Is sitagliptin effective for SARS-CoV-2 infection: false or true prophecy?

Coronavirus disease 2019 (Covid-19) is caused by severe acute respiratory syndrome type 2 (SARS-CoV-2). Covid-19 is characterized by hyperinflammation, oxidative stress, and multi-organ injury (MOI) such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Covid-19 is mainly presented with respiratory manifestations; however, extra-pulmonary manifestations may also occur. Extra-pulmonary manifestations of Covid-19 are numerous including: neurological, cardiovascular, renal, endocrine, and hematological complications. Notably, a cluster of differentiation 26 (CD26) or dipeptidyl peptidase-4 (DPP-4) emerged as a new receptor for entry of SARS-CoV-2. Therefore, DPP-4 inhibitors like sitagliptin could be effective in treating Covid-19. Hence, we aimed in the present critical review to assess the potential role of sitagliptin in Covid-19. DPP-4 inhibitors are effective against the increased severity of SARS-CoV-2 infections. Moreover, DPP-4 inhibitors inhibit the interaction between DPP-4 and scaffolding proteins which are essential for endosome formation and replication of SARS-CoV-2. Therefore, sitagliptin through attenuation of the inflammatory signaling pathway and augmentation of stromal-derived factor-1 (SDF-1) may decrease the pathogenesis of SARS-CoV-2 infection and could be a possible therapeutic modality in treating Covid-19 patients. In conclusion, the DPP-4 receptor is regarded as a potential receptor for the binding and entry of SARS-CoV-2. Inhibition of these receptors by the DPP-4 inhibitor, sitagliptin, can reduce the pathogenesis of the infection caused by SARS-CoV-2 and their associated activation of the inflammatory signaling pathways.

Of interest, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor and entry-point in the host cells (Al-Kuraishy et al. 2021c). Down-regulation of ACE2 by SARS-CoV-2 induces dysregulation of the renin-angiotensin system with augmentation of vasoconstrictor angiotensin II (AngII) and reduction of vasodilator of Ang1-7 (Schmidt et al. 2022).
These changes together with the oxidative and inflammatory disorders can cause endothelial dysfunction, coagulation disorders, and the development of critical ALI/ARDS (Al-Kuraishy et al. 2021b).
Notably, the cluster of differentiation 26 (CD26) or dipeptidyl peptidase-4 (DPP-4) emerged as a new receptor for entry of SARS-CoV-2 (Al-Kuraishy et al. 2021e). Therefore, DPP-4 inhibitors like sitagliptin could be effective in treating Covid-19. Thus, the main aim of the present critical review was to assess the potential role of sitagliptin in Covid-19.

DPP-4 inhibitors and viral infections
DPP-4 is highly expressed in different immune cells and they are involved mainly in the regulation of blood glucose and inflammation. DPP-4 induces cleavage of glucagon-like peptide (GLP-1) and other incretins (Al-Kuraishy et al. 2020). DPP-4 inhibitors are widely used and tolerated in the management of type 2 diabetes mellitus (T2DM) with minimal or no hypoglycemia as an adverse effect (Al-Kuraishy et al. 2020). DPP-4 receptors are also involved in the regulation of other biological processes like immune response during viral infections owing to their expression on T cells, B cells, natural killer (NK) cells (Elekhnawy et al. 2021a), and macrophages (Amori et al. 2007) as shown in Fig. 1.
Previous meta-analyses illustrated that using of DPP-4 inhibitors was linked with a higher risk of respiratory viral infections (Amori et al. 2007). Similarly, a controlled study depended on the database of the World Health Organization (WHO) also implicates the use of DPP-4 inhibitors in increasing the risk of different viral infections (Yang et al. 2016). However, a recent meta-analysis by Yang et al. (2016) illustrated that uses of DPP-4 inhibitors were not related to increased risk of viral infections as compared with placebo. In addition, there is an updated meta-analysis which showed that that using DPP-4 inhibitors was not linked with a higher risk of respiratory viral infections (Grenet et al. 2021).
The immunological effects of DPP-4 inhibitors are related to the decrease of T cell activity and release of costimulatory chemokines and cytokines with upregulation of immunosuppressive cytokines (Yang et al. 2016;Grenet et al. 2021). Though these effects were not confirmed in experimental and preclinical studies.
These observations suggested that the uses of DPP-4 inhibitors in T2DM patients are safe and do not increase the risk of viral infections. In addition, immunomodulatory effects of DPP-4 inhibitors may reduce exaggeration of the immune response in viral infections; thereby decreasing the risk of immune-mediated tissue injury as in Covid-19 (Al-Kuraishy et al. 2021e).

