What are nucleic acid polymers?
Nucleic acid polymers (NAPs) are oligonucleotides whose biochemical function is strictly dependent on the polymer chemistry of phosphorothioate oligonucleotides. This functionality can be preserved independently of the sequence of nucleotides present and in the presence of naturally occurring nucleotide modifications.
Replicor’s NAP technology is based on the ability of phosphorothioate oligonucleotides to adopt an uncharged state in the phosphodiester linkage when sulfur is present (see below), which allows them to bind with high affinity along exposed hydrophobic surfaces in protein structures such as amphipathic α-helices (see below). The strength of this binding can be increased with longer NAP polymers by virtue of the increased number of co-operative interactions occurring between the NAP and its hydrophobic target surface.
Interactions between phosphorothioated NAPs and amphipathic protein targets.
Phosphorothioation involves the replacement of one non-bridging oxygen in the phosphodiester linkage with sulfur (indicated on the right in red).
These exposed hydrophobic surfaces in proteins are very rare in normal human biology but are required for various stages of viral replication in virtually all types of enveloped viruses and other infectious diseases as well. 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 oligonucleotides, and siRNA: their activity is not sequence-dependent. Replicor has taken advantage of this flexibility to engineer its lead NAP compound, REP 2139, with a sequence that retains activity but does not have off-target effects (such as immunoreactivity), which results in it being safe and very well tolerated.
As antiviral agents, REP 2139-based therapy will not result in the development of resistant strains of the virus due to the large binding interface between NAPs and the target protein, which is insensitive to mutation.