Host cell entry receptors as pharmacological targets in respiratory viral infections: from biology to clinical translation
Respiratory viral infections caused by seasonal influenza, respiratory syncytial virus (RSV), and pandemic-potential coronaviruses are responsible for several million hospitalisations and an estimated several hundred thousand deaths each year, a burden underscored by the severe 2024–2025 influenza season and the continued emergence of zoonotic threats such as clade 2.3.4.4b H5N1. This review critically examines the pharmacological basis for targeting host cell-surface receptors as a strategy for the treatment and prophylaxis of respiratory viral infections, evaluates the current evidence for each major receptor axis, and identifies the key translational gaps that must be addressed. Respiratory viruses, including influenza, RSV, SARS-CoV-2, and MERS-CoV, collectively cause millions of hospitalisations annually, and the persistent challenges of antigenic drift, zoonotic emergence, and antiviral resistance highlight the need for mechanistically distinct strategies. Host-directed therapies (HDTs) targeting conserved receptors (ACE2, DPP4, sialic acids, TMPRSS2) exploit genetically stable host factors required for viral entry. Across the receptor axes reviewed here, we appraise more than a dozen candidate agents spanning preclinical development through Phase III evaluation, including TMPRSS2 inhibitors, soluble ACE2 decoys, anti-CD147 and receptor-blocking monoclonal antibodies, the sialidase fusion protein DAS181, and avian IgY preparations. This evidence reveals a consistent gap between robust preclinical activity and as-yet-limited clinical efficacy. We conclude that host receptor targeting is a mechanistically rational but still clinically unproven component of the respiratory antiviral landscape; its value is most plausibly realised in defined niches—prophylaxis, early outpatient treatment, and combination with direct-acting antivirals—and within pandemic preparedness frameworks, provided that the safety, delivery, and trial-design challenges identified here are resolved.