Resolving the 3D structure of Integrase offer better treatments for HIV

A recent study published in the journal Nature concluded a breakthrough in HIV research, which dynamically lead to better treatments for HIV.  The study was conducted by the researchers from Imperial College London and Harvard University.  In the study, the researcher have developed  a crystal strucutre that reveals the  enzyme integrase, which is found in retroviruses like HIV.  Integrase is an enzyme produced by HIV that enables its genetic material to be integrated into the DNA of the infected cell.  The researchers grew a crystal using a version of  integrase  from PFV.PFV, Prototype Foamy Virus is a little known retrovirus.  Besides the knowledge of PFV integrase and function, the team found it very similar to HIV integrase.

During the research, which takes over 4 years, the team carried about 40,000 trials.  Out of these, they were able to grow just seven kinds of crystals.  Interestingly, only one one of out of seven was of sufficient quality to resolve the 3D structure.  Following the crystal generation, the researchers used the giant synchrotron machine at the Diamond Light Source in South Oxfordshire to collect X-ray diffraction data from these crystals.  The X-ray diffraction data allowed the researchers to determine the needed structure.  Afterwards the reseachers soaked the crystals in solutions of the integrase inhibiting drugs Raltegravir (also known as Isentress) and Elvitegravir. Thus they observed how these antiretroviral drugs bind to inactivate integrase.

This innovative study undoubtedly illustrate  the retroviral integrase structure. Accessibility of the integrase structure allows the researchers to fully understand how existing drugs that inhibit integrase are working, how they might be improved, and how to stop HIV developing resistance to them.  Dr Peter Cherepanov, the lead author of the study from the Department of Medicine at Imperial College London, said: “It is a truly amazing story. When we started out, we knew that the project was very difficult, and that many tricks had already been tried and given up by others long ago. Therefore, we went back to square one and started by looking for a better model of HIV integrase, which could be more amenable for crystallization. Despite initially painstakingly slow progress and very many failed attempts, we did not give up and our effort was finally rewarded.”

Available Integrase Drugs.

Raltegravir is a 1-N-alkyl-5-hydroxypyrimidinone. As such, it is a structural analogue of the di-keto acid class of compounds and shares their β-hydroxy-ketone structural motif .  This structural motif possesses metal-chelating functions, and it is postulated that compounds bearing these functional groups interact with divalent metals within the active site of HIV-1 integrase.The insertion of HIV-1 viral genomic DNA into the host chromosome is a process often referred to as strand transfer. Raltegravir and its related molecules inhibit this latter step, and as a result are often referred to as “strand-transfer inhibitors.

Elvitegravir is a dihydroquinoline carboxylic acid compound that exhibits the active integrase-inhibitor–conferring β-hydroxy-ketone structural motif.  Like raltegravir, elvitegravir is a specific inhibitor of the strand-transfer step of HIV integration. This drug is active against HIV-1 and HIV-2. Elvitegravir has also demonstrated activity against isolates resistant to nucleoside reverse-transcriptase inhibitors (NRTIs), non-nucleoside reverse-transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs).