ABSTRACT
Worldwide, over 250 million people are chronically infected with the hepatitis B virus (HBV). Infected patients have an up to 100-fold increased risk for liver-related complications, including cirrhosis, hepatic decompensation and hepatocellular carcinoma. Nonetheless, the majority of the infections remains asymptomatic, stressing the importance of HBV screening and linkage to care. Excellent clinical outcomes are seen during nucleos(t)ide analogue (NA) therapy, which often is continued indefinitively due to a lack of functional cure. Increasing evidence suggests that NA discontinuation following long-term treatment induced viral suppression in patients without a functional cure may be a favourable option. Reliable biomarkers are, however, urgently needed to select the patients that would benefit from NA withdrawal. In addition, renewed and novel approaches to improve screening and linkage to care are other fundamental factors in the optimisation of the clinical management of chronic hepatitis B.
Subject(s)
Asymptomatic Diseases , Hepatitis B virus , Hepatitis B, Chronic/drug therapy , Aged , Antiviral Agents/therapeutic use , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/therapy , Chemoembolization, Therapeutic , Esophageal and Gastric Varices , Hepatic Encephalopathy , Hepatitis B Surface Antigens , Hepatitis B e Antigens/immunology , Hepatitis B virus/genetics , Hepatitis B virus/immunology , Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/virology , Humans , Liver Failure/etiology , Liver Neoplasms/etiology , Liver Neoplasms/therapy , Male , Seroconversion , Tenofovir/therapeutic use , Withholding TreatmentABSTRACT
Kinetoplastid parasites are the causative agents of neglected tropical diseases with an unmet medical need. These parasites are unable to synthesize the purine ring de novo, and therefore rely on purine salvage to meet their purine demand. Evaluating purine nucleoside analogs is therefore an attractive strategy to identify antikinetoplastid agents. Several anti-Trypanosoma cruzi and anti-Trypanosoma brucei 7-deazapurine nucleosides were previously discovered, with the removal of the 3'-hydroxyl group resulting in a significant boost in activity. In this work we therefore decided to assess the effect of the introduction of a 3'-fluoro substituent in 7-deazapurine nucleosides on the anti-kinetoplastid activities. Hence, we synthesized two series of 3'-deoxy-3'-fluororibofuranosyl and 3'-deoxy-3'-fluoroxylofuranosyl nucleosides comprising 7-deazaadenine and -hypoxanthine bases and assayed these for antiparasitic activity. Several analogs with potent activity against T. cruzi and T. brucei were discovered, indicating that a fluorine atom in the 3'-position is a promising modification for the discovery of antiparasitic nucleosides.
