Novel Nucleic Acid Binding Small Molecules Discovered Using DNA-Encoded Chemistry.

Inspired by the many reported successful applications of DNA-encoded chemical libraries in drug discovery projects with protein targets, we decided to apply this platform to nucleic acid targets. We used a 120-billion-compound set of 33 distinct DNA-encoded chemical libraries and affinity-mediated selection to discover binders to a panel of DNA targets. Here, we report the successful discovery of small molecules that specifically interacted with DNA G-quartets, which are stable structural motifs found in G-rich regions of genomic DNA, including in the promoter regions of oncogenes. For this study, we chose the G-quartet sequence found in the c-myc promoter as a primary target. Compounds enriched using affinity-mediated selection against this target demonstrated high-affinity binding and high specificity over DNA sequences not containing G-quartet motifs. These compounds demonstrated a moderate ability to discriminate between different G-quartet motifs and also demonstrated activity in a cell-based assay, suggesting direct target engagement in the cell. DNA-encoded chemical libraries and affinity-mediated selection are uniquely suited to discover binders to targets that have no inherent activity outside of a cellular context, and they may also be of utility in other nucleic acid structural motifs.

Hepatocellular carcinoma among US and non-US-born patients with chronic hepatitis B: Risk factors and age at diagnosis.

BACKGROUND: Risk factors for hepatocellular carcinoma (HCC) have not been well characterized among African immigrants with chronic hepatitis B virus (HBV) infection. We conducted a case-control study to identify demographic and clinical factors associated with HCC among a diverse cohort of patients with chronic HBV infection seen in a large academic health setting. METHODS: We identified a total of 278 patients with HCC and chronic HBV seen at two medical centers in a 14-year span from January 2002 to December 2015. These cases were age- and sex-matched in a 1:3 ratio with 823 non-cancer control subjects with chronic HBV. Conditional logistic regression was used to estimate the odds of HCC by race, with black race stratified by African-born status, after adjusting for diabetes, HIV or HCV coinfection, alcohol misuse and cirrhosis. RESULTS: Of the 278 HCC cases, 67% were 60 years of age or older, 78% were male, 87% had cirrhosis and 72% were Asian. HIV infection was present in 6% of cases. Only 7% (19 of 278) of HCC cases were black, of whom 14 were African immigrants. The median age at HCC diagnosis was 44 years in Africans. Notably, nearly all (93%) of the African-born patients with HCC were diagnosed at an age younger than 60 years compared with 52% of Asian cases (P<0.001). The main factors independently associated with greater odds of HCC overall were Asian race (adjusted odds ratio [aOR] 3.3, 95% confidence interval [CI] 1.9-5.5) and cirrhosis (aOR 19.7, 95% CI 12.2-31.8). CONCLUSION: African immigrants accounted for a small proportion of HBV-associated HCC cases overall compared with Asians but appeared to have greater likelihood of early-onset HCC. Optimal strategies for HCC prevention in these key subroups with chronic HBV warrant further study.

Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology.

Millions of individuals are infected with and die from tuberculosis (TB) each year, and multidrug-resistant (MDR) strains of TB are increasingly prevalent. As such, there is an urgent need to identify novel drugs to treat TB infections. Current frontline therapies include the drug isoniazid, which inhibits the essential NADH-dependent enoyl-acyl-carrier protein (ACP) reductase, InhA. To inhibit InhA, isoniazid must be activated by the catalase-peroxidase KatG. Isoniazid resistance is linked primarily to mutations in the katG gene. Discovery of InhA inhibitors that do not require KatG activation is crucial to combat MDR TB. Multiple discovery efforts have been made against InhA in recent years. Until recently, despite achieving high potency against the enzyme, these efforts have been thwarted by lack of cellular activity. We describe here the use of DNA-encoded X-Chem (DEX) screening, combined with selection of appropriate physical properties, to identify multiple classes of InhA inhibitors with cell-based activity. The utilization of DEX screening allowed the interrogation of very large compound libraries (1011 unique small molecules) against multiple forms of the InhA enzyme in a multiplexed format. Comparison of the enriched library members across various screening conditions allowed the identification of cofactor-specific inhibitors of InhA that do not require activation by KatG, many of which had bactericidal activity in cell-based assays.

Immigration within the United States: prevalence of childhood hearing loss revisited.

PURPOSE: As more adult and child immigrants enter the United States each year, there is a high likelihood that the prevalence of childhood hearing loss in the United States is underestimated, given estimations of the number of immigrant children entering the country with hearing loss. METHOD: Information was collected using online search engines and peer-reviewed journals. The most recent articles available through search engines included in EBSCOhost at the time were used. The gathered data were organized by emigrating country, and the 2 countries with the highest immigration rates were presented. Estimations of the number of children immigrating with hearing loss were made using data from published peer-reviewed articles and government reports on immigration. CONCLUSIONS: The prevalence of hearing loss in the United States is underestimated when considering undetected hearing loss in immigrant children. The addition of the immigrant children from only Mexico and China presents a 7.5% increase in the total number of children in the United States with hearing loss. This reinforces the importance of early detection of hearing loss in these children, resulting in more accurate estimation of the rate of childhood hearing loss in the United States and better planning for intervention programs.