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Inhibition of platelet adhesion, thrombus formation, and fibrin formation by a potent ?IIb?3 integrin inhibitor from ticks.

ABSTRACT:

Background

Ticks puncture the skin of their hosts and secrete saliva, containing antiplatelet proteins, into the blood. Here, we studied disagregin, a potent platelet-inhibiting protein derived from the salivary glands of Ornithodoros moubata, an African soft tick. Whereas conventional ?IIb?3 antagonists contain an Arg-Gly-Asp (RGD) sequence for platelet integrin binding, disagregin contains an Arg-Glu-Asp (RED) sequence, hypothesizing a different mode of inhibitory action.

Objectives

We aimed to compare the inhibitory effects of disagregin and its RGD variant (RGD-disagregin) on platelet activation and to unravel the molecular basis of disagregin-?IIb?3 integrin interactions.

Methods

Disagregin and RGD-disagregin were synthesized by tert-butyloxycarbonyl -based solid-phase peptide synthesis. Effects of both disagregins on platelet aggregation were assessed by light transmission aggregometry in human platelet-rich plasma. Whole-blood thrombus formation was investigated by perfusing blood over collagen I with and without tissue factor at a high wall-shear rate (1000 s^-1) in the presence of disagregin, RGD-disagregin, or eptifibatide.

Results

Disagregin showed inhibition of collagen- and ADP-induced platelet aggregation with half maximal inhibitory concentration values of 64 and 99 nM, respectively. This resembled the complete antiaggregatory effect of eptifibatide. Multiparameter assessment of thrombus formation showed highly suppressed platelet adhesion and aggregate formation with both disagregins, in contrast to eptifibatide treatment, which incompletely blocked aggregation under flow. Fibrin formation under flow was delayed by both disagregin and RGD-disagregin (P < .01) and eptifibatide (P < .05).

Conclusions

Both ?IIb?3-blocking disagregins have a strong potential to suppress collagen-tissue factor-mediated platelet adhesion, thrombus formation, and fibrin formation. Both disagregins can be seen as potential new ?IIb?3 inhibitors.

SUBMITTER: van den Kerkhof DL

PROVIDER: S-EPMC7845065 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Inhibition of platelet adhesion, thrombus formation, and fibrin formation by a potent αIIbβ3 integrin inhibitor from ticks.

van den Kerkhof Danique L DL Nagy Magdolna M Wichapong Kanin K Brouns Sanne L N SLN Heemskerk Johan W M JWM Hackeng Tilman M TM Dijkgraaf Ingrid I

Research and practice in thrombosis and haemostasis 20201218 1

<h4>Background</h4>Ticks puncture the skin of their hosts and secrete saliva, containing antiplatelet proteins, into the blood. Here, we studied disagregin, a potent platelet-inhibiting protein derived from the salivary glands of <i>Ornithodoros moubata</i>, an African soft tick. Whereas conventional αIIbβ3 antagonists contain an Arg-Gly-Asp (RGD) sequence for platelet integrin binding, disagregin contains an Arg-Glu-Asp (RED) sequence, hypothesizing a different mode of inhibitory action.<h4>Obj ...[more]

PMID: 33537548

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