Illuminating Old Catalysts for the Synthesis of Anti-infective HIV Peptides

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PROJECT SUMMARY Since its first recognition in the early 1980s, HIV has claimed more than 32 million lives worldwide. Before the introduction of antiretroviral therapy in the 1990s, an individual infected with HIV could progress to AIDS the most advanced stage of HIV infection, and the deadliest (~11-month survival after diagnosis)very quickly. But today, with early treatment, a person diagnosed with HIV can live nearly as long as someone without the disease. Unfortunately, there is no cure for HIV. More troubling, the current repertoire of life-saving antiretroviral drugs that keep the HIV infection in check are losing their hold over the infection. In the last decade, poor patient compliance (skipping daily antiretroviral doses) combined with environmental factors have led to mutations in the HIV virus that lead to drug-resistant strains. Now more than ever, new therapies that attack new viral targets are desperately needed to combat the global HIV pandemic. Like all viruses, the life-cycle of HIV-1 relies on host cell machinery. The virus infects CD4+ T-lymphocytes (a specific population of white blood cells) and uses the cell to replicate the viral genome, assemble new virus particles, and unleash copies of the virus to infect more CD4+ T-lymphocytes. The formation of new virus particles can only occur if the viral RNA is identified among the vast array of other RNAs within the cell and successfully recruited to the Gag complex. This essential recognition and recruitment process is accomplished entirely by the Gag-nucleocapsid protein (NCp7). In brief, the nucleocapsid identifies a conserved region of viral RNA (known as RNA), located on stem loop 3 (SL3) of the viral RNA strand and then helps to package the collected RNA strands into a new virus particle. If this assembly process is interrupted, the virus will be unable to produce replication competent virions and to exit the host cell, thereby inhibiting the final stages of viral replication. Those considerations in mind, the SL3RNA-NCp7 complex has become a prime target for next- generation antiretrovirals. The quest for molecules which selectively inhibit the SL3RNA-NCp7 interaction has followed several lines of approach. One promising avenue has been to use peptides. To this end, a synthetic hexapeptide (HKWPWW; HP1) was recently described that showed high affinity for the SL3 tetraloop of RNA, disrupting the binding of NCp7 and causing inhibition of HIV-1 replication in vitro. While a promising lead for drug development, the mechanism by which HP1 recognizes and binds to SL3-RNA is still ill-defined. Our goals will be to interrogate the structure activity relationships for HP1 binding to RNA using high-throughput amino acid diversification (substituting key residues in HP1 for non-proteinogenic variants) in tandem with in silico modeling. From these insights, structural optimization of HP1 to enhance its binding affinity to RNA will be explored as a contemporary strategy to develop a new class of inhibitors of HIV-1 replication.