8, 9 By using these model systems, the specific receptor binding site of HBV has been narrowed down to a critical region of the pre-S1 protein spanning amino acid (aa) residues 9-18, with aa residues 29-48 enhancing infection inhibition, whereas aa residues 19-28 and 1-8 were dispensable.8 Interestingly, HDV, which replicates

in HBV-infected hepatocytes and packages its ribonucleoprotein in the HBV envelope, can also be inhibited by these acylated HBV pre-S derived peptides (e.g., preS/2-48myr) with the same specificity.10 This shows that HDV has at least one step in common with HBV for entering hepatocytes. Despite not knowing the identity of the receptor, Urban and colleagues managed to develop a way to block it, based Quizartinib manufacturer on a detailed understanding of the receptor’s binding partner, the HBV pre-S1 protein. From these observations, the investigators have developed a novel therapeutic MK-2206 price against HBV and HDV: Myrcludex B based on pre S/2-48myr (Fig. 1). This drug has entered clinical trials after showing efficient blocking of both HBV and HDV infection as well as inhibition of replication in a uPA-SCID mouse

model.11 The therapeutic implications of using a drug like Myrcludex B for treating CHB and chronic HDV infection are profound. Blocking entry protects new hepatocytes from de novo infection, whereas preinfected hepatocytes are not subjected to multiple rounds of reinfection (Fig. 1). This latter pathway may turn out to be an even more important mechanism of persistence in chronic HBV infection than previously recognized, possibly accounting for the failure of NAs to affect HBV cccDNA levels or promoting its accelerated decay or silencing.12-14 Thus, one would anticipate that blocking re-entry would result in a significant decrease in the medchemexpress number of infected cells, reducing the intrahepatic burden of HBV cccDNA, with associated significant declines in viremia

and HBs antigenemia. The flow-on effects in CHB would be substantial, especially in combination with IFN-α or highly potent, high genetic barrier NAs. Myrcludex B could also have application for preventing perinatal transmission or reinfection after liver transplantations in HBV-infected individuals. Because there is no effective therapy for HDV infection, except long-term IFN-α, a drug like Myrcludex B would represent the first selective therapy for this debilitating disease. The two papers by Urban and colleagues build on existing data establishing that the myristoylated N terminus of the HBV L-protein mediates the highly specific interaction of HBV with susceptible hepatocytes in vitro and in vivo. Furthermore, potential applications of liver targeting in vivo are also explored.