Optical Manipulation of F-Actin with Photoswitchable Small Molecules

Abstract

Cell-permeable photoswitchable small molecules, termed optojasps, are introduced to optically control the dynamics of the actin cytoskeleton and cellular functions that depend on it. These light-dependent effectors were designed from the F-actinstabilizing marine depsipeptide jasplakinolide by functionalizing them with azobenzene photoswitches. As demonstrated, optojasps can be employed to control cell viability, cell motility, and cytoskeletal signaling with the high spatial and temporal resolution that light affords. Optojasps can be expected to find applications in diverse areas of cell biological research. They may also provide a template for photopharmacology targeting the ubiquitous actin cytoskeleton with precision control in the micrometer range.

Chemoproteomics‐Enabled De Novo Discovery of Photoswitchable Carboxylesterase Inhibitors for Optically Controlled Drug Metabolism

“…[1a, 2] More recently,however,small molecule photoswitches that enable repeated isomerization between the active and inactive state have emerged as apowerful tool to optically and reversibly control receptors,h ydrolases [3] and other enzymes, [4] and even the cytoskeleton. [5] Most commonly, photoswitchable probes are developed through "azologization", replacement of am oiety such as as tilbene,b enzyl aniline,o rN-aryl benzamide with as tructurally similar azobenzene group. [1a,b,6] An exemplifying application of this strategy is the recent development of photostatins based on the natural product combretastatin A-4 to modulate microtubule dynamics.…”

Photoswitchable paclitaxel-based microtubule stabilisers allow optical control over the microtubule cytoskeleton

“…Against this background, photopharmaceuticals-photoswitchably potent exogenous small molecule inhibitors-have been extensively developed in recent years [16][17][18][19] . Photopharmaceuticals conceptually enable studies not otherwise accessible to biology, marrying the spatiotemporal precision of light application known from optogenetics, to the flexibility and system-independence of exogenous small molecule inhibitors.…”

Cryo‐EM Resolves Molecular Recognition Of An Optojasp Photoswitch Bound To Actin Filaments In Both Switch States

“…Recently, optojasps, cell-permeable and photo-switchable small molecules derived from the natural F-actin inhibitor jasplakinolide (JASP, 2, Figure 1) [5] were shown to provide direct optical spatiotemporal control of the actin cytoskeleton. [6] The design of optojasps originated from in silico molecular modelling data of the JASP binding site and thorough analysis of structureactivity-relationship data. [7] It features a modified cyclodepsipeptide macrocycle with a bistable azobenzene attached via a linker chain to the Ala residue position (3, Figure 1).…”

“…The diazene bond can be isomerized from its trans-configured ground state to a high-energy cis form that thermally reverts back to trans with a specific half life, or by irradiation with green light. [6] Figure 1. Chemical structures of F-actin stabilizing natural product toxins and of optojasp-8.…”

“…Conditions: a) hn = 380 nm; b) hn = 520 nm or DT (t 1/2 = 15 min in PBS buffer at 37 8C). [6] Recent high-resolution electron cryo microscopy (cryo-EM) structures of JASP-stabilized F-actin allowed a nearatomic analysis of the JASP binding pocket and its interactions with F-actin, [2,8,9] highlighting the potential of cryo-EM for structure-based drug design. [10] Surprisingly, these data suggested the photoswitch moiety of functional optojasps to be placed in the interior of the actin filament.…”