There is an urgent need to develop new therapeutics that safely limit the severity of respiratory viral infections. Severe and fatal influenza virus (IAV) infections are associated with significant viral replication and damaging hyperinflammatory responses which can lead to morbidity, mortality and long-term multi-system organ damage. LAT8881 (is a 16 amino acid synthetic form of the naturally occurring C-terminal fragment of growth hormone (GH). LAT8881 has been previously shown to act independently of the GH receptor to reduce inflammatory damage and promote tissue repair in a rabbit model of arthritis. Additionally, LAT8881 has been investigated in several clinical trials in healthy volunteers and for the treatment of obesity and has an established safety record.
In light of its effects in improving inflammatory damage in animal models, we investigated the potential of LAT8881 and related compounds as a treatment using a pre-clinical mouse model of severe IAV infection (104 PFU HKx31 H3N2). Daily, intranasal delivery of LAT8881 from 1 day following IAV infection significantly reduced disease susceptibility and resulted in a dose dependent reduction in infectious viral loads, innate immune cell infiltrates and pro-inflammatory cytokines in the lungs. LAT8881 treatment also had protective effects with a reduction in alveolar macrophage cell death and ATP levels in the airways. The efficacy of LAT8881 treatment was comparable to that of daily, oral administration of neuraminidase inhibitor, oseltamivir, however, LAT8881 did not hinder IAV replication in vitro, which suggests against a direct antiviral role for the peptide. Intriguingly, similar results are achievable using a small peptide derived from the C-terminus of prolactin, a structural homolog of GH. LAT8881 and similar peptides are potent modulators of influenza disease and are novel candidate therapeutics that limit viral replication and reduce airway hyperinflammation. Furthermore, the demonstrated clinical safety profile of LAT8881 warrants future clinical studies of influenza disease and may facilitate its rapid deployment as a treatment for respiratory virus infections.