Modulators of pharmacological agents
The biological activity of nucleic acid ligand is regulated (i.e. enhanced or inhibited) in vivo to produce a desired biological effect. This is accomplished through the administration of a modulator, or regulator, that changes the binding of the nucleic acid ligand for its target or that degrades or otherwise cleaves, metabolizes or breaks down the nucleic acid ligand while the ligand is still exerting its effect. Modulators of the present invention can be administered in real time as needed based on various factors, including the progress of the patient, as well as the physician's discretion in how to achieve optimal therapy. Thus, this invention provides for the first time a regulatable therapeutic regime in the course of nucleic acid ligand therapy.
1. A method of altering the affinity of an aptamer for a coagulation factor in a host comprising administering to the host a modulator that binds to the aptamer, wherein the modulator is a nucleic acid binding peptide, polypeptide or protein which,
(a) comprises a helix-loop-helix domain, a zinc finger domain, or a tripeptide which is selected from a combinatorial library to bind the aptamer, or
(b) comprises an arginine rich motif, and
wherein conditions are such that the modulator binds to the aptamer and alters the affinity of the aptamer for the coagulation factor.
2. The method according to claim 1 wherein upon binding of the modulator to the aptamer, the affinity of the aptamer for the target molecule is reduced.
3. The method according to claim 1 wherein upon binding of the modulator to the aptamer, the affinity of the aptamer for the coagulation factor is enhanced.
4. The method according to claim 1 wherein the modulator binds to free aptamer present in the host.
5. The method according to claim 1 wherein the modulator binds to aptamer ligand present in the host in association with the coagulation factor.
6. The method according to claim 1 wherein the coagulation factor is selected from the group consisting of a platelet receptor gpIIbIIIa; a platelet receptor gpIbIX; platelet receptor gpVI; a Gas6 receptor; angiogenesis factor 1 (Ang 1); angiogenesis factor 2 (Ang2); thrombin; a tissue factor/coagulation factor VIIa enzyme complex (TF/FVIIa); a coagulation factor VIIIa/coagulation factor IXa enzyme complex (FVIIIa/FIXa); a coagulation factor Va/coagulation factor Xa enzyme complex (FVa/FXa); plasminogen activator inhibitor 1 (PAI-1); coagulation factor XIIIa (FXIIIa); anti-thrombin III (ATIII); coagulation factor FIXa (FIXa); and coagulation factor XIa (FXIa).
7. The method according to claim 1 wherein the coagulation factor is Factor IXa.
8. The method of claim 1 wherein the nucleic acid binding peptide, polypeptide or protein comprises an arginine-rich motif.
9. The method of claim 8 , wherein the nucleic acid binding peptide, polypeptide or protein comprises an arginine-rich motif about 10-20 amino acids in length.