Diarylethene-Based Photoswitchable Inhibitors of Serine Proteases.

Oleg Babii,Anne S Ulrich,Serhii Koniev,Igor V Komarov,Sergii Afonin,Jennifer Dommermuth,Andrii Hrebonkin,Marcel Huhn,Alexander Nesterov‐Mueller,Tim Schober,Christian Diel

doi:10.1002/anie.202108847

Abstract

A bicyclic peptide scaffold was chemically adapted to generate diarylethene‐based photoswitchable inhibitors of serine protease Bos taurus trypsin 1 (T1). Starting from a prototype molecule—sunflower trypsin inhibitor‐1 (SFTI‐1)—we obtained light‐controllable inhibitors of T1 with Ki in the low nanomolar range, whose activity could be modulated over 20‐fold by irradiation. The inhibitory potency as well as resistance to proteolytic degradation were systematically studied on a series of 17 SFTI‐1 analogues. The hydrogen bond network that stabilizes the structure of inhibitors and possibly the enzyme–inhibitor binding dynamics were affected by isomerization of the photoswitch. The feasibility of manipulating enzyme activity in time and space was demonstrated by controlled digestion of gelatin‐based hydrogel and an antimicrobial peptide BP100‐RW. Finally, our design principles of diarylethene photoswitches are shown to apply also for the development of other serine protease inhibitors.

Highlights

Oleg Babii,* Sergii Afonin, Christian Diel, Marcel Huhn, Jennifer Dommermuth, Tim Schober, Serhii Koniev, Andrii Hrebonkin, Alexander Nesterov-Mueller, Igor V
When designing the analogues of the sunflower trypsin inhibitor-1 (SFTI-1), we relied on the known mechanism of inhibition and the relationship between structure and activity of SFTI-1.[9,15] We considered the changes in molecular dynamics that the diarylethene moiety causes upon photoisomerization.[5e,16] SFTI-1 inhibits trypsin by the Laskovski mechanism,[17] that is, it binds tightly to the protease (Figure 2 A) but resists hydrolysis, thereby blocking the enzyme
Modifications of the reactive loop are known to drastically deteriorate the inhibitory activity, while the structural loop can be modified without substantial activity drop.[13a,19] we incorporated the photoswitch within the structural loop of SFTI-1, using building block 1 (Figure 3) developed previously by us.[20]

Summary

Introduction

Oleg Babii,* Sergii Afonin, Christian Diel, Marcel Huhn, Jennifer Dommermuth, Tim Schober, Serhii Koniev, Andrii Hrebonkin, Alexander Nesterov-Mueller, Igor V. One (Figure 1 A) is based on the incorporation of a photoisomerizable fragment (photoswitch) into a known inhibitor as part of the enzyme-binding moiety.

Results

Conclusion