Naturally derived cytokine peptides limit virus replication and severe disease during influenza A virus infection

Abstract

Objectives. Novel host-targeted therapeutics could treat severe influenza A virus (IAV) infections, with reduced risk of drug resistance. LAT8881 is a synthetic form of the naturally occurring C-terminal fragment of human growth hormone. Acting independently of the growth hormone receptor, it can reduce inflammation-induced damage and promote tissue repair in an animal model of osteoarthritis. LAT8881 has been assessed in clinical trials for the treatment of obesity and neuropathy and has an excellent safety profile. We investigated the potential for LAT8881, its metabolite LAT9991F and LAT7771 derived from prolactin, a growth hormone structural homologue, to treat severe IAV infection. Methods. LAT8881, LAT9991F and LAT7771 were evaluated for their effects on cell viability and IAV replication in vitro, as well as their potential to limit disease in a preclinical mouse model of severe IAV infection. Results. In vitro LAT8881 treatment enhanced cell viability, particularly in the presence of cytotoxic stress, which was countered by siRNA inhibition of host lanthionine synthetase C-like proteins. Daily intranasal treatment of mice with LAT8881 or LAT9991F, but not LAT7771, from day 1 postinfection significantly improved influenza disease resistance, which was associated with reduced infectious viral loads, reduced pro-inflammatory cytokines and increased abundance of protective alveolar macrophages. LAT8881 treatment in combination with the antiviral oseltamivir phosphate led to more pronounced reduction in markers of disease severity than treatment with either compound alone. Conclusion. These studies provide the first evidence identifying LAT8881 and LAT9991F as novel host-protective therapies that improve survival, limit viral replication, reduce local inflammation and curtail tissue damage during severe IAV infection. Evaluation of LAT8881 and LAT9991F in other infectious and inflammatory conditions of the airways is warranted.

Investigational Drugs for the Treatment of Postherpetic Neuralgia: Systematic Review of Randomized Controlled Trials

“…LANCL1 and LANCL2 are peptide-modifying enzymes that can promote cell protection and survival by reducing oxidative stress [ 82 ]. Studies at the neuronal level demonstrate that the LANCL1 transgene is neuroprotective by a mechanism related with glutathione [ 83 , 84 , 85 ].…”

“…This molecule is a particularly unique case, as no analgesic properties of a GH fragment were known. In fact, the neuroprotective and antioxidant effects of LAT8881 are not mediated by hormonal activity, they are attributed to its neuroprotective activity via a mechanism dependent on LANCL1 or LANCL2 [ 82 ]. LAT8881 showed efficacy in some preclinical models of inflammatory conditions such as arthritis [ 82 , 91 ], and it also showed good tolerability in both animal and human studies [ 92 , 93 ].…”

“…In fact, the neuroprotective and antioxidant effects of LAT8881 are not mediated by hormonal activity, they are attributed to its neuroprotective activity via a mechanism dependent on LANCL1 or LANCL2 [ 82 ]. LAT8881 showed efficacy in some preclinical models of inflammatory conditions such as arthritis [ 82 , 91 ], and it also showed good tolerability in both animal and human studies [ 92 , 93 ]. The results of the mentioned clinical trial were recently published showing disappointing results (no statistical differences versus placebo were found in any of the evaluated outcomes).…”