DPP-4 Inhibitors May Prevent SARS-CoV-2 Entry into Cells

Function of the DPP-4 Enzyme

The mechanism of action of DPP-4 inhibitors (gliptins) in the treatment of diabetes involves inhibiting the degradation of glucagon-like peptide-1 (GLP-1) by blocking the enzyme dipeptidyl peptidase-4 (DPP-4). DPP-4, also known as CD26, is a transmembrane glycoprotein expressed on the surface of various cell types. Besides its catalytic activity, it functions as a binding protein and ligand for extracellular factors and is involved in numerous physiological processes.

Occurrence of DPP-4 in the Human Body

It has been found that SARS-CoV-2 uses DPP-4, similar to another human coronavirus MERS-CoV, in addition to angiotensin-converting enzyme 2 (ACE2) to penetrate human cells. DPP-4 is expressed by immune cells, epithelial cells, endothelial cells in systemic circulation, cells of the kidneys, small intestine, lungs, pancreas, spleen, and heart, smooth muscle cells, and hepatocytes, and it is also soluble in plasma.

Importance of DPP-4 in COVID-19 Disease

Current findings show that the aggressive impact of coronaviruses on tissues and organs is at least partially modulated by DPP-4. The distribution of DPP-4 in the human respiratory tract may facilitate the virus's entry into airway tissues and contribute to the development of a cytokine storm and immunopathological processes leading to fatal pneumonia in COVID-19 disease. Therefore, inhibiting DPP-4 could counteract this mechanism and prevent the virus's entry and replication in the respiratory tract.

Conclusion

Italian authors in their recent article hypothesize that DPP-4 inhibition by gliptins, especially drugs with high selectivity for DPP-4, could be a novel simple strategy aiding the treatment of COVID-19 in patients with and without diabetes.

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Source: Solerte S. B., Di Sabatino A., Galli M., Paolo Fiorina P. Dipeptidyl peptidase-4 (DPP4) inhibition in COVID-19. Acta Diabetol 2020 Jul; 57 (7): 779−783, doi: 10.1007/s00592-020-01539-z.