Arg-Gly-Asp (RGD) is a unique minimal integrin-binding sequence that is found within several glycoprotein ligands. This sequence has also been found in snake-venom anti-platelet proteins, including the disintegrins and dendroaspin, a natural variant of short-chain neurotoxins isolated from the venom of Dendroaspis jamesonii. In the present study, the motifs RYD and RCD were introduced into the dendroaspin scaffold to replace RGD. Both motifs in dendroaspin caused inhibition of ADP-induced platelet aggregation with IC50 values of 200 and 300nM respectively, similar to that of the wild-type RGD motif (170nM). In comparison with wild-type dendroaspin, both RYD- and RCD-containing dendroaspins were more selective in the inhibition of the adhesion of K562 cells to laminin rather than to fibrinogen and fibronectin, even though they were 10–30-fold less potent at inhibiting K562 cell (containing α5β1 integrin) adhesion to laminin compared with wild-type. Interestingly, the RYD motif produced a similar IC50 value to the RGD motif at inhibiting A375-SM cell (β3 integrin) adhesion to collagen, whereas the RCD motif was approx. 2–6-fold less potent compared with either RGD or RYD. These findings show that the selectivity of dendroaspin binding to β1 and β3 integrins can be modulated by the introduction of alternative cell recognition sequences.

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