key: cord-0932353-yyk6af7u authors: Pitocco, Dario; Tartaglione, Linda; Viti, Luca; Di Leo, Mauro; Pontecorvi, Alfredo; Caputo, Salvatore title: SARS-CoV-2 and DPP4 inhibition: is it time to pray for Janus Bifrons? date: 2020-04-23 journal: Diabetes Res Clin Pract DOI: 10.1016/j.diabres.2020.108162 sha: fd2b6e82c69e8f6544f1afbf629df30fe6897549 doc_id: 932353 cord_uid: yyk6af7u Abstract Diabetes could be a risk factor for severity and mortality in patients with coronavirus disease 2019 Covid-19. It has been hypothesized that DPP4 inhibition, a therapy currently available for type 2 diabetes, might represent a target for decreasing the risk of the acute respiratory complications of the COVID-19 infection but 1) lack of demonstration of SARS-CoV2 binding to DPP4 2) possible protective role of sDPP4 in Middle East respiratory Syndrome (MERS-CoV 3) demonstrated inhibition and downregulation of DPP4 by HIV1 and MERS-CoV and 4) not exclusive role of the receptor binding in tropism of the Coronavirus family, support that DPP4 inhibition at present doesn’t represent a plausible approach to mitigate Covid-19. Dario Pitocco 1 *, Linda Tartaglione A recent commentary on Diabetes Research and Clinical Practice described the interplay between the Middle East Respiratory Syndrome (MERS-CoV), another coronavirus responsible for an outbreak of acute respiratory syndrome, and human dipeptidyl peptidase 4 (DPP4) identified as a functional receptor for virus spike protein 3 . It has been interestingly hypothesized that DPP4 inhibition, a therapy currently available for type 2 diabetes, might represent a target for decreasing the risk of the acute respiratory complications of the COVID-19, but, unfortunately, this hypothesis is on the basis of another hypothesis. To the best of our knowledge, no one has yet shown that DPP4 is a possible receptor for SARS-COV2. On the contrary most recent data exclude this possibility, confirming that human angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV2, in analogy to SARS-CoV 4 . DPP4, like the ancient roman god Janus Bifrons (Two-Faced), is a dual and multifunctional molecule: it exists as soluble form (sDPP4) in the circulation 5 , but also as a type II transmembrane glycoprotein located on endothelial, epithelial cells and immune cells (CD26) 6 . DPP4 in the bloodstream and at surface membrane rapidly inactivates biologically active molecules as gastrointestinal hormones, neuropeptides and chemokines, but in some cases shifts their receptor preference and thus modifies their functional activity. In addition to enzymatic cleavage, CD26 executes other multiple physiological mechanisms, as adhesion to extracellular matrix proteins, and it plays a co-stimulatory role in T-cell maturation, activation and interaction with antigen-presenting cells. Thus, DPP4 inhibition is associated with some degree of immune suppression and may be useful in some autoimmune diseases 7 . However, in most patients long-term immune suppression, albeit mild, could represent an undesirable side effect 8 . We described a case of a type 2 diabetes subject with a severe leucopenia as a consequence of DPP4 inhibitor Sitagliptin therapy 9 . In diabetic subjects treated with DPP4 inhibitors there is no increase in respiratory tract infections 10 , but we want to highlight that they could produce respiratory side effects as angioedema 11 , rhinorrhea 12 , cough and dyspnea 13 , as consequences of reduced degradation of bradykinin and substance P. MERS is another example of DPP4 ambivalence. As expected, human DPP4 transgenic mice following MERS-CoV infection develop an acute inflammatory response of the lung with progressive pulmonary fibrosis 14 . However hDPP4+/+ mice were more resistant than hDPP4+/− mice to MERS-CoV infection, as judged from increased LD50, reduced lung viral infection, attenuated morbidity and mortality, and reduced histopathology 15 . A possible explanation of this paradoxical protective effect of DPP4 against MERS-CoV is that the soluble DPP4 can act as a "buffer" competitively inhibiting virus entry into host cells. In fact, in human patients affected by MERS there is a reduction in circulating levels of sDDP4 with an inverse relationship with IL-10 level. In support of an antiviral effect of sDPP4, the authors demonstrated that viral infection was inhibited by 50% in the presence of more than 8000 ng/ml of sDPP4 16 Finally, virus tropism is a complex phenomenon. In the case of the Coronavirus family, while understanding the expression pattern of the receptor can define which cells can be infected, it does not mean all cells that express the receptor or even the cells with the highest expression are the major targets. In the case of ACE2 the human lung is the 22 th tissue for the amount of receptors 20 . Probably is not only the spike protein that impacts on tissue tropism; other "background genes," including nucleocapsid, replicase and accessory genes, are also important determinants of tropism. In conclusion, 1) lack of demonstration of SARS-CoV2 binding to DPP4 2) possible protective role of Funding. The authors did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Characteristic of and important lessons from the Coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention COVID-19 and diabetes: can DPP4 inhibition play a role? Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses A new dipeptide naphthylamidase hydrolyzing glycil-prolyl-beta-naphthylamide CD26: a surface protease involved in T-cell activation Role of CD26/dipeptidyl peptidase IV in human T cell activation and function Inhibition of multifunctional dipeptodyl peptidase-IV: is there a risk of oncological and immunological adverse effects? 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