Core protein thoughts? (attn: studyforhope)

[Incrementalism]

Curious if anyone has any thoughts on the potential efficacy of core protein allosteric modulators? in vitro research indicates they could speed up capsid assembly kinetics (creating empty and misshapen capsids) and thereby also reducing availability of cP to <1/500th  - which could potentially  inhibit several major life cycle processes thought to be  dependent on cP - and that these same conformational changes in cP could also have potential upstream effects on cccDNA in addition to impacting pgRNA and subsequent downstream processes... Seeing two main companies (assembly and novira) working on variations of this but very limited information so far outside of the prolific research (focused more on cP dynamics, structures, and pleiotropic roles Vs specific cPAM solutions) from zlotnicks team at IU... To the extent cPAMs can be effectively delivered to hepatocytes in vivo wondering if they could have effects additive to nucs/infs with potentially improved safety profile given lack of human analogues for cP...???

[Incrementalism]

Perhaps the barrier to resistance could be taken higher with the combination of HAPs and phenylpropenamides given they seem to differentially bind quasi-equivalent pockets (Karen 2013). Although even with this combination one would think one may still need to add on an immune modulator to ramp up a response in CHB patients to overcome T cell exhaustion and perhaps a mechanism for sAg suppression...

[studyforhope]

The strict requirements for the core protein structure will restrict many possible mutations. But enough mutability remains, as we have seen in the multiple mutational adaptions in the class I and II epitopes residing in the core. Rejecting the binding of an allosteric modulator from its niche is easily obtained, without modifications in the backbone configuration.

[Incrementalism]

Thanks for the reply. Have not seen much research on hbv assembly effector mutants other than Tan, 2013 paper which used a mutant with the allosteric pocket (HAP) bound - they found although capsid assembly occurred w this mutant, binding that site impeded replication (note author has a conflict w affiliation w assembly).

Seen some work on F97L mutant which has a slightly altered cP but the mutation is only buried in dimer and not interface or pocket. Was wondering if the cP's multiple functions in hbv might result in the barriers to resistance for allosteric effectors being a bit higher for hbv cP's...?

[studyforhope]

Core protein inhibitors or allosteric modifiers could be synergistic to polymerase inhibitors and further reduce the production of HBv DNa containing cores that replenish the cccDNa pool or form complete virions that normally get out to reinfect despite the use of antivirals.

But like all allosteric modifiers they have to be very selective in order not to create problematic side effects. they also lend themselves to easy mutational adaption and such resistance.

One has to wait and see if this approach ever reaches clinical significance.