RNA interference approaches for treatment of HIV-1 infection

HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi-based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery

Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores

Carboranes represent a potentially rich but underutilized class of inorganic and catabolism-inert pharmacophores. The regioselectivity and ease of derivatization of carboranes allows for facile syntheses of a wide variety of novel structures. The steric bulk, rigidity, and ease of B- and C-derivatization and lack of π-interactions associated with hydrophobic carboranes may be exploited to enhance the selectivity of previously identified bioactive molecules. Transthyretin (TTR) is a thyroxine-transport protein found in the blood that has been implicated in a variety of amyloid related diseases. Previous investigations have identified a variety of nonsteroidal antiinflammatory drugs (NSAIDs) and structurally related derivatives that imbue kinetic stabilization to TTR, thus inhibiting its dissociative fragmentation and subsequent aggregation to form putative toxic amyloid fibrils. However, the cyclooxygenase (COX) activity associated with these pharmaceuticals may limit their potential as long-term therapeutic agents for TTR amyloid diseases. Here, we report the synthesis and evaluation of carborane-containing analogs of the promising NSAID pharmaceuticals previously identified. The replacement of a phenyl ring in the NSAIDs with a carborane moiety greatly decreases their COX activity with the retention of similar efficacy as an inhibitor of TTR dissociation. The most promising of these compounds, 1-carboxylic acid-7-[3-fluorophenyl]-1,7-dicarba-closo-dodecaborane, showed effectively no COX-1 or COX-2 inhibition at a concentration more than an order of magnitude larger than the concentration at which TTR dissociation is nearly completely inhibited. This specificity is indicative of the potential for the exploitation of the unique properties of carboranes as potent and selective pharmacophores

Alex Baine's women's emancipation in Uganda: a visual archive of the history of a new generation of women in Uganda

Alex Baine is a contemporary Ugandan woman artist who graduated from the Margaret Trowell School of Industrial and Fine Art (or MTSIFA) in 1989. During her final year, she painted a large work, Women's Emancipation in Uganda (Fig. 1) (1989), in which she represented women in domestic and nondomestic (conventional and unconventional) economies, spaces, and histories. Baine has not produced any other painting since her graduation. It is evident that Baine's art career, like those of several other female graduates of the Art School, has been interrupted by many issues including family, business, further education, and diversion into other professions. However, in this article I acknowledge that she championed women's emancipation in Uganda's contemporary art in the 1980s, a debate that I trace in her work