Structural analysis of a series of antiviral agents complexed with human rhinovirus 14.

Abstract

The binding to human rhinovirus 14 of a series of eight antiviral agents that inhibit picornaviral uncoating after entry into host cells has been characterized crystallographically. All of these bind into the same hydrophobic pocket within the viral protein VP1 beta-barrel structure, although the orientation and position of each compound within the pocket was found to differ. The compounds cause the protein shell to be less flexible, thereby inhibiting disassembly. Although the antiviral potency of these compounds varies by 120-fold, they all induce the same conformational changes on the virion. The interactions of these compounds with the viral capsid are consistent with their observed antiviral activities against human rhinovirus 14 drug-resistant mutants and other rhinovirus serotypes. Crystallographic studies of one of these mutants confirm the partial sequencing data and support the finding that this is a single mutation that occurs within the binding pocket.

Structural and Virological Studies of the Stages of Virus Replication That Are Affected by Antirhinovirus Compounds

“…5 and 6), with ring A close to the entrance of the pocket and ring C at the toe end. This orientation is the same as in nearly all other related compounds, except for very long compounds, such as WIN52084 and WIN51711, that bind into the pocket in the opposite direction (3,48). Rings B and C are roughly coplanar, whereas ring A is approximately perpendicular to the other two rings when pleconaril or related WIN compounds (Fig.…”

“…The largest of these changes is for the Tyr1144 that is displaced by ring B of pleconaril. More substantial changes occurred when pleconaril was introduced into empty HRV14 pockets, resulting in a displacement of the C ␣ atoms in residues 1213 to 1224 by as much as 4.3 Å , similar to displacements produced by other compounds (3,48).…”

“…The cocrystal structures of several capsid-binding antiviral compounds complexed with human rhinovirus 14 (HRV14) (3,6,15,48), HRV16 (14,34), HRV1A (20), HRV3 (50), HRV2 (49), polioviruses (13,19,27), coxsackievirus A9 (18), and coxsackievirus B3 (33) are known. The hydrophobic binding pocket consists of a closed "toe" at one end and an open "pore" at the other.…”

Viral cell recognition and entry

“…These compounds bind to many picornaviruses in a hydrophobic pocket located under the canyon floor ( Fig. 2) and, in most cases, block virus from uncoating (Smith et al, 1986;Badger et al, 1988;K.H. Kim et al, 1993).…”

Discrimination among Rhinovirus Serotypes for a Variant ICAM-1 Receptor Molecule

“…In the absence of the pocket factor, the roof of the pocket is collapsed, thus also lowering the floor of the canyon. Small hydrophobic compounds can enter this pocket, displacing the pocket factor if present (2,19,47). Filling the hydrophobic pocket with a hydrophobic compound stabilizes the virus and damps the normal dynamic "breathing" of the virion, causing the inhibition of uncoating (30).…”