Developing inexpensive nicotinamide cofactor biomimetics to replace the expensive NAD(P)/H cofactors is an ongoing research activity. Here we present mutational studies on a thermostable glucose dehydrogenase from Saccharolobus solfataricus (SsGDH) using a novel set of synthetic cofactors. Furthermore, we show the successful oxidation of a variety of different sugars in the context of cofactor regeneration. This combined approach resulted in an 160-fold improved system compared to the native enzyme with the standard biomimetic BNA+. These findings pave the way towards competitive industrial utilization of artificial cofactor regeneration systems.