Dipeptidyl-Peptidase 4 (Cd26): a Possible Therapeutic Target in Covid-19

ARS-COV-2, a novel β-coronavirus, is the cause of a severe inflammatory infectious disease of the respiratory tract (COVID-19). The spread has already taken on pandemic proportions, affecting over 2,5 million people and causing more than 170,000 deaths. The mechanisms and strategies underlying the virus power of penetrating human cells and causing the well-known spectrum of diseases induced by SARS-COV-2 have been explored worldwide. Two host receptors able to specifically inducing virus-host linkage, entry and, consequently, productive infection, have been suggested to interact with the outer membrane spike viral glycoprotein: the angiotensin converting enzyme 2 (ACE2) and the dipeptidyl-peptidase 4 (DPP4), also known as CD26. Both these receptors are highly expressed on several human tissues (i.e. kidney, pancreas, gut, lung, endothelium, pleura, myocardium, connective tissue) accounting for the variable clinical manifestations of COVID-19. CD26 is also over-expressed in stimulated T, B, and NK cells, thus representing an activation marker of the immune system. However, CD26 is not only the functional host receptor for SARS- CoV-2. Indeed, published data available from the previous SARS-CoV and MERS-CoV outbreaks showed that CD26 is also utilized for sustaining inflammation and counteracting the host immune response. Specifically, through CD26, coronavirus may increase inflammatory cytokine production, down- modulate the autophagy, and increase levels of adenosine, hence further deactivating the host immune response. Thus, compounds able to inhibit the DPP4/CD26 pathway might be useful against COVID-19. In this respect, promising therapeutic approaches could include: 1) DPP4 inhibitors, such as sitagliptin, already used for treating diabetic patients; 2) Begelomab, the anti-CD26 monoclonal antibody already successfully employed in the treatment of graft-versus-host disease, and 3) adenosine deaminase agonists, already used in the immunodeficiencies sustained by the adenosine deaminase gene mutations. The article will review some pathogenic landscapes and will hypothesize some promising drugs to face the COVID-19 emergency.