Methods are described for improvement of the serum
half life of therapeutic nucleic acids by 3′ conjugation to useful target proteins, or other large molecules with useful function. In one embodiment, a 3′ A, C or G overhang is added to ds-
DNA and the primary amines conjugated using biocompatible
bifunctional linkers to proteins. The resulting
nucleic acid-3′-conjugates are serum
nuclease-resistant and retained
in vivo for long periods without rapid
kidney clearance. Further, the choice of conjugate imparts additional functionality to the
nucleic acid-3-conjugate. For example, if the
protein in the
DNA-
protein conjugate is the first component of the complement
cascade (Clq or Clqrs) and the
DNA aptamer has been developed against surface components of a target
cell, it can be used to treat bacterial or parasitic infections and cancers. If the
protein is
serum albumin or another common (nonimmunogenic) blood protein and the
aptamer is directed against a
toxin or
venom, the
aptamer-protein conjugate can be used as an
antidote that binds and neutralizes the
toxin or
venom. Similar DNA (aptamer)-
nanotube, -
enzyme, and -
toxin conjugates could also be used to target and selectively kill
bacteria, parasites, and
cancer cells
in vivo. If the protein is an Fc
antibody fragment or C3b protein from the
complement system and the aptamer is developed against a bacterial
cell capsular material, other
cell surface component or viral cell surface component, then the aptamer-3′-protein conjugate can aid in opsonization of the target cells or viruses by phagocytic leukocytes.