Hepatititis Delta Virus (HDV) Replication and Prenylation
Hepatitis delta virus (HDV) is composed of four specific components. The first component is envelope protein, which contains hepatitis B surface antigens (HBsAg). The second and third components are nucleocapsid proteins, referred to as small and large hepatitis delta antigens (HDAgs). The final component is a single-stranded circular RNA molecule known as the viral genome. The HDV large delta antigen protein (HDAgs) contains a terminal CXXX box (cysteine + 3 amino acids) rendering it a substrate for protein prenylation by the prenyl lipid, farnesyl, within the host liver cell or hepatocyte. Host cell prenylation of HDAgs is required for HDV to obtain HBsAg and complete HDV packaging and replication. Molecular genetic experiments determined that specific mutation of the prenylation site on the large HDAgs prevents the host prenylation process and thus, prevents HDV particle formation.
The oncogene Ras also undergoes prenylation and is thought to play a role in cell pathway signaling in a variety of solid tumors, prompting the development of specific inhibitors of ras prenylation. Multiple prenylation inhibitors were developed over the last twenty years and extensively studied pre-clinically and clinically. Several prenylation inhibitors, including EBP921 and EBP994, are now well characterized in the clinic setting because of this work. Unfortunately, after extensive human study, inhibiting Ras prenylation alone has been shown to be ineffective in the treatment of solid tumors. However, available data suggests that these prenylation inhibitors also inhibit hepatitis delta antigen prenylation, and may be sufficient to inhibit replication of the HDV life cycle in humans infected with HDV. Pharmacologic inhibition of host prenylation has now been demonstrated in a variety of experimental systems including: the HDV virus-like particle (VLP) assembly model; a cell culture model of infectious HDV; and a mouse model of HDV viremia. Additionally, since prenylation inhibitors are known to target a host function, not under genetic control of the virus, there is a theoretical higher barrier to the development of resistance.
Collectively, the above data provides a compelling rationale for the hypothesis that prenylation inhibitors represent a potential practical clinical therapy for the treatment of HDV. Moreover, because prenylation inhibitors have already been tested extensively in the clinic the safety and tolerability profiles of these agents has been well characterized. Protocols have been designed the first human proof of concept trials using prenylation inhibitors, EBP921 and EBP994, to treat HDV infection. US and International studies are enrolling.