DPP-4 Inhibitors as a savior for COVID-19 patients with diabetes

Abstract

Diabetic patients are at particular risk of severe COVID-19. Human dipeptidyl peptidase-4 (DPP-4) is a membrane-bound aminopeptidase that regulates insulin release by inactivating incretin. DPP-4 inhibitors (DPP-4is) are therefore used as oral anti-diabetic drugs to restore normal insulin levels. These molecules also have anti-inflammatory and anti-hypertension effects. Recent studies on the interactions of SARS-CoV-2 spike glycoprotein and DPP-4 predict a possible entry route for SARS-CoV-2. Therefore, DPP-4is could be effective at reducing the virus-induced 'cytokine storm', thereby ceasing inflammatory injury to vital organs. Moreover, DPP-4is may interfere with viral entry into host cells. Herein, we have reviewed the efficacy of DPP-4is as potential repurposed drugs to reduce the severity of SARS-CoV-2 infection in patients with diabetes.

Keywords: SARS-CoV-2; TLR4 signaling; cytokine storm; diabetes; dipeptidyl peptidase-4 (DPP-4); gliptins.

Figure 1.. Entry of SARS-CoV-2 in host cell using DPP-4.

Furin and TMPRSS2 are host cell proteases that cleave specific target regions in virus spike glycoprotein and promote endocytosis into host cells. Domain structure of SARS-CoV-2 spike glycoprotein with furin and TMPRSS2 cleavage sites are also shown.

Figure 2.. Hypothetical illustration of how SARS-CoV-2 interacts with membrane-bound DPP-4/CD26 to facilitate the entry of the virus into the host cells, for example the epithelial cells of alveoli.

Viral spike glycoprotein can bind to both soluble and membrane-bound receptor. Binding of spike protein to membrane-bound DPP-4 facilitates the viral entry to the target cell. The exact domain of DPP-4 wherein the spike protein occupies, is an open question. Potential interactive residues between DPP-4 and SARS-CoV-2 spike RBD have been shown [11].

Figure 3.. DPP-4 inhibitors targeting TLR4 mediated immunopathogenesis of COVID-19. DPP-4 inhibitors mediated therapeutic strategies to target human TLR4, NF-κB, ERK, NLR-P3/ASC and T-cell activation against SARS-CoV-2 and to protect multiorgan damage.

The anti-DPP-4 drug sitagliptin can directly binds to TLR4 to inhibit the downstream inflammatory cascade while alogliptin inhibits ERK which is one of crucial the downstream signaling mediator originated of TLR4 signaling pathway. In direct inhibitory effects of the gliptins on the T cell-induced secretion of the pro-inflammatory cytokines has also been presented. These inhibitory actions could be useful in mitigating the cytokine storm in the COVID-19 patients. Inhibition of ERK plays useful role in limiting the effects of the MMPs on the blood vessels and also blocks the activation of AP-1 mediated synthesis of the inflammatory molecules. Linagliptin has inhibitory effects on the NLRP3-mediated activation of IL-1β which in turn prevents cardiac inflammation in COVID-19 patients.