The considerable successes associated with the chemotherapy of HIV infection notwithstanding, there remains an urgent need for additional pharmaceutical-based interventions that have reduced toxicities, capitalize upon other mechanisms involved in HIV replication, combat emerging virus strains, and provide salvage therapies when required. A key regulatory component of the HIV genome codes for the tat protein that binds to TAR (Transactive Responsive Region) of HIV RNA to up regulate its transcription by two orders of magnitude. Imbedded in that Tat protein is a short peptide sequence that is largely responsible for binding of Tat to the TAR HIV. Moreover, a similar, overlapping and somewhat longer peptide sequence is responsible for the membrane translocation of Tat protein. Fusion or conjugation of the short membrane translocation sequence to proteins or nucleic acids results in the increased transport (,f normally poorly transportable cargoes across cell membranes. Conjugation of the unique 2',5'-phosphodiester oligoadenylate (p5'A2'p5'A2'p5'A2'p5'A, also known as 2-5A) to antisense oligonucleotides provides a strategy to target the antisense-specified (or complementary) RNA for degradation by recruitment of the constitutive, latent. 2-5A-dependent ribonuclease L (RNase L). This proposal seeks to target the 2-5A to HIV RNA by using the Tat peptide-HIV TAR RNA recognition sequence. In this scenario, the 2-5A moiety covalently appended to the Tat peptide recognition sequence would recruit RNase L to the HIV TAR RNA to insure its selective degradation. A major bonus of this proposed 2-5A-Tat conjugate would be that it would be expected to be taken up efficiently by intact cells by virtue of the tat membrane translocation sequence. This Tat lector-driven transport of 2-5A cargo would provide a major advantage over standard antisense nucleiccid strategies that suffer from inefficient cellular uptake,
| Zhou, Longhu; Thakur, Chandar S; Molinaro, Ross J et al. (2006) Delivery of 2-5A cargo into living cells using the Tat cell penetrating peptide: 2-5A-tat. Bioorg Med Chem 14:7862-74 |
