Research Article For reprint orders, please contact: reprints@future-science.com Peptide drugs for photopharmacology: how much of a safety advantage can be gained by photocontrol? Oleg Babii 1 , Sergii Afonin 1 , Tim Schober 2 , Liudmyla V Garmanchuk 3 , Liudmyla I Ostapchenko 3 , Volodymyr Yurchenko 4 , Sergey Zozulya 4 , Oleksandr Tarasov 4 , Iryna Pishel 4 , Anne S Ulrich 1,2 & Igor V Komarov* ,4,5,6 1 Karlsruhe Institute of Technology (KIT), Institute of Biological Interfaces (IBG-2), POB 3640, 76021 Karlsruhe, Germany 2 KIT, Institute of Organic Chemistry (IOC), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany 3 Taras Shevchenko National University of Kyiv (TSNUK), Institute of Biology & Medicine, prosp. Hlushkova 2, 03022 Kyiv, Ukraine 4 Enamine Ltd, vul. Chervonotkatska 78, 02066 Kyiv, Ukraine 5 TSNUK, Institute of High Technologies, vul. Volodymyrska 60, 01601 Kyiv, Ukraine 6 Lumobiotics GmbH, Auerstraße 2, 76227 Karlsruhe, Germany *Author for correspondence: Tel.: +380 675 001 151; igor.komarov@lumobiotics.com Aim: To verify whether photocontrol of biological activity could augment safety of a chemotherapeu- tic agent. Materials & methods: LD 50 values for gramicidin S and photoisomeric forms of its photo- switchable diarylethene-containing analogs were determined using mice. The results were compared with data obtained from cell viability measurements taken for the same compounds. Absorption, Distribution, Metabolism, and Elimination (ADME) tests using a murine cancer model were conducted to get insight into the underlying reasons for the observed in vivo toxicity. Results: While in vitro cytotoxicity values of the photoisomers differed substantially, the differences in the observed LD 50 values were less pronounced due to unfavorable pharmacokinetic parameters. Conclusion: Despite unfavorable pharmacokinetic prop- erties as in the representative case studied here, there is an overall advantage to be gained in the safety profle of a chemotherapeutic agent via photocontrol. Nevertheless, optimization of the pharmacokinetic parameters of photoisomers is an important issue to be addressed during the development of photophar- macological drugs. Lay abstract: To critically assess the photopharmacological impact at the cellular and organismal level, systematic toxicity studies were conducted on representative types of photoswitchable drug candidates and their nonphotoswitchable counterparts. We analyzed the in vivo toxicity profles of photocontrollable peptide derivatives of the natural antibiotic gramicidin S by comparing the effects of their two photoiso- meric forms in mice. The LD 50 values of the photoisomers were optimized to differ substantially. Hence, it was concluded that the maximum tolerated dose of the less-toxic isomer could be much higher than that of the parent compound, gramicidin S. This result justifes the use of peptidic photoswitchable compounds for future medical applications and encourages further efforts toward their development. First draft submitted: 17 November 2019; Accepted for publication: 17 January 2020; Published online: 6 February 2020 Keywords: diarylethenes • in vivo toxicity • peptides • peptidomimetics • photocontrollable compound safety • photopharmacology • photoswitchable compounds Photopharmacology is a rapidly expanding and highly innovative area of research focused on the development and application of photocontrollable compounds for therapeutic purposes. Even though the idea of using such compounds for the treatment of human diseases has been around for many decades, recent discoveries and the emergence of enabling technologies have transformed photocontrollable compounds into viable candidates as therapeutic agents in a clinical setting [1–4]. Initially, the term ‘photopharmacology’ referred to the use of photoreactive species as therapeutic agents [5], but that definition has been expanded to take into account current trends in this field. One such area of interest is the use of photoswitchable compounds for medical purposes, as Future Drug. Discov. (2020) 2(1), FDD28 eISSN 2631-3316 10.4155/fdd-2019-0033 C  2020 The authors