DPP4-directed therapeutic strategies for MERS-CoV.

Christian Drosten and colleages provided the first complete virological profile of a patient infected with Middle East respiratory syndrome coronavirus (MERS-CoV). Previous study findings have shown that dipeptidyl peptidase 4 (DPP4; also known as CD26) serves as the functional receptor for MERS-CoV. In view of the importance of DPP4 in regulating immune responses, inhibitors of DPP4 binding and activity could modulate the pathogenesis of viral infection and serve as potential therapeutics.

Targeting of the site between the binding domain on the virus surface and the receptor might provide pharmacological action to suppress MERS-CoV infection. Studies have provided new insights into DPP4 interaction with substrates and inhibitors, and numerous inhibitors with varying selectivity have been characterised in DPP4 binding and functional assays. Additionally, on the basis of our work on the use of DPP4 inhibitors as a treatment for autoimmune disease, DPP4 inhibition could suppress the damaging aspects of the body's own antiviral immune response by modulating inflammation. Reversible inhibitors of DPP4 enzymatic activity suppress T-cell proliferation and production of proinflammatory cytokines as well as interleukin 10. As we have shown, DPP4 inhibitor-mediated suppression acts partly through the induction of transforming growth factor β 1 (TGFβ1) production by effector T cells. Consistent with this mechanism, we noted a significant increase of TGFβ1 concentrations in tissue and plasma of mice treated with DPP4 inhibitors. TGFβ1 induction at the site of inflammation could be an additional therapeutic benefit of DPP4 inhibitor treatment, because TGFβ1 is an essential regulator of immune responses in severe respiratory infections. Notably, Carlson and colleagues reported that injection of TGFβ1 delayed mortality and reduced viral titres of mice infected with H5N1 influenza virus, whereas neutralisation of TGFβ1 during H5N1 and pandemic 2009 H1N1 infection had opposing effects.

As a caveat, a side-effect of DPP4 inhibitor treatment could be suppression of immunity mediated by effector T cells. This action could limit their use in severe infection because it might inhibit the protective antiviral immune response.

In sum, it could well be worthwhile to establish the antiviral action of various DPP4 inhibitors through in-vitro and preclinical testing and, depending on the results, cautiously to examine their potential therapeutic effect in severe viral infections, including infection by MERS-CoV.