Photoswitches Very Important Paper DOI: 10.1002/anie.201310019 Controlling Biological Activity with Light: Diarylethene-Containing Cyclic Peptidomimetics** Oleg Babii, Sergii Afonin, Marina Berditsch, Sabine Reiber, Pavel K. Mykhailiuk, Vladimir S. Kubyshkin, Thomas Steinbrecher, Anne S. Ulrich,* and Igor V. Komarov* Abstract: Photobiological processes in nature are usually triggered by nonpeptidic chromophores or by modified side chains. A system is presented in which the polypeptide backbone itself can be conformationally switched by light. An amino acid analogue was designed and synthesized based on a reversibly photoisomerizable diarylethene scaffold. This analogue was incorporated into the cyclic backbone of the antimicrobial peptide gramicidin S at several sites. The bio- logical activity of the resulting peptidomimetics could then be effectively controlled by ultraviolet/visible light within strictly defined spatial and temporal limits. Molecules with structures and properties that can be reversibly controlled by light (photoswitches) have attracted considerable interest in different branches of science. Amongst the known photoswitches, [1] two classes are prom- inently represented, namely cis–trans interconvertible azo- benzenes (Figure 1A) and diarylethenes that undergo rever- sible photoisomerization between “open” and “closed” forms (Figure 1B). These photoswitches have found use in molec- ular electronics and various other applications. [2] One of the most exciting concepts in this field involves the incorporation of photoswitching units into biomolecules, in particular peptidomimetics, in order to control their biological activity by light. [3] In nature, light-driven conformational changes in proteins play a fundamental role in mediating photobiological pro- cesses. [4] They are usually triggered by nonpeptidic chromo- phores or by modified side chains, [5] yet there are no examples in which the polypeptide backbone itself undergoes direct photoconversion. To bridge this gap, photoswitchable amino acid analogues have been designed and incorporated into peptides. Most of the reported peptidomimetics are azoben- zene derivatives. [6] Light-triggered < changes in their con- formation, [7] binding affinities, [8] aggregation properties, [9] and folding [10] have been be demonstrated. However, reports on the use of diarylethene-based photoswitches for the same purposes are still scarce [11] despite the fact that the diaryl- ethene moiety offers advantages in terms of the thermo- stability of both isomers, and high fatigue resistance. [12] This fact is attributable to the relatively modest light-induced structural changes in the diarylethene fragment. Since small changes can usually be accommodated by a flexible peptido- mimetic backbone, the pronounced structural rearrange- ments that would be necessary to affect biological activity might not be readily attained. Nevertheless, it has been possible to photoregulate biological activity through the use of diarylethene derivatives. By exploiting the differences in molecular flexibility between the “open” and “closed” forms, diarylethene-based two-pronged enzyme inhibitors have been designed and successfully applied. [11a,b] We and others [11d] have hypothesized that photoisomeri- zation of the diarylethene unit could lead to significant Figure 1. Two classes of molecular photoswitching fragments: azoben- zenes (A) and diarylethenes (B). R 1 ,R 4 = H, alkyl, or aryl; R 2 ,R 3 = alkyl; Y = S, O or N. [*] O. Babii, Dr. M. Berditsch, Dr. V. S. Kubyshkin, Prof. A. S. Ulrich Karlsruhe Institute of Technology (KIT) Institute of Organic Chemistry and CFN Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany) Dr. S. Afonin, S. Reiber, Prof. A. S. Ulrich Institute of Biological Interfaces (IBG-2), KIT, POB 3640, 76021 Karlsruhe (Germany) E-mail: Anne.Ulrich@kit.edu Homepage: http://www.ibg.kit.edu/nmr/ S. Reiber, Dr. T. Steinbrecher Department of Theoretical Chemical Biology, Institute of Physical Chemistry, KIT, Kaiserstr. 12, 76131 Karlsruhe (Germany) Prof. I. V. Komarov Institute of High Technologies (IHT) Taras Shevchenko National University of Kyiv Vul. Volodymyrska 60, 01601 Kyiv (Ukraine) E-mail: ik214@yahoo.com Homepage: http://418lab.chem.univ.kiev.ua Dr. P. K. Mykhailiuk Faculty of Chemistry, Taras Shevchenko National University of Kyiv Vul. Volodymyrska 64, 01601 Kyiv (Ukraine); Enamine Ltd., Vul. Oleksandra Matrosova 23, 01103 Kyiv (Ukraine) [**] This manuscript is dedicated to the 72nd anniversary of the antimicrobial peptide gramicidin S discovery. We thank Dr. D. Sysoev for discussions and advice on the synthesis of compound 1. O.B. is grateful to KHYS for a fellowship. Financial assistance from Enamine Ltd. (http://www.enamine.net) is also acknowledged. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201310019. . Angewandte Communications 3392  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2014, 53, 3392 –3395