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that in some HRVs (particularly HRV14 and to a lesser extent in HRV3, but not HRV16) the addition of
ICAM-1 itself, in the absence of acid, can induce structural changes that mimic uncoating in the capsid
[34]. However, these changes are unlikely to lead to productive uncoating because they occur in the
extracellular space. Therefore, the binding of ICAM alone, at the cell surface, is unlikely to be sufficient
to cause productive uncoating of HRVs.
It seems that the hydrophobic pocket in HRVs is maintained to allow an induced transition around the
GH loop that is required for productive uncoating. This transition could be induced by acidification in
the endosome, receptor binding, or a combination of the two. Filling this pocket in VP1 with a drug or
naturally occurring factor would inhibit this transition, thus inhibit uncoating. As expected, binding of
compounds in the VP1 pocket has also been shown to inhibit intracellular uncoating as well as either
acid-or heat-induced uncoating of the virus [28,29,47].
An attractive hypothesis suggests that the GH loop transition precedes or allows the externalization of
VP4, which would be required for the formation of the uncoating intermediate particles. Remember,
VP4 contains the myristoyl moiety, which can signal VP4 to associate with a membrane. The VP4
would drag the N-terminal region of VP1 (to which it is closely associated) to the exterior of the virion.
This would result in a particle with the N-terminus of VP1 exposed, as has been observed in poliovirus
[48–50]. The sequence of this exposed region of VP1 suggests that it can form an amphipathic helix.
The VP1 helices could then insert into the membrane and form a pore, which could allow the passage of
RNA through the lipid bilayer into the cytosol. This is reminiscent of the pore formation by colicin [51].
The observation that both the Ca 2+ ion plus the β cylinder and VP4 become disordered under acidic
conditions are consistent with this hypothesis. These are regions that would need to disorder to allow the
externalization of VP4 and the N-terminus of VP1.
IV. Capsid-Binding Compounds
Capsid-binding compounds were discovered long before the emergence of the HRV crystal structure
[52]. They were initially discovered on screening of compounds that had been produced by an insect
pheromone project at Sterling Winthrop. Examples of compounds known or presumed to bind in this
pocket are shown in Figure 5 [52–69]. The prototypical WIN drug contains an oxazoline ring attached to
a phenoxy group, which is in turn linked by an aliphatic chain to an isoxazole ring. The three rings will
be termed A, B, and C here (Figure 6). Compounds of this type were the first to be shown to inhibit the
viral uncoating and also to stabilize the virion to heat-induced denaturation [29].
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