Light-Controlled Lipid Interaction and Membrane Organization in Photolipid Bilayer Vesicles

Urban, Patrick; Pritzl, Stefanie D.; Konrad, David; Frank, James A.; Pernpeintner, Carla; Roeske, Christian R.; Trauner, Dirk; Lohmüller, Theobald

doi:10.1021/acs.langmuir.8b03241

Cited by 67 publications

(122 citation statements)

References 47 publications

(75 reference statements)

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…Photopharmacological approaches to generate high-spatiotemporal-precision reagents for non-invasive studies of endogenous protein function have made significant progress over recent years. Their original applications to neuroscience 45,46 have now been extended to studies of membrane 47,48 and intracellular 6 biology, and recent advances such as long-wavelength-responsive photoswitches 26,49,50 offer beguiling prospects for in vivo photopharmacology. However, the conceptual scope of photopharmacology has been somewhat chemically restricted, in that the overwhelming majority of photopharmaceutical designs employ azobenzenes as the photoswitch moiety, and that independent of the desired biological target, the azobenzene motif incurs functional limitations on biological applications: (1) the diazene's nucleophilic and metabolic susceptibility is problematic for addressing intracellular targets or when aiming at long-term, systemic in vivo applications; (2) its isomerisation-inducing nπ* transition in the blue-green spectral region overlaps with imaging of common biological tags (e.g.…”

Section: Discussion and Outlookmentioning

confidence: 99%

Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton

Gao

Kraus

Wranik

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Here we present GFP-orthogonal optically controlled reagents for reliable and repetitive in cellulo modulation of microtubule dynamics and its dependent processes. Optically controlled reagents ("photopharmaceuticals") have developed into powerful tools for high-spatiotemporal-precision control of endogenous biology, with numerous applications in neuroscience, embryology, and cytoskeleton research. However, the restricted chemical domain of photopharmaceutical scaffolds has constrained their properties and range of applications. Styrylbenzothiazoles are an as-yet unexplored scaffold for photopharmaceuticals, which we now rationally design to feature potent photocontrol, switching microtubule cytoskeleton function off and on according to illumination conditions. We show more broadly that this scaffold is exceptionally chemically and biochemically robust as well as substituent-tolerant, and offers particular advantages for intracellular biology through a range of desirable photopharmaceutical and drug-like properties not accessible to the current classes of photoswitches. We expect that these reagents will find powerful applications enabling robust, high precision, optically controlled cell biological experimentation in cytoskeleton research and beyond. Introduction:Molecular photoswitches have been used to install optical control over a broad range of phenomena, with applications from material sciences 1,2 through to reversible photocontrol of ligand binding affinities 3 and manipulation of diverse cellular processes in chemical biology 4,5 . For studies of temporally-regulated and spatially anisotropic biological systems, particularly those that simultaneously support several cellular functions, photoswitchable inhibitors conceptually enable a range of powerful studies not accessible with other tool systems. [6][7][8] A prime example of such spatiotemporally regulated, multifunctional systems is the microtubule (MT) cytoskeleton. This complex cellular network plays central roles in nearly all directed mechanical processes, such as intracellular transport and cell motility; its crucial function in cell proliferation has also made it a central anticancer drug target. 9-11 Yet, whereas cytoskeleton research typically aims to study a subset of MT-dependent processes that are spatially and/or temporally localised, nearly all MT inhibitors reported as tool compounds for biological research are drugs that are active wherever they are distributed, including at sites and at times where drug activity is not desired. 12 This restricts the scope of applications and utility of these inhibitors for selective research into the various, highly dynamic, anisotropic processes dependent on MTs. 13 The structure of the colchicine site MT inhibitor combretastatin A-4 (CA4; Fig 1a) 14 has recently inspired photoswitchable solutions to the problem of achieving spatiotemporal control over MT inhibition. CA4 is a stilbene whose Z-isomer (cis) binds tubulin, acts as a low nanomolar cytotoxin in cellulo, and reached Phase III trials as an ...

