Effects of antivirals on the assembly pathway of hepatitis B virus capsids

Hepatitis B virus (HBV) is one of the most serious human pathogens with more > 0.8 million people dying yearly from chronic HBV. Empty HBV capsids made of truncated subunits containing the N-terminal 149 residues (Cp149) can be assembled in vitro. Compounds binding at the interfaces between subunits, also known as CpAMs for capsid assembly modulators, disrupt the assembly pathway. They are powerful inhibitors of HBV replication in vitro and several are in advanced clinical trials. The objective of the proposal is to elucidate the assembly pathways of Cp149 capsids in the presence of CpAMs. The pathways are probed by time-resolved SAXS (TR-SAXS) and the structure of intermediate species extracted by custom-made algorithms. In a first proposal, we thus performed the first TR-SAXS study of capsid assembly in the presence of antivirals. In this continuation proposal, we will apply this methodology to a new and very promising class of CpAMs.