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coordinating ligands to the metal(s). This could be accomplished by sterically blocking access to the
active site or by specifically binding the acidic residues themselves. Such a mechanism has been
suggested to explain the inhibition of integrase by curcumin [55], which could bind to the active site
aspartates or glutamates via its hydroxy groups. Compounds could also be devised that chelate the
metal(s) once bound, preventing access of the active site to the substrate or distorting the active site
geometry preventing phosphate bond cleavage. An intriguing approach to disrupting metal binding has
recently been reported for the Zn 2+-binding HIV nucleocapsid (NC) protein [63]. In this case,
compounds were developed that specifically eject Zn 2+ from the zinc-finger region of NC, interfering
with viral replication. Such an approach might be applied to Mn 2+ or Mg 2+ binding at the active site,
although the Zn 2+-binding domain at the N terminus of integrase also suggests itself as a target.
It is curious that approaches have not been devised for mechanism-based inhibitors, particularly since
the stereochemical mechanism of integration has been understood for some time now [8].
Interfering with Multimerization
The structures of the domains of HIV-1 integrase determined to date both reveal dimers [3,28,29,36]. It
may be possible to develop compounds that bind specifically to the dimer interfaces, preventing
interactions between monomers that may be necessary for activity. The success of this approach
presumes that during the retroviral lifecycle there is a point where the monomer surfaces are accessible.
It is not clear that integrase in the context of preintegration complexes is in equilibrium between the
monomeric and higher order forms. This approach need not be restricted to preventing dimer formation
if higher order interactions (e.g. formation of a tetramer) are also mechanistically relevant. To this end,
the structure of an integrase tetramer, such as that formed by the full-length protein, would be useful in
identifying dimer-dimer interface(s).
Other Ways to Confound Integrase
There are other parts of the retroviral life cycle involving integrase that could be targeted for inhibition.
For example, integrase can bind other proteins such as human Ini1 [64], and most likely interacts with
the viral proteins that are part of the preintegration complex [65]. Although it is not known if these
interactions are essential for viral replication, preventing protein-protein binding would provide another
site at which to attack integrase. It is possible that interactions between integrase and other proteins in
the preintegration complex are crucial for maintaining the integrity of this complex and its ability to
migrate to the cell nucleus. Interfering with these protein-protein or protein-nucleic acid interactions
may be another approach to halting viral replication. For example, prein-
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