Speaking at the International Aids Society (IAS) conference held this week in Sydney, Dr Karl Salzwedel of Panacos said the research team was currently selecting leads but hoped to start Investigational New Drug (IND)-enabling studies by the end of the year - the last step before a Phase I clinical trial. All three sets of molecules are structurally different, yet share a common mechanism of action. Salwedel explained that since Fuzeon is given twice daily by injection, a new oral drug could increase patient compliance - something that is very valuable in the fight against HIV building up resistance. This has historically been difficult to do as fusion inhibitors seek to disrupt a protein-protein interaction, which is tricky with a small molecule. When the virus enters CD4 cells, the envelope protein, Env, (which is a precursor of both gp120 and gp41), undergoes a series of conformational changes. One of those changes causes a six helical bundle to be formed in the gp41 subunit. This change is crucial to the virus fusing to the target cell. Panacos scientists screened 400,000 drug like compounds to look for ones that might prevent the conformational changes that lead to the formation of this bundle. Such molecules were identified by an assay which sought a reduction in antibody binding to Env. The three series of compounds, unlike Fuzeon, affect gp120 conformation through binding before ENV binds to a receptor and thus helping keep it neutralised. They also bind to Env after it has bound to CD4 cells and make gp120 and gp41 more stable together. By preventing gp120 from falling off, the drugs also slow the entry of HIV into target cells. The drugs are effective against the virus, irrespective of whether it uses CCR5 or CXCR4 as its means of entry into the cells, according to Salzwedel. He also said that the drugs work downstream of attachment inhibitors, having no effect on CD4 binding. Fuzeon was originally developed by US company Trimeris, which later signed a collaboration deal with Roche. Once the drug was approved in both the EU and US in 2003, Trimeris has concentrated on developing next generation fusion inhibitors. These are currently in preclinical testing and will rival Panacos' drug, should they both make it to approval.