Nucleic acid polymers (NAPs) are oligonucleotides whose biochemical function is strictly dependent on the polymer chemistry of oligonucleotides. This functionality can be preserved independently of the sequence of nucleotides present.
Replicor’s NAP technology is based on the premise that nucleic acid polymers which are phosphorothioated become more amphipathic, allowing them to bind with high affinity to amphipathic protein structures such as amphipathic α-helices (see Figure 1 below). The strength of this binding can be increased with longer NAP polymers by virtue of the increased number of co-operative interactions between the NAP and its target.
Figure 1. Interactions between phosphorothioated NAPs and amphipathic protein targets. Phosphorothioation involves the replacement of one non-bridging oxygen in the phosphodiester linkage with sulfur (indicated in red in the figure above).
The amphipathic protein structures which are targets for NAP interaction are very rare in normal human biology as these structures are normally found already complexed with each other inside proteins where they help stabilize the protein structure. Replicor has discovered however that amphipathic targets susceptible to NAP targeting are required for various stages of viral replication in virtually all types of enveloped viruses. NAPs effectively block the functions of these proteins, providing an effective, broad-spectrum antiviral activity.
NAPs have a very important safety advantage over all other existing oligonucleotide-based drugs such as aptamers, antisense oligonuclelotides and siRNA: their activity is not sequence dependent. Replicor has taken advantage of this flexibility to engineer NAPs with sequences which retain activity but which do not have pro-inflammatory activity or off target effects (which have caused problems with several oligonucleotide-based drugs in development), rendering them safe and well tolerated.
As antiviral agents, NAP treatment will not result in the development of resistant strains of virus due to the large binding interface between NAPs and the target protein, which is insensitive to substantial mutation. On the other hand, the antiviral approach of using antisense or siRNA compounds to target specific viral genes has been shown to readily elicit the development of drug resistant strains of virus (1,2); gene targeting by these compounds is lost with even one nucleotide mismatch between the antisense / siRNA and the gene sequence targeted, a frequently occurring event due to the error-prone nature of viral replication.
Note: NAPs have been referred to as “amphipathic DNA polymers” in Replicor’s earlier publications.