Host cell endonucleases

The term "Endonucleases involved in REP 2165 backbone cleavage" refers to the group of host-derived enzymes responsible for the metabolic degradation of the nucleic acid polymer (NAP) known as REP 2165. REP 2165 is a 40-mer phosphorothioate-modified oligonucleotide developed by Replicor for the treatment of chronic Hepatitis B (HBV) and Hepatitis D (HDV) infections (Bazinet et al., 2020). While the primary therapeutic mechanism of REP 2165 involves binding to the Hepatitis B surface antigen (HBsAg) to prevent subviral particle release, its pharmacokinetic profile is governed by its stability against host nucleases (Vaillant, 2016). These endonucleases, such as the lysosomal enzyme DNase II, catalyze the slow hydrolytic cleavage of the phosphorothioate backbone, which is the rate-limiting step in the drug's systemic clearance (Eckstein, 2014). Although the phosphorothioate modification significantly enhances resistance to nuclease-mediated hydrolysis compared to natural phosphodiester bonds, endonucleolytic cleavage eventually occurs, leading to the formation of shorter, inactive metabolites (Geary et al., 2015). Consequently, these enzymes are not therapeutic targets in the traditional sense but are critical determinants of the drug's half-life and tissue accumulation, particularly within the liver.

Other names

Nuclease enzymesEndonucleasesDNase IIOligonucleotide-degrading enzymesHost nucleases

These enzymes catalyze the hydrolytic cleavage of the phosphorothioate or phosphodiester backbone of nucleic acid polymers, leading to drug inactivation and systemic clearance.