use of "permuted chemical control" compounds.