Middle East Respiratory Syndrome Coronavirus spike–Dipeptidyl peptidase 4 protein-protein interaction (MERS-CoV S–DPP4 PPI)

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) spike–Dipeptidyl peptidase 4 (DPP4) protein-protein interaction is the fundamental gateway for MERS-CoV entry into human host cells (1, 4). The viral spike (S) protein, specifically the receptor-binding domain (RBD) located in the S1 subunit, recognizes and binds with high affinity to the β-propeller domain of the host cell receptor DPP4, also known as CD26 (4, 9). This binding event is a prerequisite for subsequent conformational changes and membrane fusion mediated by the S2 subunit, which allows the viral genome to enter the host cytoplasm (1, 2). Because this interaction is essential for initiating infection, it serves as a critical therapeutic target for the development of entry inhibitors, including neutralizing monoclonal antibodies and antiviral peptides (1, 2). Therapeutic strategies targeting this interaction aim to block viral attachment and reduce the viral load, particularly in high-risk patients or as a prophylactic measure (2). While several potent human neutralizing monoclonal antibodies, such as m336 and LCA60, have demonstrated high efficacy in preclinical models by competing for the RBD-binding site, no specific inhibitors are currently approved for clinical use (1). Challenges in targeting this protein-protein interaction include the potential for viral escape through mutations in the RBD and the therapeutic necessity of avoiding interference with the physiological functions of DPP4, such as its role in glucose metabolism and immune regulation (1, 7). Monitoring viral RNA levels and soluble DPP4 concentrations may provide valuable biomarkers for assessing the efficacy of drugs designed to disrupt this complex (2, 7).

Other names

MERS-CoV S–DPP4 complexMERS-CoV RBD–DPP4 interactionMERS-CoV S1–DPP4 interactionMERS-CoV entry complexMiddle East Respiratory Syndrome Coronavirus receptor-binding domain–CD26 interaction

Inhibition of viral entry by competitively blocking the interaction between the MERS-CoV spike protein receptor-binding domain (RBD) and the host cell receptor dipeptidyl peptidase 4 (DPP4)