Among those drugs emphasised during a special session of the conference was one that prevents HIV being released from macrophage reservoirs and another compound that prevents two crucial HIV proteins from coming together, thus preventing viral development.
As the number of people with the virus soars - the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that there are 40 million people infected with HIV worldwide - new treatments are desperately required as the virus can quickly become resistant to available drugs.
Ukrainian scientist Dmytro Kovalskyy, of the National Taras Shevchenko University in Kiev, revealed how he and a team of collaborators have designed small molecule drugs that interfere with the binding together of two proteins: transactivator of transcription (Tat) and protein phosphatise 1 (PP1). Disrupting this process can inhibit HIV transcription and so slow the virus' development.
The scientists selected a hydrophobic groove on PP1 as the targeted binding site for new drugs. Normally, this cleft accommodates a PP1 subunit that contains a particular amino acid sequence (termed RVxF), but is also the site where Tat binds to PP1.
They initially selected 262 molecules from a portion of chemical services company Enamine's compound library (which was whittled from around 300,000 candidates). The molecules were selected using a computer 'docking' programme, which simulates the interaction between target and small molecule. The programme used in this case was called QXP.
Those molecules were then tested in vitro (in CEM-GFP and 293T cells) to check for inhibition. The inhibition of Tat-PP1 interaction was tested using a phosphorylase phosphatase assay. The potential cytotoxicity of the candidate drugs was also examined.
In all, sixty compounds were found to be active, although only five showed strong enough inhibition. Having established a proof of concept, one compound called 1H4 has been selected for further testing. The work was carried out in collaboration with scientists at Howard University, US, and the US National Institute of Allergy and Infectious Diseases (NIAID).
Another drug on show was Biotron's BIT225. The drug recently began Phase I clinical trials and is designed to attack HIV in macrophage reservoir cells. The Australian biotech company maintains that, although most of the virus originates from the T cells, it also 'hides' from the immune system in reservoirs, making it difficult to completely clear from the body. It is these back-up supplies of virus that the company is hoping to destroy (some other antiretroviral therapies also affect these reservoirs, but none target them specifically).
The potential first-in-class drug is an amiloride analog that blocks HIV replication and has so far been shown to be over 90 per cent effective at preventing reverse transcriptase activity. Speaking at the conference, Dr John Wilkinson said he envisages BIT225 being used in conjunction with other treatments as the reservoir is "set up very early in HIV infection and then becomes a long term chronic problem."
Meanwhile, Japanese scientist Yasuhiro Koh from Kunamoto University along with others at Osaka University and US researchers (at the National Cancer Institute (NCI), and Purdue University), have been investigating existing drugs and have discovered an additional mechanism of action for some of them: they prevent protease monomers joining together to form a 'mature' protease complex. Although HIV protease inhibitors are an established class of HIV drug, the drugs were previously thought to work on the mature protein complex, and this new mechanism could enable better drugs to be developed.
The team developed a fluorescence resonance energy transfer (FRET) based assay to measure HIV expression levels. They tagged protease monomers with either a cyan or yellow colour.
Through this work, they identified several non-peptide inhibitors that prevent the dimerisation reaction, including Tobotec's Prezista (darunavir).
As well as the latest drug discovery research, the 5,000 scientists, clinicians and community leaders that have converged in Sydney this week, have also come to discuss how best to manage the health of the growing numbers of HIV positive people living into old age and thus encountering the health problems associated with being elderly, strategies to ensure all those with HIV get access to treatments, and the latest preventative techniques such as male circumcision. This has now been shown in several separate clinical trials to cut the risk of woman-to-man HIV infection by up to 60 per cent compared with uncircumcised men.
This finding alone has the potential to save millions of lives in certain countries, and when combined with the latest drugs, both approved and in development, the outlook for those who are HIV positive is increasingly bright.