Expanding the known structure space for RNA binding: a test of 2,5-diketopiperazine.

As the importance of RNA as a therapeutic target has become increasingly recognized, the need for new chemotypes able to bind RNA has grown in significance. We hypothesized that diketopiperazines (DKPs), common substructures in natural products and protein-targeting therapeutic agents, could serve as effective scaffolds for targeting RNA. To confirm this hypothesis, we designed and synthesized two analogs, one incorporating a DKP and one not, of compounds previously demonstrated to bind an RNA critical to the life cycle of HIV-1 with high affinity and specificity. Prior to compound synthesis, calculations employing density functional methods and molecular mechanics conformational searches were used to confirm that the DKP could present functionality in a similar (albeit not identical) orientation to the non DKP-containing compound. We found that both the DKP-containing and parent compound had similar affinities to the target RNA as measured by surface plasmon resonance (SPR). Both compounds were found to have modest but equal anti-HIV activity. These results establish the feasibility of using DKPs to target RNA.

Antibacterial Copper-Hydroxyapatite Composite Coatings via Electrochemical Synthesis.

Antibacterial copper-hydroxyapatite (Cu-HA) composite coatings on titanium were synthesized using a novel process consisting of two consecutive electrochemical reactions. In the first stage, HA nanocrystals were grown on titanium using the cathodic electrolytic synthesis. The HA-coated titanium was then used as the cathode in a second reaction stage to electrochemically reduce Cu2+ ions in solution to metallic Cu nanoparticles. Reaction conditions were found that result in nanoscale Cu particles growing on the surface of the HA crystals. The two-stage synthesis allows facile control of copper content in the HA coatings. Antibacterial activity was measured by culturing Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive) in the presence of coatings having varying copper contents. The coatings displayed copper concentration-dependent antibacterial activity against both types of bacteria, likely due to the slow release of copper ions from the coatings. The observation of antibacterial activity from a relatively low loading of copper on the bioactive HA support suggests that multifunctional implant coatings can be developed to supplement or supplant prophylactic antibiotics used in implant surgery that are responsible for creating resistant bacteria strains.

HIV-1 Frameshift RNA-Targeted Triazoles Inhibit Propagation of Replication-Competent and Multi-Drug-Resistant HIV in Human Cells.

The HIV-1 frameshift-stimulating (FSS) RNA, a regulatory RNA of critical importance in the virus' life cycle, has been posited as a novel target for anti-HIV drug development. We report the synthesis and evaluation of triazole-containing compounds able to bind the FSS with high affinity and selectivity. Readily accessible synthetically, these compounds are less toxic than previously reported olefin congeners. We show for the first time that FSS-targeting compounds have antiviral activity against replication-competent HIV in human cells, including a highly cytopathic, multidrug-resistant strain. These results support the viability of the HIV-1 FSS RNA as a therapeutic target and more generally highlight opportunities for synthetic molecule-mediated interference with protein recoding in a wide range of organisms.