Photocatalysis in Chemical Biology: Extending the Scope of Optochemical Control and Towards New Frontiers in Semisynthetic Bioconjugates and Biocatalysis

Biomedical research has been empowered by tools that enable spatial and temporal control of biological systems. These have predominantly come from photocaged bioactive molecules (optochemical control; N. Ankenbruck, T. Courtney, Y. Naro, A. Deiters, Angew. Chem. Int. Ed. 2018 , 57, 2768–2798) and light-dependent proteins (optogenetic control; L. Fenno, O. Yizhar, K. Deisseroth, Annu. Rev. Neurosci. 2011 , 34, 389–412). Recent advances in photocatalysis offer the opportunity to amplify these strategies by providing new dimension of biorthogonality. Photocatalysis also empowers bioconjugation with unprecedented reactivities enabling new crosslinking chemistry or biomolecule functionalization, while merging photocatalysis with biocatalysis extends the scope of both of these powerful classes of transformation.     

Light-controlled tools

Spatial and temporal control over chemical and biological processes plays a key role in life, where the whole is often much more than the sum of its parts. Quite trivially, the molecules of a cell do not form a living system if they are only arranged in a random fashion. If we want to understand these relationships and especially the problems arising from malfunction, tools are necessary that allow us to design sophisticated experiments that address these questions. Highly valuable in this respect are external triggers that enable us to precisely determine where, when, and to what extent a process is started or stopped. Light is an ideal external trigger: It is highly selective and if applied correctly also harmless. It can be generated and manipulated with well-established techniques, and many ways exist to apply light to living systems-from cells to higher organisms. This Review will focus on developments over the last six years and includes discussions on the underlying technologies as well as their applications.     

Biologically active molecules with a "light switch"

Biologically active compounds which are light-responsive offer experimental possibilities which are otherwise very difficult to achieve. Since light can be manipulated very precisely, for example, with lasers and microscopes rapid jumps in concentration of the active form of molecules are possible with exact control of the area, time, and dosage. The development of such strategies started in the 1970s. This review summarizes new developments of the last five years and deals with "small molecules", proteins, and nucleic acids which can either be irreversibly activated with light (these compounds are referred to as "caged compounds") or reversibly switched between an active and an inactive state.     

Optical Control of a Biological Reaction–Diffusion System

Patterns formed by reaction and diffusion are the foundation for many phenomena in biology. However, the experimental study of reaction–diffusion (R–D) systems has so far been dominated by chemical oscillators, for which many tools are available. In this work, we developed a photoswitch for the Min system of Escherichia coli, a versatile biological in vitro R–D system consisting of the antagonistic proteins MinD and MinE. A MinE‐derived peptide of 19 amino acids was covalently modified with a photoisomerizable crosslinker based on azobenzene to externally control peptide‐mediated depletion of MinD from the membrane. In addition to providing an on–off switch for pattern formation, we achieve frequency‐locked resonance with a precise 2D spatial memory, thus allowing new insights into Min protein action on the membrane. Taken together, we provide a tool to study phenomena in pattern formation using biological agents.     

Reporting the release of caged species by a combination of two sequential photoreactions, a molecular switch, and one color of light

In the right light: UV light triggers bond breaking, liberates a caged carboxylic acid, and generates the central C=C double bond in the photoresponsive hexatriene molecule of a dithienylethene molecular switch. Light of the same wavelength converts the colorless isomer into its colored counterpart in a visually convenient method to report on the success of the release event.     

Caged Phosphate and the Slips and Misses in Determination of Quantum Yields for Ultraviolet‐A‐Induced Photouncaging

The quantum yields for photouncaging reactions are mostly determined relative to other uncaging reactions, often using 1‐(2‐nitrophenyl)ethyl‐phosphate (“caged phosphate”). Herein, we demonstrate that the quantum yields acquired by using this method can be off by an order of magnitude at the typical irradiation wavelengths around 350 nm and describe an easy‐to‐use alternative procedure using inexpensive azobenzene.     

Spectral Tuning of Azobenzene Photoswitches for Biological Applications

Longer switching wavelengths and good photochemical yields and stabilities of the cis isomers in reducing aqueous environments are achieved by introducing 2,2′‐aminoalkyl substituents into 4,4′‐diamido‐substituted azobenzenes. The products are thus suitable for photocontrol of biomolecular structures in intracellular environments, such as switching between two peptide configurations (see picture).

