Table 1

Novel antiplatelet agents targeting GPIb, GPIIb/IIIa and GPVI mechanosensing axes

AxisTargetAgentDescriptionAntithrombotic effectPhase of developmentClinical trials gov identifierReferences
GPIbVWFLp (Q1238-E1260)The N-terminal polypeptide sequence of VWF-A1 that autoinhibits VWF-A1 binding to platelet GPIb.Inhibits platelet attachment on VWF in whole blood perfusion in vitro.Preclinical 57
14-3-3ζMPαCDesigned based on the 14-3-3ζ-binding sequence in GPIbα. Blocks 14-3-3ζ binding to GPIbα.Weakens GPIbα-VWF interaction and inhibits GPIbα mechanosignalling.Preclinical 92 93
VWFBAX 930Recombinant ADAMTS13; cleaves VWF at A2 domain to weaken its activity.Inhibits arterial thrombosis.IIINCT03393975 88 89
VWFNMC4A monoclonal antibody against VWF-A1.Inhibits arterial thrombosis.Preclinical 73
VWFCaplacizumabA nanobody against VWF-A1.Showed inhibitory effects on thrombosis in primate models without causing adverse side effects.FDA approved 71 72
VWFARC1779An anti-VWF aptamer.Showed encouraging results in inhibiting thrombosis.II (terminated)NCT00742612 75 85
GPIbαp0p/BAn antibody against GPIbα.Dramatically reduces infarct volumes in cerebral ischaemia model.Preclinical 77
GPIbαH6B4An antibody against GPIbα.Inhibits high-shear arterial thrombosis in baboons without causing adverse side effects.Preclinical 76
GPIbαGPG-290A recombinant human GPIbα chimeric protein which blocks GPIbα binding to VWF.Inhibits coronary artery thrombosis in a canine model.Preclinical 74
GPIbαagkistinBlocks GPIbα binding to VWF.Reduces thrombus formation under arterial shear conditions.Preclinical 78
GPIbαAnfibatideInhibits both VWF and α-thrombin binding to GPIbα.In experimental models, inhibits platelet adhesion, aggregation and thrombus formation without increasing bleeding time.I, IINCT01585259 79
GPIIb/IIIaPI3KβAZD6482Inhibits PI3Kβ downstream GPIIb/IIIa mechanosignaling and shear-induced platelet activation.Inhibits thrombus formation in vivo in preclinical models with minimal effects on bleeding.INCT00853450 138
13 mP6 A myristoylated peptide (Myr-FEEERA) that inhibits association of Gα13 with integrin β3 cytoplasmic tail and suppresses the early phase of GPIIb/IIIa outside-in signalling.Inhibits platelet spreading and thrombus formation in preclinical models with no effects on bleeding time.Preclinical 104
PDIIsoquercetinInhibits PDI activity in plasma and decreases platelet-dependent thrombin generation; also reduces levels of coagulation markers at higher doses.Inhibits platelet thrombus formation and fibrin formation in preclinical models. Partial inhibition does not cause serious bleeding.II–IIINCT02195232 141
Active GPIIb/IIIascFv SCE5Single-chain antibody that specifically inhibits the active conformation of GPIIb/IIIa; can also be used to deliver clot-directed thrombolytic, antiplatelet and anticoagulant agents.Inhibits platelet aggregation and thrombus formation in preclinical models without major increase in bleeding time.Preclinical 145
GPIIb/IIIaRUC-4A small molecule that binds to the metal ion-binding site on the GPIIIa without causing major conformational changes; specific to GPIIb/IIIa (αIIbβ3) over αVβ3 integrins.Inhibits platelet aggregation and thrombus formation in preclinical models; effects on bleeding not yet evaluated.INCT03844191 150
GPIIb/IIIaPSI A1, PSI B1, PSI C1, PSI E1Antibodies against GPIIIa PSI domain, inhibiting its thiol isomerase function.Inhibits platelet aggregation and thrombus formation in preclinical models.Preclinical 128
GPVIGPVI9O12A monoclonal antibody Fab that blocks the collagen/fibrin-binding site of GPVI with high affinity. The recombinant scFv version is also available.Inhibits thrombosis and appears to maintain haemostasis in preclinical models.Preclinical 163
CollagenRevaceptDimeric GPVI-Fc that blocks vascular collagen at sites of plaque or vascular erosion and collagen-induced platelet activationInhibits platelet thrombus formation at sites of vascular injury in preclinical models; no effect on bleeding time.I, IINCT01645306 165
GPVILosartan (DuP-753)An angiotensin II (Ang II) type I receptor (AT1R) antagonist that has been reported to exert an anti-platelet activity besides its antihypertensive effect.Inhibits platelet adhesion to collagen and subsequent collagen induced platelet activation and aggregation via GPVI.IVNCT00805311 169
  • PDI, protein disulfide isomerase; scFv, single-chain variable fragment.