Photoactivated peptides are modified natural or synthetic peptides the functions of which can be activated with light. This can be done either irreversibly or in a reversible way. Caged peptides [1] which contain photocleavable protecting groups belong to irreversibly activated peptides. Reversible activation/deactivation of peptide function are achieved by incorporation photo-controllable fragments (molecular photoswitches) in the side chains or in the backbone of peptide templates to get the photo-controlled peptides, which can reversibly change their structure upon irradiation with light of different wavelength. As the consequence, the properties, function and biological activity of the modified peptides can be controlled by light. Since light can be directed to specific areas, such peptides can be activated only at targeted sites. Azobenzenes, [2] [3] [4] and diarylethenes [5] [6] can be used as the photoswitches. For therapeutic use, photoswitches with longer wavelengths (near-infrared, to penetrate tissue) or the use of two-photon excitation [7] are required, coupled with improved methods for peptide delivery to live cells. [8] [9]
Photoactivated peptides are potentially useful for cancer therapy, other light-controlled drugs and in tools to probe molecular interactions in intact cells and whole organisms. [8]
The initial peptides were successfully used to kill B-cell lymphoma cancer cells. The reference synthetic short peptide was alkylated with azobenzene crosslinkers and used to photo-stimulate mitochondrial membrane depolarization and cytochrome c release in permeabilised cells, which were the initial events of the intrinsic apoptosis pathway. [8] Gramicidin S analogues containing a diarylethene fragment [6] display clear-cut reversible change of antimicrobial activity. In an inactive, UV-inducible photo-form they are harmless to bacteria cells, but are bactericidal after the activation with visible (amber) light.
Photoswitchable peptides to inhibit protein-protein interactions in a light-controlled manner have been developed and applied to inhibit clathrin-mediated endocytosis in mammalian cells [10] [11] and in yeast. [12] The same design principle has been applied to inhibit protein-protein interactions involved in cancer [13] and can be used for any interaction mediated by a helical motif.
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. Endocytosis includes pinocytosis and phagocytosis. It is a form of active transport.
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice that surrounds the vesicle, hence the protein's name, which is derived from the Latin clathrum meaning lattice. Coat-proteins, like clathrin, are used to build small vesicles in order to transport molecules within cells. The endocytosis and exocytosis of vesicles allows cells to communicate, to transfer nutrients, to import signaling receptors, to mediate an immune response after sampling the extracellular world, and to clean up the cell debris left by tissue inflammation. The endocytic pathway can be hijacked by viruses and other pathogens in order to gain entry to the cell during infection.
Azobenzene is a photoswitchable chemical compound composed of two phenyl rings linked by a N=N double bond. It is the simplest example of an aryl azo compound. The term 'azobenzene' or simply 'azo' is often used to refer to a wide class of similar compounds. These azo compounds are considered as derivatives of diazene (diimide), and are sometimes referred to as 'diazenes'. The diazenes absorb light strongly and are common dyes.
Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane (invagination). This process forms vesicles containing the absorbed substances and is strictly mediated by receptors on the surface of the cell. Only the receptor-specific substances can enter the cell through this process.
Photochromism is the reversible change of color upon exposure to light. It is a transformation of a chemical species (photoswitch) between two forms by the absorption of electromagnetic radiation (photoisomerization), where the two forms have different absorption spectra.
A photoswitch is a type of molecule that can change its structural geometry and chemical properties upon irradiation with electromagnetic radiation. Although often used interchangeably with the term molecular machine, a switch does not perform work upon a change in its shape whereas a machine does. However, photochromic compounds are the necessary building blocks for light driven molecular motors and machines. Upon irradiation with light, photoisomerization about double bonds in the molecule can lead to changes in the cis- or trans- configuration. These photochromic molecules are being considered for a range of applications.
Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamin is part of the "dynamin superfamily", which includes classical dynamins, dynamin-like proteins, Mx proteins, OPA1, mitofusins, and GBPs. Members of the dynamin family are principally involved in the scission of newly formed vesicles from the membrane of one cellular compartment and their targeting to, and fusion with, another compartment, both at the cell surface as well as at the Golgi apparatus. Dynamin family members also play a role in many processes including division of organelles, cytokinesis and microbial pathogen resistance.
The AP2 adaptor complex is a multimeric protein that works on the cell membrane to internalize cargo in clathrin-mediated endocytosis. It is a stable complex of four adaptins which give rise to a structure that has a core domain and two appendage domains attached to the core domain by polypeptide linkers. These appendage domains are sometimes called 'ears'. The core domain binds to the membrane and to cargo destined for internalisation. The alpha and beta appendage domains bind to accessory proteins and to clathrin. Their interactions allow the temporal and spatial regulation of the assembly of clathrin-coated vesicles and their endocytosis.
Cortactin is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin cortex around the cellular periphery. It is present in all cell types. When activated, it will recruit Arp2/3 complex proteins to existing actin microfilaments, facilitating and stabilizing nucleation sites for actin branching. Cortactin is important in promoting lamellipodia formation, invadopodia formation, cell migration, and endocytosis.
A molecular switch is a molecule that can be reversibly shifted between two or more stable states. The molecules may be shifted between the states in response to environmental stimuli, such as changes in pH, light, temperature, an electric current, microenvironment, or in the presence of ions and other ligands. In some cases, a combination of stimuli is required. The oldest forms of synthetic molecular switches are pH indicators, which display distinct colors as a function of pH. Currently synthetic molecular switches are of interest in the field of nanotechnology for application in molecular computers or responsive drug delivery systems. Molecular switches are also important in biology because many biological functions are based on it, for instance allosteric regulation and vision. They are also one of the simplest examples of molecular machines.
T-cell surface glycoprotein CD3 gamma chain is a protein that in humans is encoded by the CD3G gene.
Clathrin heavy chain 1 is a protein that in humans is encoded by the CLTC gene.
Dynamin-1 is a protein that in humans is encoded by the DNM1 gene.
AP-1 complex subunit beta-1 is a protein that in humans is encoded by the AP1B1 gene.
Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing alpha polypeptide is an enzyme that in humans is encoded by the PIK3C2A gene.
Sorting nexin-9 is a protein that in humans is encoded by the SNX9 gene.
Stefan Hecht is a German chemist.
BIM-1 and the related compounds BIM-2, BIM-3, and BIM-8 are bisindolylmaleimide-based protein kinase C (PKC) inhibitors. These inhibitors also inhibit PDK1 explaining the higher inhibitory potential of LY33331 compared to the other BIM compounds a bisindolylmaleimide inhibitor toward PDK1.
Targeted covalent inhibitors (TCIs) or Targeted covalent drugs are rationally designed inhibitors that bind and then bond to their target proteins. These inhibitors possess a bond-forming functional group of low chemical reactivity that, following binding to the target protein, is positioned to react rapidly with a proximate nucleophilic residue at the target site to form a bond.
Photopharmacology, an emerging approach in medicine, involves activating and deactivating photoswitchable molecules with light for target drug delivery. Clinicians use the energy of light to change the shape and chemical properties of a drug, resulting in different biological activity. This is done to ultimately achieve control of when and where drugs are active in a reversible manner, and to prevent side effects and exposure to the environment of antibiotics. Switching drugs "on" and "off" is achieved by introducing photoswitches such as azobenzene, spiropyran or diarylethene into the drug. Photopharmalogical drugs with a photoswitch have two different states, which light can toggle between. Since both states have a different structure, the activity of the drug is different, hence the "on" and "off" state of the drug. An example is photostatin, which is an inhibitor that can be switched on and off in vivo to optically control microtubule dynamics.
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