     

Near‐IR‐Triggered,Remote‐Controlled Release of Metal Ions: A Novel Strategy for Caged Ions

A ligand incorporating a dithioethenyl moiety is cleaved into fragments which have a lower metal‐ion affinity upon irradiation with low‐energy red/near‐IR light. The cleavage is a result of singlet oxygen generation which occurs on excitation of the photosensitizer modules. The method has many tunable factors that could make it a satisfactory caging strategy for metal ions.     

From One‐Photon to Two‐Photon Probes: “Caged” Compounds,Actuators, and Photoswitches

Molecular systems that can be remotely controlled by light are gaining increasing importance in cell biology, physiology, and neurosciences because of the spatial and temporal precision that is achievable with laser microscopy. Two‐photon excitation has significant advantages deep in biological tissues, but raises problems in the design of “smart” probes compatible with cell physiology. This Review discusses the chemical challenges in generating suitable two‐photon probes.     

吉林大学超分子化学生物学学科的建设与发展:从超分子化学到生命机制探索及疫苗、药物研发

吉林大学是国内较早进行化学与生物学交叉研究的高校之一。为了推动吉林大学化学与生物学的深度融合,同时结合本校在超分子化学领域的积累与优势形成研究特色,本校提出了发展超分子化学生物学的构想,并建立了吉林大学超分子化学生物学研究中心。回顾了吉林大学化学与生物学交叉融合的发展历程,介绍了超分子化学生物学学科的发展现状及未来发展方向。     

Vinyl Ether/Tetrazine Pair for the Traceless Release of Alcohols in Cells

The cleavage of a protecting group from a protein or drug under bioorthogonal conditions enables accurate spatiotemporal control over protein or drug activity. Disclosed herein is that vinyl ethers serve as protecting groups for alcohol‐containing molecules and as reagents for bioorthogonal bond‐cleavage reactions. A vinyl ether moiety was installed in a range of molecules, including amino acids, a monosaccharide, a fluorophore, and an analogue of the cytotoxic drug duocarmycin. Tetrazine‐mediated decaging proceeded under biocompatible conditions with good yields and reasonable kinetics. Importantly, the nontoxic, vinyl ether duocarmycin double prodrug was successfully decaged in live cells to reinstate cytotoxicity. This bioorthogonal reaction presents broad applicability and may be suitable for in vivo applications.     

Optochemical Control of mRNA Translation in Eukaryotes

A major stage in the expression of genes is the translation of messenger RNA (mRNA), and the regulation of this process is essential for protein production in cells. How tightly controlled gene expression can be spatially and temporally, is particularly evident in polar cells and embryonic development. We need tools to dissect these complex processes, if we wish to understand the underlying links, especially the difficulties brought on by malfunction. External bioorthogonal triggers are very helpful in this area, if they let us precisely control where and when a process is started. Equipping nucleic acids with light-responsive groups has proven to be an effective approach to examine the dynamic regulatory route of mRNA translation in living cells. In this review, we present an overview of the most recent methods for optochemically controlling translation, focusing on cis-acting technologies.     

Light‐Induced Protein Dimerization by One‐ and Two‐Photon Activation of Gibberellic Acid Derivatives in Living Cells

We developed a highly efficient system for light‐induced protein dimerization in live cells using photo‐caged derivatives of the phytohormone gibberellic acid (GA₃). We demonstrate the application of the photo‐activatable chemical inducer of dimerization (CID) for the control of protein translocation with high spatiotemporal precision using light as an external trigger. Furthermore, we present a new two‐photon (2P)‐sensitive caging group, whose exceptionally high two‐photon cross section allows the use of infrared light to efficiently unleash the active GA₃ for inducing protein dimerization in living cells.     

Biological Effects of Black Phosphorus Nanomaterials on Mammalian Cells and Animals

The remarkable progress of applied black phosphorus nanomaterials (BPNMs) is attributed to BP's outstanding properties. Due to its potential for applications, environmental release and subsequent human exposure are virtually inevitable. Therefore, how BPNMs impact biological systems and human health needs to be considered. In this comprehensive Minireview, the most recent advancements in understanding the mechanisms and regulation factors of BPNMs’ endogenous toxicity to mammalian systems are presented. These achievements lay the groundwork for an understanding of its biological effects, aimed towards establishing regulatory principles to minimize the adverse health impacts.