NS5B polymerase inhibitors in phase II clinical trials for HCV infection

Introduction: Hepatitis C virus (HCV) infection might be the first chronic viral disease to be eradicated without the introduction of a prophylactic vaccine. This is essentially due to therapeutic revolution encapsulated by the advent of direct-acting antivirals (DAA) agents, whose efficacy, safety and tolerability (all oral regimens) have made the previous standard of care (interferon plus ribavirin) a vestige of the past. The new regimens achieve very high response rates and have an excellent tolerability profile. Notwithstanding, the first wave of DAAs has brought over problems regarding costs and failures which warrant research and development of further antiviral molecules.

Areas covered: This review outlines the main clinical data concerning novel NS5B polymerase inhibitors currently in pipeline, focusing on the ones that have completed a phase 2 trial.

Expert opinion: NS5B is one the main viral target for anti-HCV therapy. The large majority of the approved regimens so far include a NS5B inhibitor. Although not frequently, failure related to mutations can occur. The potential place in therapy in the mid-term of new NS5B inhibitors may be, in the first instance, the role of backbone in salvage combinations with DAAs of other classes.     

Potential candidate genomic biomarkers of drug induced vascular injury in the rat

Drug-induced vascular injury is frequently observed in rats but the relevance and translation to humans present a hurdle for drug development. Numerous structurally diverse pharmacologic agents have been shown to induce mesenteric arterial medial necrosis in rats, but no consistent biomarkers have been identified. To address this need, a novel strategy was developed in rats to identify genes associated with the development of drug-induced mesenteric arterial medial necrosis. Separate groups (n = 6/group) of male rats were given 28 different toxicants (30 different treatments) for 1 or 4 days with each toxicant given at 3 different doses (low, mid and high) plus corresponding vehicle (912 total rats). Mesentery was collected, frozen and endothelial and vascular smooth muscle cells were microdissected from each artery. RNA was isolated, amplified and Affymetrix GeneChip® analysis was performed on selectively enriched samples and a novel panel of genes representing those which showed a dose responsive pattern for all treatments in which mesenteric arterial medial necrosis was histologically observed, was developed and verified in individual endothelial cell- and vascular smooth muscle cell-enriched samples. Data were confirmed in samples containing mesentery using quantitative real-time RT-PCR (TaqMan™) gene expression profiling. In addition, the performance of the panel was also confirmed using similarly collected samples obtained from a timecourse study in rats given a well established vascular toxicant (Fenoldopam). Although further validation is still required, a novel gene panel has been developed that represents a strategic opportunity that can potentially be used to help predict the occurrence of drug-induced mesenteric arterial medial necrosis in rats at an early stage in drug development.     

Recent developments in the medicinal chemistry of single boron atom-containing compounds

Various boron-containing drugs have been approved for clinical use over the past two decades, and more are currently in clinical trials. The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets; for example, boron substitution can be used to modulate biological activity, pharmacokinetic properties, and drug resistance. In this perspective, we aim to comprehensively review the current status of boron compounds in drug discovery, focusing especially on progress from 2015 to December 2020. We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments.