Inverting α-glucosidase inhibitors as potential drugs for SARS-CoV-2

Viral infections are still a major challenge in medical therapy. The recent outbreak of SARS-CoV-2 has again shown the immense threat these pathogens pose. In contrast to the direct-acting antivirals approach (targeting viral proteases, polymerases or other viral enzymes involved in replication), which is mostly followed by the pharmaceutical industry, this proposal targeting host cell enzymes involved in the biogenesis of infectious virions. In this context inverting α-glucosidases are of special interest. They play an important role in cell functions, such as the correct folding of proteins in the endoplasmic reticulum (ER). However, up to now selective inverting α-glucosidase inhibitors are scarce, and chemical probes that report on these selectively in biological samples non-existent. The dedicated aim of this proposal is to overcome this absence of inhibitors and probes. To identify novel inhibitors, activity-based protein profiling (ABPP) will be applied. This powerful analytical method is a driving force in chemical biology and medicinal chemistry but depends heavily on the availability of mechanism-based enzyme inhibitors. Based on current knowledge on retaining α-glucosidase inhibitors, unprecedented inhibitors and probes for inverting α-glucosidases will be developed and applied to ABPP. Their synthesis follows a divergent synthesis method to efficiently produce a wide library of compounds, that will be screened on the target enzyme, human ER α-glucosidase I. As the work on retaining α-glycosidase has shown, inverting α-glucosidase inhibitors are likely to be important tools for advancing many areas of application that are outside the primary scope of the proposed research (antiviral agents). Overall, my proposal on inverting α-glycosidase inhibitors and probes will therefore make a significant contribution to the current state of the art in glycan research.