The establishment of bioorthogonal chemistry is one of the most significant advances in chemical biology using exogenous chemistry to perturb and study biological processes. Photo-modulation of biological systems has realized temporal and spatial control on biomacromolecules in living systems. The combination of photo-modulation and bioorthogonal chemistry is therefore emerging as a new direction to develop new chemical biological tools with spatiotemporal resolution. This minireview will focus on recent development of bioorthogonal chemistry subject to spatiotemporal control through photo-irradiation. Different strategies to realize photo-control on bioorthogonal bond-forming reactions and biological applications of photo-controllable bioorthogonal reactions will be summarized to give a perspective on how the innovations on photo-chemistry can contribute to the development of optochemical biology. Future trends to develop more optochemical tools based on novel photochemistry will also be discussed to envision the development of chemistry-oriented optochemical biology.
Bispecific chimeras bridging cell membrane proteins with lysosome‐trafficking receptors (LTRs) provide an effective therapeutic approach through lysosomal degradation of disease‐relevant targets. Here, we report a novel dendronized DNA chimera (DENTAC) strategy that uses a dendritic DNA to engage cell surface scavenger receptors (SRs) as LTR. Using bioorthogonal strain‐promoted alkyne‐azide cycloaddition to conjugate the dendritic DNA with protein binder, the resulting DENTAC is able to traffic the protein target into the lysosome for elimination. We demonstrated the utility of DENTAC by degrading oncogenic membrane nucleolin (NCL) and epidermal growth factor receptor (EGFR). The anti‐cancer application of NCL‐targeting DENTAC was validated in a mouse xenograft model of lung cancer. This work thus presents a new avenue for rapid development of potent degraders against membrane proteins, with also broad research and therapeutic prospects.
Confining the protein degradation activity of proteolysis-targeting chimera (PROTAC) to cancer lesions ensures precision treatment. However, it still remains challenging to precisely control PROTAC function in tumor regions in vivo. We herein describe a near-infrared (NIR) photoactivatable nano-PROTAC (NAP) for remote-controllable proteolysis in tumorbearing mice. NAP is formed by molecular self-assembly from an amphiphilic conjugate of PROTAC linked with an NIR photosensitizer through a singlet oxygen ( 1 O 2 )-cleavable linker. The activity of PROTAC is initially silenced but can be remotely switched on upon NIR photoirradiation to generate 1 O 2 by the photosensitizer. We demonstrated that NAP enabled tumorspecific degradation of bromodomain-containing protein 4 (BRD4) in an NIR light-instructed manner. This in combination with photodynamic therapy (PDT) elicited an effective suppression of tumor growth. This work thus presents a novel approach for spatiotemporal control over targeted protein degradation by PROTAC.
Bispecific chimeras bridging cell membrane proteins with lysosome‐trafficking receptors (LTRs) provide an effective therapeutic approach through lysosomal degradation of disease‐relevant targets. Here, we report a novel dendronized DNA chimera (DENTAC) strategy that uses a dendritic DNA to engage cell surface scavenger receptors (SRs) as LTR. Using bioorthogonal strain‐promoted alkyne‐azide cycloaddition to conjugate the dendritic DNA with protein binder, the resulting DENTAC is able to traffic the protein target into the lysosome for elimination. We demonstrated the utility of DENTAC by degrading oncogenic membrane nucleolin (NCL) and epidermal growth factor receptor (EGFR). The anti‐cancer application of NCL‐targeting DENTAC was validated in a mouse xenograft model of lung cancer. This work thus presents a new avenue for rapid development of potent degraders against membrane proteins, with also broad research and therapeutic prospects.
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