10 Aptamers for Thrombotic Diseases
307
Fig. 10.9 Structural basis of the antithrombotic mechanism of aptamer ARC1172. a ARC1172-A1
complex with the surface of A1 domain, negative and positive electrostatic potential colored in red
and blue, respectively. b Yellow: the surface of vWF A1within 4.2 Åof ARC1172. c Magenta: the
surface of vWF A1in contact with GPIba. The yellow dashed line: the surface of vWF A1in contact
withARC1172. d Surface of vWF A1 domain binding to botrocetin (cyan) and GPIba (magenta),
suggesting similar binding sites both botrocetin and ARC1172. e Stereoview of vWF A1 complexed
with ARC1172 (yellow cartoon) and GPIba (magenta) would clash upon binding to vWF A1 domain.
The A1 domain has the same orientation in (A, D, and E), and is turned approximately 90° around
the vertical axis in (Band C). Reprinted with permission from Ref. [123]
In another report, in vivo activity and in vitro inhibition of vWF-induced platelet
aggregation by ARC1779 was determined in a cynomolgus monkey carotid electrical
injury thrombosis model. The investigation revealed that ARC1779 inhibited platelet
aggregation and reduced platelet adhesion to collagen-coated matrices, as well as
inhibited the formation of occlusive thrombi in cynomolgus monkeys. These studies
indicated that ARC1779 holds potential as an anti-vWF agent in vWF-mediated
thrombosis, in particular, ACS [124].
Furthermore, the phase 1 clinical study conducted in 47 healthy volunteers demonstrated that ARC1779 dose/concentration-dependently inhibited vWF activity and
platelet function with durative effect and without serious adverse events, such as
bleeding and deaths [126]. In the patients of double antiplatelet therapy for CAD,
platelet adhesion was significantly reduced after treatment of ARC1779 while platelet
aggregation was not affected [127]. In phase 2 clinical trials, intravenous injection
of ARC1779 was effective in reducing cerebral embolism in 36 patients undergoing carotid endarterectomy (CEA). However, increased perioperative bleeding
307
Fig. 10.9 Structural basis of the antithrombotic mechanism of aptamer ARC1172. a ARC1172-A1
complex with the surface of A1 domain, negative and positive electrostatic potential colored in red
and blue, respectively. b Yellow: the surface of vWF A1within 4.2 Åof ARC1172. c Magenta: the
surface of vWF A1in contact with GPIba. The yellow dashed line: the surface of vWF A1in contact
withARC1172. d Surface of vWF A1 domain binding to botrocetin (cyan) and GPIba (magenta),
suggesting similar binding sites both botrocetin and ARC1172. e Stereoview of vWF A1 complexed
with ARC1172 (yellow cartoon) and GPIba (magenta) would clash upon binding to vWF A1 domain.
The A1 domain has the same orientation in (A, D, and E), and is turned approximately 90° around
the vertical axis in (Band C). Reprinted with permission from Ref. [123]
In another report, in vivo activity and in vitro inhibition of vWF-induced platelet
aggregation by ARC1779 was determined in a cynomolgus monkey carotid electrical
injury thrombosis model. The investigation revealed that ARC1779 inhibited platelet
aggregation and reduced platelet adhesion to collagen-coated matrices, as well as
inhibited the formation of occlusive thrombi in cynomolgus monkeys. These studies
indicated that ARC1779 holds potential as an anti-vWF agent in vWF-mediated
thrombosis, in particular, ACS [124].
Furthermore, the phase 1 clinical study conducted in 47 healthy volunteers demonstrated that ARC1779 dose/concentration-dependently inhibited vWF activity and
platelet function with durative effect and without serious adverse events, such as
bleeding and deaths [126]. In the patients of double antiplatelet therapy for CAD,
platelet adhesion was significantly reduced after treatment of ARC1779 while platelet
aggregation was not affected [127]. In phase 2 clinical trials, intravenous injection
of ARC1779 was effective in reducing cerebral embolism in 36 patients undergoing carotid endarterectomy (CEA). However, increased perioperative bleeding