DPP4 inhibition: Preventing SARS-CoV-2 infection and/or progression of COVID-19?

Dipeptidyl peptidase 4 (DPP4), also known as cluster of differentiation 26 (CD26), is a serine exopeptidase expressed ubiquitously in several tissues, including but not limited to lung, kidney, liver, gut, and immune cells. The question has been raised on whether DPP4 modulation or inhibition may prevent infection and/or progression of the COVID-19. A docked complex model of the SARS-CoV-2 spike glycoprotein and DPP4 has been proposed, showing a large interface between the proteins and proposing close similarity with other coronaviruses using DPP4 as functional receptor. In absence of experimental validation, these data should be interpreted with caution. Nevertheless, this observation may rise the question on whether DPP4 is directly involved in SARS-CoV-2 cell adhesion/virulence, and whether DPP4 inhibition might be a therapeutic strategy for preventing infection. Although a direct involvement of DPP4 in SARS-CoV-2 infection needs to be clarified, there is also evidence suggesting that DPP4 inhibitors modulate inflammation and exert anti-fibrotic activity. These properties may be of potential use for halting progression to the hyperinflammatory state associated with severe COVID-19. Taken together these findings may suggest a potential role for DPP4 inhibition or modulation in one or more steps of COVID-19 immunopathogenesis.