DPP-4 inhibitors and Covid-19
Many recent studies reported that DPP-4 inhibitors are effective in decreasing the severity of SARS-CoV-2 infections (Al-Kuraishy et al. 2021e;Noh et al. 2021). Of note, DPP-4 receptors are highly expressed in the case of obesity and T2DM (Grenet et al. 2021). Upregulation of DPP-4 receptors in the respiratory tract in obese and T2DM patients increase the risk for SARS-CoV-2 infection (Noh et al. 2021). Thus, overexpression of the membrane-bound DPP-4 increases the entry of SARS-CoV-2 into the host cells and is associated with augmentation of Covid-19 severity (Krejner-Bienias et al. 2021). However, soluble DPP-4 (sDPP-4) which are mainly released from the activated T lymphocytes may have a protective activity by neutralizing SARS-CoV-2 spike protein and preventing the binding with the bounded DPP-4 (Krejner-Bienias et al. 2021). It has been shown that sDPP-4 is decreased in SARS-CoV-2 infection and is correlated with lymphopenia in patients suffering from severe Covid-19 (Krejner-Bienias et al. 2021).
Moreover, DPP-4 inhibitors inhibit the interaction between DPP-4 and scaffolding proteins which are essential for endosome formation and replication of SARS-CoV-2 ( Bardaweel et al. 2021). Furthermore, DPP-4 inhibitors have potent anti-inflammatory effects by reducing interleukin (IL-6) serum levels in Covid-19 patients. This property may diminish the risk of the progress of the cytokine storm (Bardaweel et al. 2021). Remarkably, an Italian prospective study comprising 338 Covid-19 patients revealed that the use of sitagliptin was correlated with a significant reduction in hospitalization time, severity, and mortality (Solerte et al. 2020). A narrative review and meta-analysis demonstrated inconsistent findings on the association between the use of DPP-4 inhibitors and clinical outcomes of Covid-19 patients (Bonora et al. 2021).
In this state, most of after mentioned studies did not discuss the possible beneficial mechanistic pathways of DPP-4 inhibitors in the amelioration of inflammatory signaling pathways in SARS-CoV-2 infection.
Undoubtedly, p38 mitogen-activated protein kinase (p38MAPK) is a pro-inflammatory pathway connected with the progress of ALI and acute cardiac injury in Covid-19 (Al-Kuraishy et al. 2022b). Overactivation of p38MAPK in Covid-19 might be due to down-regulation of ACE2 and upsurge of AngII level. In addition, SARS-CoV-2 can in a straight line activate the p38MAPK signaling pathway causing endothelial dysfunction, vasoconstriction, and thrombosis (Gaohong et al. 2019). Gaohong et al. (2019) confirmed that sitagliptin inhibits p38MAPK signaling pathway-induced renal tubules epithelial cell injury in the experimental animals.
Likewise, the mechanistic target of the rapamycin (mTOR) pathway which is the intimate regulator of cell growth, proliferation, metabolism, and survival is found to be activated during SARS-CoV-2 infection. Moreover, it has a role in the transcription and mRNA translation of SARS-CoV-2 particles . Notably, sitagliptin attenuates cadmium-induced testicular injury by inhibiting the activation of the mTOR pathway in rats (Arab et al. 2021).
Therefore, sitagliptin through attenuation of these inflammatory signaling pathways and augmentation of SDF-1 may decrease the pathogenesis of SARS-CoV-2 infection and could be a possible therapeutic modality in treating Covid-19 patients as shown in Fig. 2.

Conclusions
DPP-4 receptors are highly expressed in T2DM and they are linked with the propagation of the inflammatory disorders. DPP-4 receptors are regarded as potential receptors for binding and entry of SARS-CoV-2. Inhibition of these receptors by the DPP-4 inhibitor, sitagliptin, can reduce the pathogenesis of SARS-CoV-2 infection and the associated activation of the inflammatory signaling pathways. This critical review excites for further clinical and preclinical studies to confirm the potential role of sitagliptin and other DPP-4 inhibitors in Covid-19. Funding M.D.W. thanks the French Agence Nationale de la Recherche and the Région Pays de la Loire for financial support on Covid-19 research (ANR Flash COVID 19 call -name: CoV2-E-TARGET -grant number: 2020 07132).
Data availability All data are available in the manuscript.

Conflict of interest
The authors have no relevant financial or non-financial interests to disclose.
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