Picornavirus capsid protein VP1 hydrophobic pocket (VP1 pocket)

The Picornavirus capsid protein VP1 hydrophobic pocket is a critical structural site located beneath the "canyon" floor of the viral capsid in many enteroviruses and rhinoviruses (PMID: 12163547). In its natural state, this pocket often contains a host-derived lipid known as a "pocket factor," which regulates the stability of the virus particle (PMID: 15105515). During the infection process, the displacement of this factor is necessary for the capsid to undergo the conformational changes required for uncoating and the subsequent release of the viral RNA genome into the host cytoplasm (PMID: 27030261). Small molecule inhibitors, often referred to as "capsid binders" or "WIN compounds," are designed to occupy this pocket with higher affinity than the natural pocket factor (PMID: 11850500). By binding here, these drugs over-stabilize the capsid, effectively locking it in a rigid state that prevents the uncoating process and inhibits viral replication (PMID: 25332331). This target has been the focus of extensive antiviral research for treating conditions ranging from the common cold to more severe enteroviral infections like poliomyelitis and hand-foot-and-mouth disease (PMID: 27030261). However, the clinical utility of drugs targeting this pocket is often challenged by the rapid emergence of resistance mutations within the VP1 sequence that alter the pocket's shape or binding affinity (PMID: 17005653). Additionally, some inhibitors like pleconaril have faced regulatory hurdles due to drug-drug interactions involving the induction of cytochrome P450 enzymes (PMID: 15105515).

Other names

VP1 hydrophobic tunnelVP1 drug-binding pocketCanyon floor pocketVP1 pocketPicornavirus capsid binding site

Binding to the hydrophobic pocket within the VP1 protein stabilizes the viral capsid, preventing the conformational changes and disassembly required for the release of the viral RNA genome into the host cell (PMID: 12163547, 15105515).