Dipeptidyl Peptidase-4 Inhibition in SARS-CoV-2 Infection

Dipeptidyl peptidase-4 (DPP4), also known as CD26, is a multifunctional serine protease expressed on numerous cell types and circulating in a soluble form. Beyond its established role in glucose homeostasis and incretin inactivation, DPP4 has been implicated as an entry co-receptor for certain coronaviruses and as a modulator of innate and adaptive immune responses. In the context of SARS-CoV-2, mounting evidence has explored whether the viral spike protein can engage DPP4 in addition to the primary receptor ACE2. Computational and biophysical studies have sought to clarify the strength and nature of this interaction, revealing variant-specific nuances and potential links to disease severity in patients with comorbidities. Meanwhile, pharmacological inhibition of DPP4—via the so-called gliptins—has attracted attention for its dual capacity to temper inflammatory cascades and improve glycaemic control in vulnerable populations. Emerging work combines network biology, structural modelling and clinical observations to define how DPP4 inhibitors might attenuate viral entry, modulate cytokine release and prevent long-term organ damage, thereby informing repurposing efforts and the rational design of novel antiviral strategies.

Research from Nature Portfolio

A recent protein-interaction network analysis mapped the landscape of DPP4-related targets in patients with diabetes mellitus, a group at heightened risk for severe COVID-19. By integrating high-confidence diabetes targets with DPP4 in silico, researchers identified three functional modules: one centred on insulin secretion and glucagon signalling, and two associated with receptor binding and inflammatory mediators. Key nodes such as leptin, apolipoprotein B, insulin and interleukin-6 emerged as central to network stability. This systems-level perspective suggests that DPP4 inhibition, perhaps in combination with interleukin-6 antagonists, could not only regulate glycaemia but also blunt SARS-CoV-2-driven hyperinflammation in diabetic individuals.

Dipeptidyl Peptidase-4 Inhibition in SARS-CoV-2 Infection publication trend

The graph below shows the total number of articles in dipeptidyl peptidase-4 inhibition in sars-cov-2 infection across all publications each year (not limited to Nature Index journals).

Technical terms

Dipeptidyl Peptidase-4 (DPP4): A serine protease present on cell surfaces and in soluble form; regulates incretin hormones and modulates immune signalling.

Receptor Binding Domain (RBD): The region of the coronavirus spike protein responsible for recognising and binding host-cell receptors.

Gliptins: A class of small-molecule DPP4 inhibitors approved for the treatment of type 2 diabetes mellitus.

Molecular Docking: A computational technique for predicting the preferred orientation and interaction strength between two molecules, such as a protein and ligand.

Soluble DPP4 (sDPP4): The circulating, cleaved form of DPP4 found in plasma; can act as a decoy receptor for viral particles.

References

1. Unraveling DPP4 Receptor Interactions with SARS-CoV-2 Variants and MERS-CoV: Insights into Pulmonary Disorders via Immunoinformatics and Molecular Dynamics. Viruses (2023).
2. COVID‐19 and comorbidities: A role for dipeptidyl peptidase 4 (DPP4) in disease severity?. Journal of Diabetes (2020).
3. Circulating levels of soluble Dipeptidylpeptidase-4 are reduced in human subjects hospitalized for severe COVID-19 infections. International Journal of Obesity (2020).
4. Does the SARS-CoV-2 Spike Protein Receptor Binding Domain Interact Effectively with the DPP4 (CD26) Receptor? A Molecular Docking Study. International Journal of Molecular Sciences (2021).
5. Interrelationship between 2019-nCov receptor DPP4 and diabetes mellitus targets based on protein interaction network. Scientific Reports (2022).