Keywords: HIV; virus entry; RNA aptamers; SELEX; protein/RNA interaction; X-ray crystallography; NMR
In this project, therapeutic RNA aptamers, which inhibit HIV entry, will be developed to give an alternative approach for the treatment of HIV infection. Aptamers are short single-stranded oligonucleotides that adopt defined, stable conformations and bind tightly to very specific targets. VirApt will primarily focus on the design of the aptamers that target membrane fusion, but will also endeavour to select aptamers that inhibit HIV entry at the level of receptor or co-receptor binding. Furthermore, the analysis of structural interaction mechanisms between RNA aptamer and virus envelope protein should provide a guide for drug design.
As the limitation of anti-HIV drug therapy becomes evident, alternative therapeutic strategies are gaining in interest. Peptides derived from the heptad repeats of the HIV-1 gp41 envelope glycoprotein have shown a strong potential to inhibit HIV-1 fusion and entry. However, the lack of bioavailability, high production costs and the rapid emergence of resistant virus strains still exclude a broad application. To overcome these disadvantages, RNA molecules interacting with the HIV-1 trimeric-coiled coil structures, and thus blocking membrane fusion, could be an option. For this purpose, VirApt combines profound expertise in oligonucleotide chemistry, analysis of RNA-protein interaction, molecular virology and the establishment of high throughput assays to study different steps of viral entry.
By using the SELEX technology, the aim is to isolate RNA structures, which are binding to epitopes derived from the HIV envelope, and to characterise the function of the isolated RNA aptamers on binding properties and virus entry inhibition. In addition, molecular interactions between the HIV target structures and the bound RNA aptamers will be analysed.
RNA aptamers will be designed that inhibit HIV entry efficiently. The project also expects to identify structural components involved in membrane fusion, thus offering a better understanding of the molecular mechanisms of virus entry.
RNA aptamers could be developed as potential therapeutic agents, similar to antiviral drugs and topical microbicides, as well as being a basis for the design of a small molecular weight entry inhibitor.
Dorothee von Laer
60596 Frankfurt am Main
Tel: +49 69 63395 232
Fax: +49 69 63395 297
|Official Address||Other Information|
|2 ||Peter G. Stockley ||Astbury Centre for Structural Molecular Biology |
University of Leeds
|Tel: +44 113 343 3092 |
Fax: +44 113 343 3092
|3 ||Félix Rey ||Department of Virology |
25 rue du Dr Roux
|Tel: +33 1 45 68 85 63 |
Fax: +33 1 45 68 89 66