Target-based Design, Structural Optimization and Characterization of Novel Hepatitis B Virus Capsid Assembly Modulators

Despite the availability of a prophylactic vaccination, chronic hepatitis B still remains a serious global health issue. Current FDA-approved drugs can only prevent the adverse outcomes of the disease, but do not provide an effective cure. Small-molecule capsid assembly modulators (CAMs) have been recently recognized as promising antiviral agents for curing chronic HBV infection.

This industrial doctoral thesis is included within the VIRO-FLOW project, which aims at the fast and efficient identification of novel curative agents for HBV, integrating the advantages of continuous flow chemistry with microfluidic technologies. A combination of ligand- and structure-based approaches were explored in the research work described in this thesis for the design and optimization of focused libraries of HBV capsid assembly modulators and to guide and support the synthesis of those molecules either in batch or flow.

During this thesis an in silico workflow was established in order to identify novel HBV CAMs. Two virtual collections of derivatives were generated via bioisosteric replacement methods. A computer-aided scaffold hopping study was also carried out leading to the generation of two novel series of modulators, resulting in the discovery of a new lead compound with in vitro potency in the nanomolar range. From this point an extensive target-based virtual screening was performed allowing the identification of novel small molecules that misdirect HBV capsid formation. A lead compound was identified with in vitro antiviral activity in the sub-micromolar range along with good physico-chemical and safety profile in vitro. Furthermore, computational studies performed in our group determined that the [1,2,4]triazolo[1,5-a]pyridine core could be efficiently used as a bioisosteric replacement of N-rich bicyclic rings of known active HBV CAMs. A new method for the synthesis of ethyl [1,2,4]triazolo[1,5-a]pyridine-2-carboxylate 3-oxide, was developed in continuous flow in this thesis clarifying the mechanism of the process by DFT calculations.

Due to confidentiality reasons, it will be a closed event.