If targeting a virus directly promotes drug resistance, why not take a different approach? Zeger Debyser and colleagues at the Catholic University of Leuven, Flanders, Belgium, suggest an alternative

Until very recently, the prospect of using small molecules to block specific protein-protein interactions was viewed with much skepticism. But protein-protein interactions play a key role in most biological processes and therefore are an important class of therapeutic targets. These interactions were overlooked for a long time, since developing drugs against the traditional targets such as enzymes and receptors was more cost effective. Since the cost of developing these classical drugs is increasing rapidly and pipelines are running dry, research into protein-protein interactions is becoming feasible and warranted.

Targeting protein-protein interactions such as that between HIV-1 integrase (green and blue) and the cellular cofactor LEDGF/p75 (purple) could lead to new antiviral drugs

This idea can be applied to the human immunodeficiency virus type 1 (HIV-1). The virus relies on several cellular proteins to replicate, proteins referred to as cofactors. Not only does understanding the interaction between HIV proteins and cellular cofactors shed light on the virus's effects but it provides new strategies for antiviral therapy. 

Developing drugs to target cellular cofactors constitutes a paradigm shift in antiviral research as present day antivirals typically target viral proteins. In the case of chronic viral infection this specificity for the viral target comes at a cost since viruses, with their high mutation rate, can become resistant to the antiviral drugs. The answer could be to develop drugs that target specific virus protein-cofactor interactions. 

The conserved nature of cellular proteins may provide a critical advantage in the struggle against antiviral resistance. The virus may find more difficulties in developing resistance against drugs targeting interactions between invariable cellular proteins and conserved viral protein domains. Also, since a specific protein-protein interaction is targeted and not the cellular protein per se, this should circumvent cellular toxicity. Moreover, outside the field of infectious diseases, drugs can target cellular targets in a non-toxic way.

One of the major obstacles to finding small molecule protein-protein interaction inhibitors (SMPPIIs) is the flat nature of the protein-protein interface. X-ray structures have shown that a large part of the interaction area is buried, with atoms closely packed together, implying a lack of available cavities for small molecule binding. Yet, it has become clear that some protein-protein interfaces have a well-defined compact area, commonly referred to as a hot spot, which plays a major role in the interaction. These hot spots define potential targets for SMPPII development. 

Returning again to the HIV example, our group discovered the cellular cofactor LEDGF/p75 which plays a crucial role in HIV replication. The cofactor is essential to the viral enzyme HIV integrase, which helps incorporate the viral DNA into regions of the host cell where it will be transcribed. LEDGF/p75 had previously been reported as a cellular stress response factor and a variant, p52, as a transcriptional coactivator but the link with HIV was unexpected. The interaction with integrase is specific for the p75 form; LEDGF/p52 lacks the integrase binding domain (IBD). 

A crystal structure of the dimeric catalytic core domain of HIV-1 integrase complexed to the IBD of LEDGF is available (see figure). An interhelical loop of the IBD protrudes into a pocket at the interface of the integrase core. This pocket classifies as a hot spot for interaction and a suitable drug target. We have established an assay to detect SMPPIIs for the integrase-IBD interaction. Early hits with micromolar activity in vitro and in cell culture have raised our hopes that we can effectively and safely block this protein-protein interaction in HIV infected patients in the future.

Read more in Debyser et al's review 'In search of small molecules blocking interactions between HIV proteins and intracellular cofactors' in Molecular BioSystems.