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.
|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