Covid-19 and co-morbidities: a role for Dipeptidyl Peptidase 4 (DPP4) in disease severity?

Bassendine, Margaret F; Bridge, Simon H; McCaughan, Geoffrey W; Gorrell, Mark D

The Covid-19 pandemic is caused by a novel betacoronavirus, SARS-CoV-2, similar to SARS-CoV and MERS-CoV, which cause acute respiratory distress syndrome and case fatalities. Covid-19 disease severity is worse in older obese patients with comorbidities such as diabetes, hypertension, cardiovascular disease and chronic lung disease. Cell binding and entry of betacoronaviruses is via their surface spike glycoprotein; SARS-CoV binds to the metalloprotease angiotensin-converting enzyme 2, abbreviated hereafter to ACE2, MERS-CoV utilises dipeptidyl peptidase 4, abbreviated hereafter to DPP4, and recent modelling of the structure of SARS-CoV-2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. DPP4 is a ubiquitous membrane-bound aminopeptidase that circulates in plasma; it is multifunctional with roles in nutrition, metabolism, immune and endocrine systems. DPP4 activity differentially regulates glucose homeostasis and inflammation via its enzymatic activity and non-enzymatic immunomodulatory effects. The importance of DPP4 for the medical community has been highlighted by the approval of DPP4 inhibitors, or gliptins, for the treatment of Type 2 diabetes mellitus. This review discusses the dysregulation of DPP4 in Covid-19 comorbid conditions; DPP4 activity is higher in older individuals and increased plasma DPP4 is a predictor of the onset of metabolic syndrome. DPP4 upregulation may be a determinant of Covid-19 disease severity, which creates interest regarding the use of gliptins in management of Covid-19. Also, knowledge of the chemistry and biology of DPP4 could be utilised to develop novel therapies to block viral entry of some betacoronaviruses, potentially including SARS-CoV-2. This article is protected by copyright. All rights reserved.