Control of metalloenzyme activity using photopharmacophores

Metalloenzymes are responsible for numerous physiological and pathological processes in living organisms; however, there are very few FDA-approved metalloenzyme-targeting therapeutics (only ~ 67 FDA-approved metalloenzyme inhibitors as of 2020, less than ~ 5 % of all FDA-approved therapeutics). Most metalloenzyme inhibitors have been developed to target the catalytic metal centers in metalloenzymes via the incorporation of metal-binding groups. Light-controlled inhibition of metalloenzymes has been used as a means to specifically activate and inactivate inhibitor engagement at a desired location and time via light irradiation, allowing for precise spatiotemporal control over metalloenzyme activity. In this review, we summarize the strategies that have been employed to develop biocompatible light-sensitive inhibitors for metalloenzymes via the incorporation of different photo-activatable moieties (including photoswitchable and photocleavable groups), and the application of photo-activateable inhibitors both in vitro and in vivo. We also discuss the photophysical mechanisms of different photo-activatable groups, their action under physiological conditions, and the different modes of interaction between inhibitors and proteins (i.e., inhibition mechanisms) in the presence and absence of light. Finally, we discuss considerations for the future development of light-responsive metalloenzyme inhibitors and the challenges limiting their application in vivo.