Action of Dipeptidyl Peptidase‐4 Inhibitors on SARS‐CoV‐2 Main Protease

In a recent publication, Eleftheriou et al. proposed that inhibitors of dipeptidyl peptidase‐4 (DPP‐4) are functional inhibitors of the main protease (Mpro) of SARS‐CoV‐2. Their predictions prompted the authors to suggest linagliptin, a DPP‐4 inhibitor and approved anti‐diabetes drug, as a repurposed drug candidate against the ongoing COVID‐19 pandemic. We used an enzymatic assay measuring the inhibition of Mpro catalytic activity in the presence of four different commercially available gliptins (linagliptin, sitagliptin, alogliptin and saxagliptin) and several structural analogues of linagliptin to study the binding of DPP‐4 inhibitors to Mpro and their functional activity. We show here that DPP‐4 inhibitors like linagliptin, other gliptins and structural analogues are inactive against Mpro. Getting a second opinion: In‐silico docking analysis of the main protease (Mpro) of the SARS‐CoV‐2 structure has suggested that it may be blocked by commercial dipeptidyl peptidase‐4 inhibitors. We used an assay measuring inhibition of Mpro catalytic activity in the presence of four different DPP‐4 inhibitors, measuring binding to Mpro and functional activity. No activity against Mpro was observed.