show abstract

Section: Discussion and Outlookmentioning

confidence: 99%

Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton

Gao

Kraus

Wranik

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…[4,5] The molecular picture of how photo-switchable lipids interact with membranes is largely unclear. [6,7] To enable numerical simulations of membranes with photo-switchable lipids, we derived CHARMM (Chemistry at Harvard Molecular Mechanics [8] ) force-field parameters for an azobenzene-based photo-switchable lipid.…”

Section: Introductionmentioning

confidence: 99%

Potential energy function for a photo‐switchable lipid molecule

et al. 2020

Self Cite

View full text Add to dashboard Cite

Photo‐switchable lipids are synthetic lipid molecules used in photo‐pharmacology to alter membrane lateral pressure and thus control opening and closing of mechanosensitive ion channels. The molecular picture of how photo‐switchable lipids interact with membranes or ion channels is poorly understood. To facilitate all‐atom simulations that could provide a molecular picture of membranes with photo‐switchable lipids, we derived force field parameters for atomistic computations of the azobenzene‐based fatty acid FAAzo‐4. We implemented a Phyton‐based algorithm to make the optimization of atomic partial charges more efficient. Overall, the parameters we derived give good description of the equilibrium structure, torsional properties, and non‐bonded interactions for the photo‐switchable lipid in its trans and cis intermediate states, and crystal lattice parameters for trans‐FAAzo‐4. These parameters can be extended to all‐atom descriptions of various photo‐switchable lipids that have an azobenzene moiety.

show abstract

“…In the first step, we synthesized 1-substituted-sn-glycero-3-phosphocholine4via dibutyltin oxide-mediated selective primary alcohol acylation of 1,2-diols with adamantyl chloride 2. 23 Finally, Steglich esterification 24 of variable hydrocarbon tail to the remaining hydroxyl group afforded 10 compounds, A-10 to A-17-2Z(Figure 1b,c) in 77-92% of yields. We characterized these compounds by 1 H-NMR, 13 C-NMR, and highresolution mass spectrometry (see Material and Methods), and for simplicity, termed these "constrained phospholipids".…”

Section: Resultsmentioning

confidence: 99%

Nanoparticles containing constrained phospholipids deliver mRNA to liver immune cells in vivo without targeting ligands

Gan

Lokugamage

Hatit

et al. 2020

Bioengineering & Transla Med

View full text Add to dashboard Cite

Once inside the cytoplasm of a cell, mRNA can be used to treat disease by upregulating the expression of any gene. Lipid nanoparticles (LNPs) can deliver mRNA to hepatocytes in humans, yet systemic non-hepatocyte delivery at clinical doses remains difficult. We noted that LNPs have historically been formulated with phospholipids containing unconstrained alkyl tails. Based on evidence that constrained adamantyl groups have unique properties that can improve small molecule drug delivery, we hypothesized that a phospholipid containing an adamantyl group would facilitate mRNA delivery in vivo. We quantified how 109 LNPs containing "constrained phospholipids" delivered mRNA to 16 cell types in mice, then using a DNA barcoding-based analytical pipeline, related phospholipid structure to in vivo delivery. By analyzing delivery mediated by constrained phospholipids, we identified a novel LNP that delivers mRNA to immune cells at 0.5 mg/kg. Unlike many previous LNPs, these (a) did not preferentially target hepatocytes and (b) delivered mRNA to immune cells without targeting ligands. These data suggest constrained phospholipids may be useful LNP components.

show abstract

Light-Controlled Lipid Interaction and Membrane Organization in Photolipid Bilayer Vesicles

Cited by 67 publications

References 47 publications

Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton

Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton

Potential energy function for a photo‐switchable lipid molecule

Nanoparticles containing constrained phospholipids deliver mRNA to liver immune cells in vivo without targeting ligands

Contact Info

Product

Resources

About