Periodic Reporting for period 2 - LIGHTPORT (From light-stimulated anion receptors to transmembrane carriers and pumps)
Berichtszeitraum: 2020-09-01 bis 2022-02-28
The transport of anions across the cell membrane, which is mediated by transport proteins, is essential to many important biological processes. Dysregulation of this transport has been associated to various diseases and therefore, chemists endeavor to develop artificial receptors that mimic the function of natural transporters. Despite much progress over the last decade, the current artificial systems are mostly static, while proteins are able to change their activity dynamically in response to stimuli in the environment. To integrate such stimuli-controlled behavior in synthetic systems is a key contemporary challenge. In view of this, the goal of the proposed research program is to develop anion receptors in which the binding properties can be effectively modulated by light and to apply these receptors as transmembrane carriers and pumps, in order to regulate passive transport (i.e. down a concentration gradient) and to induce active transport (i.e. against a concentration gradient).
This interdisciplinary program is divided into three work packages: WP1 aims at the development of structurally rigid and visible-light-actuated photoswitches and their use as platforms for constructing anion receptors; WP2 deals with the development of mechanically interlocked structures as photoswitchable anionic hosts; WP3 is directed at utilizing these receptors for light-gated transport and light-driven pumping of anions across phospholipid bilayers, whereas also an alternative dual-responsive anion channel will be prepared. Eventually, it is expected that this work will open a new route toward light-based localized pharmacological treatment, e.g. via light-triggered cancer or bacterial cell death. Furthermore, active transport systems, that are able to build up and maintain concentration gradients across membranes, could provide a completely new view on how to convert and store light (solar) energy.
This interdisciplinary program is divided into three work packages: WP1 aims at the development of structurally rigid and visible-light-actuated photoswitches and their use as platforms for constructing anion receptors; WP2 deals with the development of mechanically interlocked structures as photoswitchable anionic hosts; WP3 is directed at utilizing these receptors for light-gated transport and light-driven pumping of anions across phospholipid bilayers, whereas also an alternative dual-responsive anion channel will be prepared. Eventually, it is expected that this work will open a new route toward light-based localized pharmacological treatment, e.g. via light-triggered cancer or bacterial cell death. Furthermore, active transport systems, that are able to build up and maintain concentration gradients across membranes, could provide a completely new view on how to convert and store light (solar) energy.
Different types of anion receptors, in which binding affinity can be effectively controlled, have been successfully developed. Highlight is the development of a stiff-stilbene strapped calix[4]pyrrole receptor displaying an 8000-fold affinity difference between photoaddressable states. One of our classes of compounds proved very active in transmembrane transport assays allowing for in situ photocontrol over the rate of chloride transport. Furthermore, photoswitching of stiff-stilbene could be induced by visible light instead of UV by introducing electron-donating and -withdrawing substituents.
Visible-light switching of stiff-stilbene is an important achievement and moreover, the photochromic properties were gated by acid/base and unprecedented acid-catalyzed thermal isomerization was found. The 8000-fold affinity difference found for calix[4]pyrrole is a major improvement compared to the most successful previous systems, which typically had affinity differences in the range of 10-to-100-fold. Control of transmembrane transport has been demonstrated, which is one of the main goals of this project, proving the feasibility. We will further optimize this transport in terms of level of control and photoswitching properties and eventually, work towards light-powered active transport.