A Photohormone for Light-Dependent Control of PPARα in Live Cells

Abstract

Photopharmacology enables the optical control of several biochemical processes using small-molecule photoswitches that exhibit different bioactivities in their cis-and transconformations. Such tool compounds allow for high spatiotemporal control of biological signaling, and the approach also holds promise for the development of drug molecules that can be locally activated to reduce target-mediated adverse effects. Herein, we present the expansion of the photopharmacological arsenal to two new members of the peroxisome proliferator-activated receptor (PPAR) family, PPARα and PPARδ. We have developed a set of highly potent PPARα and PPARδ targeting photohormones derived from the weak pan-PPAR agonist GL479 that can be deactivated by light. The photohormone 6 selectively activated PPARα in its trans-conformation with high selectivity over the related PPAR subtypes and was used in live cells to switch PPARα activity on and off in a light-and time-dependent fashion.

Development of Light‐Activated LXR Agonists

“…[8][9][10] Photopharmacology enables the optical control of biological processes with high spatiotemporal precision by using photoswitchable molecules that exhibit different activity in their different configurations. [11][12][13][14] This concept has been established for several protein classes, including nuclear receptors, [15][16][17][18][19][20] and is also appealing for LXR activation as it may reduce systemic side effects through local activation. [21] Especially for an application in cancer treatment, this approach holds potential by spatially limiting pharmacological effects to an intended site of action.…”

Photoswitchable Diazocine-Based Estrogen Receptor Agonists: Stabilization of the Active Form inside the Receptor

“…A number of photoswitches, such as azobenzenes, spiropyrans, diarylethenes, and diazocines, have been used to design light-switchable drugs and hormones. − Diazocines stand out because of the bathochromic switching wavelengths (400–700 nm), high switching efficiencies (60–95%), very high quantum yields (70–90%) and excellent fatigue resistance . Most importantly, and in contrast to the frequently used azobenzenes, diazocines are stable in their bent Z configuration and less stable in their stretched E configuration (Figure b). ,, …”

“…In this context, azobenzene-based photoswitchable estrogen receptor ligands were recently reported by Tsuchiya et al 42 Furthermore, other photoswitchable nuclear receptor ligands targeting retinoic acid receptor α, farnesoid X receptor, and peroxisome proliferator-activated receptor α and γ were published by the Trauner group recently. 26,27,43,44 In our present study, we focused on functionalized diazocines and first performed molecular modeling to establish a respective hypothesis. Thus, superposition of 17β-estradiol with the metadihydroxy functionalized diazocine 1 suggested the E configuration to resemble 17β-estradiol in molecular shape, whereas the Z configuration of 1 showed significantly less similarity (Figure 2a,b).…”

Hypothesis-Driven, Structure-Based Design in Photopharmacology: The Case of eDHFR Inhibitors

“… 27 Such an approach has been gaining momentum also in photopharmacology in recent years, resulting in different applications for modeling: computer-assisted design 18 , 22 , 28 and a posteriori rationalization of the observed results. 29 − 32 However, proper structure-based design 33 , 34 (analysis of substitutions, reiterated cycles of design-test) is still an underexplored pathway in small-molecule-based approaches to regulating biological activity with light.…”

“…A more general approach is the application of structure-based drug design, which is a mature technique in drug discovery. , This method would broaden the scope of rational design in photopharmacology, because it can be applied not only to targets with resolved structures but also to other targets via homology modeling . Such an approach has been gaining momentum also in photopharmacology in recent years, resulting in different applications for modeling: computer-assisted design ,, and a posteriori rationalization of the observed results. − However, proper structure-based design , (analysis of substitutions, reiterated cycles of design-test) is still an underexplored pathway in small-molecule-based approaches to regulating biological activity with light.…”