6 Aptamers for Targeted Therapy
139
and HD22 individually. The inhibition of prothrombin activity by HD1-22 was superior to that of HD1, while the inhibition of thrombin-induced platelet aggregation
was more effective than bivalirudin. The polydopamine connector was employed as
a potent antidote to completely reverse the activity of HD1-22 [76, 84].
15TBA and 31TBA are DNA aptamers that were not docked to the active site
of thrombin. Effective inhibition of fibrin formation and thrombin-induced platelet
aggregation was provided by them without affecting the target enzyme active sites
[85]. In addition, a novel DNA aptamer RE31 has been identified, which was superior
to 31TBA in the inhibition of coagulation via the completely restriction for human
platelet aggregation [86].
Currently, NU172 is the unique anticoagulant aptamer that has been launched in
clinical trials [87]. The structure of thrombin-NU172 complex was shown in Fig. 6.3.
NU172 is an unmodified 26-nt DNA aptamer compared to the conventional modified
optimized therapeutic aptamers for nuclease resistance increase and half-life prolongation in vivo. After SELEX identification and truncation, NU172 was applied to
induce short-term anticoagulation attribute to its anti-thrombin activity. In phase 1b
trials, the anticoagulant effect was rapidly induced and maintained after administration of NU172. Then, the anticoagulant effect was restored to the baseline, indicating
that anticoagulant activity of NU172 could be reversed without antidotes. Phase 2
trials have been initiated to evaluate the efficacy of NU172 in patients undergoing
coronary artery bypass grafting via a median sternal incision, and the results are not
yet available [88].
6.4 Aptamers for Targeted Therapy of Inflammation
6.4.1 Aptamers Targeting Interleukins
6.4.1.1 Interleukin-1
Interleukin-1α (IL-1α) is a member of the cytokine IL-1 family [89]. Studies have
shown that antibody or interleukin-1 receptor antagonist (IL-1RA) blocking IL-1α
has potential applications in the field of human inflammatory diseases and cancer
therapy [90, 91]. In 2017, Xiaoming et al. [92] used 5-(2-naphthylformamide)deoxyuridine (2Nap-dU) instead of dT ssDNA random library to obtain the 17
nt aptamer SL1067 (K D = ∼7.3 nM) of IL-1α through seven rounds of SELEX.
In receptor competitive binding and cellular studies, SL1067 effectively inhibited the signal transduction of IL-1 α/IL-1 receptor pathway. The high-resolution
crystal structure of IL-1α/SL1067 complex was further analyzed, and the molecular
mechanism of affinity and specificity between target and aptamer was deduced.
139
and HD22 individually. The inhibition of prothrombin activity by HD1-22 was superior to that of HD1, while the inhibition of thrombin-induced platelet aggregation
was more effective than bivalirudin. The polydopamine connector was employed as
a potent antidote to completely reverse the activity of HD1-22 [76, 84].
15TBA and 31TBA are DNA aptamers that were not docked to the active site
of thrombin. Effective inhibition of fibrin formation and thrombin-induced platelet
aggregation was provided by them without affecting the target enzyme active sites
[85]. In addition, a novel DNA aptamer RE31 has been identified, which was superior
to 31TBA in the inhibition of coagulation via the completely restriction for human
platelet aggregation [86].
Currently, NU172 is the unique anticoagulant aptamer that has been launched in
clinical trials [87]. The structure of thrombin-NU172 complex was shown in Fig. 6.3.
NU172 is an unmodified 26-nt DNA aptamer compared to the conventional modified
optimized therapeutic aptamers for nuclease resistance increase and half-life prolongation in vivo. After SELEX identification and truncation, NU172 was applied to
induce short-term anticoagulation attribute to its anti-thrombin activity. In phase 1b
trials, the anticoagulant effect was rapidly induced and maintained after administration of NU172. Then, the anticoagulant effect was restored to the baseline, indicating
that anticoagulant activity of NU172 could be reversed without antidotes. Phase 2
trials have been initiated to evaluate the efficacy of NU172 in patients undergoing
coronary artery bypass grafting via a median sternal incision, and the results are not
yet available [88].
6.4 Aptamers for Targeted Therapy of Inflammation
6.4.1 Aptamers Targeting Interleukins
6.4.1.1 Interleukin-1
Interleukin-1α (IL-1α) is a member of the cytokine IL-1 family [89]. Studies have
shown that antibody or interleukin-1 receptor antagonist (IL-1RA) blocking IL-1α
has potential applications in the field of human inflammatory diseases and cancer
therapy [90, 91]. In 2017, Xiaoming et al. [92] used 5-(2-naphthylformamide)deoxyuridine (2Nap-dU) instead of dT ssDNA random library to obtain the 17
nt aptamer SL1067 (K D = ∼7.3 nM) of IL-1α through seven rounds of SELEX.
In receptor competitive binding and cellular studies, SL1067 effectively inhibited the signal transduction of IL-1 α/IL-1 receptor pathway. The high-resolution
crystal structure of IL-1α/SL1067 complex was further analyzed, and the molecular
mechanism of affinity and specificity between target and aptamer was deduced.