Recent Developments and Applications of Clickable Photoprobes in Medicinal Chemistry and Chemical Biology

Abstract

Photoaffinity labeling is a well-known biochemical technique that has grown significantly since the turn of the century, principally due to its combination with bioorthogonal/click chemistry reactions. This review highlights new developments and applications of clickable photoprobes in medicinal chemistry and chemical biology. In particular, recent examples of clickable photoprobes for target identification, activity- or affinity-based protein profiling (ABPP or AfBPP), characterization of sterol- or lipid-protein interactions and characterization of ligand-binding sites are presented.

Development of Sulfonamide Photoaffinity Inhibitors for Probing Cellular γ-Secretase

“…This benzophenone can be prepared with multiple functional groups at the para position of the other phenyl ring (CH 2 Br, CHO, CH 2 OH, CO 2 H, CH 2 NH 2 ), which constitute versatile intermediates for synthesis of clickable photoaffinity probes. 1 …”

“…In some cases, a diazirine- or aryl azide-based photoreactive probe is advantageous, while in other cases a benzophenone-based probe is preferred. 1,2,18–25 Benzophenone-based probes are commonly utilized for identification and characterization of γ -secretase, 4–6,26–31 a macromolecular complex linked with Alzheimer’s disease (AD). 32,33 Fuwa et al 34 compared different photoreactive groups and showed that only benzophenone containing γ -secretase inhibitor probes cross-linked to presenilin (PS), the catalytic subunit of γ -secretase, 35 or SPP, but not phenyl-diazirine probes, despite similar inhibitory potencies.…”

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

“…Dazu werden zellpermeable,n iedermolekulare Sonden verwendet, die einerseits eine Gruppe zur kovalenten Bindung an das Protein enthalten und außerdem über eine Funktionalität, z. [124][125][126] Ein anschauliches,j üngstes Beispiel ist die Aufklärung des Zielproteins des Pseudomonad-Sekundärmetaboliten Promysalin. Im Anschluss an die Bindung der zellulären Zielproteine und die Zelllyse kann die Alkin-Einheit zur Konjugation an Azid-modifizierte Fluorophore oder Affinitäts-Tags mittels Kupfer-katalysierter Klick-Reaktion verwendet werden.…”

Small Molecules and Their Role in Effective Preclinical Target Validation

“…Seeking to replace the acetyl lysine mimetic of the CREBBP probe SGC-CBP30, Jones and co-workers identified a novel photoreactive tropolone warhead, and hypothesized that photoaffinity labels could be developed for bromodomains. Shown to indeed be possible, a clickable derivative was accessed which was used to understand the direct biological targets of the probe and assess BRD4 target engagement by (+)-JQ-1 [15,16]. Clickable photoaffinity labeling probes have also been used to map thousands of site-specific small-molecule protein interactions within human cells, from which more potent and selective small molecules can be optimized, presenting this technique as a versatile approach to small-molecule discovery as we advance into the future [17].…”