Virology & Mycology
Open Access

Therapeutic targeting of viral RNAs: High-hanging fruit only needs a longer ladder

International Conference on Retroviruses & Novel Drugs

June 08-09, 2015 Chicago, USA

Stuart F J Le Grice

Posters-Accepted Abstracts: Virol-mycol

Abstract :

Small molecules targeting the enzymes responsible for human immunodeficiency virus (HIV) polyprotein maturation (protease), DNA synthesis (reverse transcriptase) and the subsequent insertion of ribonucleotide-free double-stranded DNA into the host chromosome (integrase) have for several years been the central components of combination antiretroviral therapy. For infected individuals harboring drug-susceptible virus, this approach has afforded complete or near-complete viral suppression. However, in the absence of a curative strategy, the predictable emergence of drug-resistant variants requires continued development of improved antiviral strategies, inherent to which is the need to identify novel targets. Cis-acting regulatory elements of the HIV-1 RNA genome that regulate its transcription (the transactivation response element, TAR), translation (the ribosomal frameshift signal), nucleocytoplasmic transport (the Rev response element or RRE),dimerization (the dimer linkage sequence or DLS), packaging (the element) and reverse transcription of the (+) strand RNA genome (the primer binding site, or PBS) should now be considered as alternative targets for small molecule, peptide- and oligonucleotidebased therapeutics, as well as combinations thereof. The first part of this talk will summarize how high-resolution 3D structural information is being used to develop small molecule and peptide-based therapeutics that targetcritical cis-acting RNA motifs of the HIV-1 genome and consequently may be less prone to resistance-conferring mutations. Subsequently, advances in the development of novel high-through put small molecule microarrays (SMMs) and RNA motifs that have been successfully targeted by this approach will be presented. An extension of the (SMM) approach to target other viral RNAs, or virus-specified RNAs, will be presented. Finally, where target specificity, endosomal release, cellular penetration and toxicity have been the primary obstacle to successful ?macromolecule therapeutics?, methodological advances will be reviewed.