Communication from one side of a virus particle to the other: cooperativity with implications for biology and drug development

A virus capsid is a multi-protein complex that contains the virus genome and releases the genome in response to a biological signal. For Hepatitis B Virus (HBV), the capsid is composed of 240 individual proteins arranged with icosahedral symmetry. The HBV capsid packages viral RNA, serves as a compartment for reverse transcription, and releases the resulting viral DNA into the nucleus of a host cell. It must assemble and disassemble. A family of experimental therapeutics, capsid assembly modulators (CAMs), promote capsid assembly and, in some cases, paradoxically also promote capsid disassembly. These are two distinct and complementary antiviral mechanisms. We hypothesize that capsid dissociation is driven when a CAM binds to capsid protein interface, strengthening a local interaction, but disfavoring icosahedral geometry. We have designed and synthesized fluorescent CAMs to facilitate binding studies. We find that a CAM that binds preformed capsid with negative cooperativity, suggesting that the CAM progressively distorts the capsid. Structural studies support this prediction. Thus, CAMs are an antiviral that act by modulating the physical properties of the virus capsid.