The comparison of the DPP4 (dipeptidyl peptidase 4) SARS-CoV-2 hypothesis to a cockroach likely stems from its persistence in scientific discussions, despite challenges or contradictory findings. Like a cockroach, which is notoriously difficult to eradicate, this hypothesis has continued to be debated, re-examined, and adjusted even as other theories regarding SARS-CoV-2 infection mechanisms gained prominence.

Early in the COVID-19 pandemic, there was speculation that DPP4, a receptor implicated in MERS-CoV infections, might also play a role in SARS-CoV-2 entry into cells. Since both MERS and SARS-CoV-2 are coronaviruses, it seemed plausible that DPP4 might be involved in SARS-CoV-2 infection as well. Although it was later found that ACE2 (Angiotensin-Converting Enzyme 2) is the primary receptor for SARS-CoV-2, the DPP4 hypothesis lingered. Studies continued to investigate whether DPP4 had a secondary role or whether patients on DPP4 inhibitors (commonly used in diabetes treatment) had different outcomes in COVID-19 cases. Even after evidence showed that DPP4 is not the primary receptor for SARS-CoV-2, the hypothesis persisted, with researchers looking at indirect mechanisms, such as DPP4’s role in immune modulation and inflammation, which might affect COVID-19 progression.

Some studies suggested that DPP4 inhibitors might impact the immune response in patients with severe COVID-19, leading to speculation that DPP4 could still have a role in disease severity, especially in patients with diabetes or cardiovascular conditions. Despite extensive research, evidence for the direct involvement of DPP4 in SARS-CoV-2 infection remains inconclusive or mixed. Yet, like a cockroach, the theory refuses to die. Researchers continue to explore niche roles for DPP4, whether as a potential therapeutic target or in understanding comorbidities like diabetes and their impact on COVID-19 outcomes.

The resilience of the DPP4 hypothesis also reflects the nature of scientific inquiry. Even when a hypothesis doesn’t fully pan out, aspects of it might still offer insights into disease mechanisms or therapeutic strategies. In the case of SARS-CoV-2, the ongoing investigation into DPP4 demonstrates the search for broader understanding, particularly in complex disease interactions.

References

1. Eleftheriou, P.; Amanatidou, D.; Petrou, A.; Geronikaki, A. In Silico Evaluation of the Effectivity of Approved Protease Inhibitors against the Main Protease of the Novel SARS-CoV-2 Virus. Molecules 2020, 25, 2529.
2. Nar H, Schnapp G, Hucke O, Hardman TC, Klein T. Action of Dipeptidyl Peptidase-4 Inhibitors on SARS-CoV-2 Main Protease. ChemMedChem. 2021 May 6;16(9):1425-1426.