Abstract
Human rotavirus is the leading cause of severe gastroenteritis in infants and children under the age of 5 years in both developed and developing countries. Human lactadherin, a milk fat globule membrane glycoprotein, inhibits human rotavirus infection in vitro, whereas bovine lactadherin is not active. Moreover, it protects breastfed infants against symptomatic rotavirus infections. To explore the potential antiviral activity of lactadherin sourced by equines, we undertook a proteomic analysis of milk fat globule membrane proteins from donkey milk and elucidated its amino acid sequence. Alignment of the human, bovine, and donkey lactadherin sequences revealed the presence of an Asp-Gly-Glu (DGE) α2β1 integrin-binding motif in the N-terminal domain of donkey sequence only. Because integrin α2β1 plays a critical role during early steps of rotavirus host cell adhesion, we tested a minilibrary of donkey lactadherin-derived peptides containing DGE sequence for anti-rotavirus activity. A 20-amino acid peptide containing both DGE and RGD motifs (named pDGE-RGD) showed the greatest activity, and its mechanism of antiviral action was characterized; pDGE-RGD binds to integrin α2β1 by means of the DGE motif and inhibits rotavirus attachment to the cell surface. These findings suggest the potential anti-rotavirus activity of equine lactadherin and support the feasibility of developing an anti-rotavirus peptide that acts by hindering virus-receptor binding.
Highlights
Human milk lactadherin protects breastfed infants against symptomatic rotavirus infections
Our main focus is on the development of rotavirus inhibitors based on derivative peptides rather than analyzing the full-length protein; one main reason is that it is very unlikely that lactadherin molecules pass through the digestive tract intact, at least not in a relevant amount
The ability of the DGE integrin binding domain to inhibit rotavirus replication can be addressed much more clearly working with small peptides rather than intact proteins, where the tertiary and eventually quaternary structure of the molecule could mask the biological activity of the inner part of some protein segment
Summary
Human milk lactadherin protects breastfed infants against symptomatic rotavirus infections. A 20-amino acid peptide containing both DGE and RGD motifs (named pDGE-RGD) showed the greatest activity, and its mechanism of antiviral action was characterized; pDGE-RGD binds to integrin ␣21 by means of the DGE motif and inhibits rotavirus attachment to the cell surface These findings suggest the potential anti-rotavirus activity of equine lactadherin and support the feasibility of developing an anti-rotavirus peptide that acts by hindering virus-receptor binding. A 20-amino acid peptide containing both DGE and RGD sequence showed the greatest activity, and its mechanism of antiviral action was characterized These findings shed light on the mechanisms of equine lactadherin inhibition of rotavirus infection and support the feasibility of developing an anti-rotavirus peptide that acts through inhibition of virus-receptor binding
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