Pharmacological targeting of the hyper-inflammatory response to SARS-CoV-2-infected K18-hACE2 mice using a cluster of differentiation 36 receptor modulator.

Preclinical animal study using a transgenic mouse model of SARS-CoV-2 infection

“Transgenic mice possessing the human ACE2 protein, which is expressed under regulation of the human cytokeratin-18 promoter in epithelial cells (K18-hACE2), were treated with a subcutaneous injection of hexarelin (10 μmol/kg) or 0.9% NaCl vehicle 30 min prior to intranasal infection with 250 TCID50 of SARS-CoV-2 (strain Delta, B.1.617.2, National Microbiology Laboratory, Winnipeg, Manitoba, Canada).”

K18-hACE2 transgenic mice

“Transgenic mice possessing the human ACE2 protein, which is expressed under regulation of the human cytokeratin-18 promoter in epithelial cells (K18-hACE2), were treated with a subcutaneous injection of hexarelin (10 μmol/kg) or 0.9% NaCl vehicle 30 min prior to intranasal infection with 250 TCID50 of SARS-CoV-2 (strain Delta, B.1.617.2, National Microbiology Laboratory, Winnipeg, Manitoba, Canada).”

7 mice per group for survival and weight analysis; 3 mice per group for cytokine analysis

“(B) Daily mean body weight of SARS-CoV-2-infected mice expressed as a percentage of body weight at day 0 (n = 7 mice per group).”

9 days of daily treatment following infection

“Thereafter, mice were treated daily with 0.9% NaCl or hexarelin for 9 days.”

Hexarelin treatment increased survival and reduced weight loss in infected mice compared to vehicle-treated mice

“Daily treatment with the CD36 ligand increased survival of the infected mice relative to vehicle-treated mice (Figure 1A).”

Hexarelin treatment significantly reduced levels of specific lung cytokines including CCL2, CCL4, IFN α, and IFN γ

“lung homogenates from the hexarelin-treated infected mice exhibited decreased cytokine levels relative to placebo-treated mice: e.g., CCL2, CCL4, interferon (IFN) α and IFN γ, were significantly reduced by 44%, 59%, 43% and 35%, respectively (Table 1).”

Hexarelin dampened pro-inflammatory pathways, reducing type I interferon activity, chemokine levels, and NLRP3 inflammasome priming

“We have found that the CD36 ligand hexarelin dampened many pro-inflammatory pathways, reducing type I interferon activity, chemokine levels and NLRP3 inflammasome priming.”

Hexarelin exhibits unselective dual binding to both CD36 and the ghrelin receptor (GHS-R1)

“A limitation of our study is the unselective, dual binding of hexarelin towards CD36 and the ghrelin receptor (GHS-R1), both of which are expressed on macrophages.”