Lab

Ai-biopharma - Cyril B Dousson's Lab -

About the lab

Research and development of new Antiviral candidate drugs (HBV & Coronavirus), Drug Discovery, Medicinal Chemistry, Artificial Intelligence & Chemoinformatic.

Featured projects (2)

Project
Develop AIB-001, a new oral liver targeted HBV Polymerase inhibitor as the Backbone component of a combination therapy for HBV Functional Cure.
Project
Research and development of second generation Coronavirus polymerase inhibitors with wider coverge and better efficacy and tolerability.

Featured research (3)

In worldwide clinical settings, several nucleos(t)ide analogues (NAs), including tenofovir disoproxil fumarate (TDF), entecavir (ETV), and tenofovir alafenamide fumarate (TAF) are used to treat patients chronically infected with HBV.1,2 NAs are easily administrated orally and have favorable pharmacologic profiles.3 Their use is generally preferred to that of the immune stimulator pegylated-interferon (Peg-IFN)-alpha, which induces more adverse effects (AEs) and less virological suppression (i.e. HBV DNA decline in serum), although it is associated with a higher rate of HBsAg loss.1,2,4 Treatment indications for these NAs have been clearly defined by international societies, including EASL.1 Their efficacy to suppress/reduce HBV viremia and overall safety have been properly assessed in randomized controlled phase III clinical trials (i.e. registration trials) and in long-term real-world studies.1,2,4 When “no virologic resistance” occurs, long-term treatments with 1 of the 3 most used NAs (TDF, ETV, TAF) are associated with a prolonged virologic responses (i.e. viremia below detection levels by qPCR) in most patients (>95%), normalized alanine aminotransferase levels, regression of fibrosis, and altogether with the prevention of disease progression, including hepatocellular carcinoma development.
Chronic Hepatitis B Virus infections afflict >250 million people and kill nearly 1 million annually. Current non-curative therapies are dominated by nucleos(t)ide analogs (NAs) that profoundly but incompletely suppress DNA synthesis by the viral reverse transcriptase. Residual HBV replication during NA therapy contributes to maintenance of the critical nuclear reservoir of the HBV genome, the covalently-closed circular DNA, and to ongoing infection of naive cells. Identification of next-generation NAs with improved efficacy and safety profiles, often through novel prodrug approaches, is the primary thrust of ongoing efforts to improve HBV replication inhibitors. Inhibitors of the HBV ribonuclease H, the other viral enzymatic activity essential for viral genomic replication, are in preclinical development. The complexity of HBV’s reverse transcription pathway offers many other potential targets. HBV’s protein-priming of reverse transcription has been briefly explored as a potential target, as have the host chaperones necessary for function of the HBV reverse transcriptase. Improved inhibitors of HBV reverse transcription would reduce HBV’s replication-dependent persistence mechanisms and are therefore expected to become a backbone of future curative combination anti-HBV therapies.
This review describes the current state of discovery of past most important nucleoside and nucleotide prodrugs in the treatment of hepatitis C virus infection as well as future potential drugs currently in discovery or clinical evaluation. I highlight first generation landmark prodrug compounds which have been the foundations of incremental improvements toward the discovery and approval milestone of Sofosbuvir. Sofosbuvir is the first nucleotide prodrug marketed for hepatitis C virus treatment and the backbone of current combination therapies. Since this approval, new nucleotide prodrugs using the same design of Sofosbuvir McGuigan prodrug have emerged, some of them progressing through advanced clinical trials and may become available as new incremental alternative hepatitis C virus treatments in the future. Although since Sofosbuvir success, only minimal design efforts have been invested in finding better liver targeted prodrugs, a few novel prodrugs are being studied and their different modes of activation may prove beneficial over the heart/liver targeting ratio to reduce potential drug–drug interaction in combination therapies and yield safer treatment to patients. Prodrugs have long been avoided as much as possible in the past by development teams due to their metabolism and kinetic characterization complexity, but with their current success in hepatitis C virus treatment, and the knowledge gained in this endeavor, should become a first choice in future tissue targeting drug discovery programs beyond the particular case of nucleos(t)ide analogs.

Lab head

Cyril B Dousson
Department
  • Medicinal Chemistry & Chemoinformatics
About Cyril B Dousson
  • Research and development of new Antiviral candidate drugs (HBV & Coronavirus), Drug Discovery, Medicinal Chemistry, Artificial Intelligence & Chemoinformatic.

Members (3)

David Dukhan
  • Idenix Pharmaceuticals, Inc.
Thierry Convard
  • Ai-biopharma

Alumni (2)

Bastien Poinot
  • Paul Sabatier University - Toulouse III
Mary Anne Maverick
Mary Anne Maverick