Lead identification to clinical candidate selection: drugs for Chagas disease.

Chagas disease affects 8 million people worldwide and remains a main cause of death due to heart failure in Latin America. The number of cases in the United States is now estimated to be 300,000, but there are currently no Food and Drug Administration (FDA)-approved drugs available for patients with Chagas disease. To fill this gap, we have established a public-private partnership between the University of California, San Francisco and the Genomics Institute of the Novartis Research Foundation (GNF) with the goal of delivering clinical candidates to treat Chagas disease. The discovery phase, based on the screening of more than 160,000 compounds from the GNF Academic Collaboration Library, led to the identification of new anti-Chagas scaffolds. Part of the screening campaign used and compared two screening methods, including a colorimetric-based assay using Trypanosoma cruzi expressing ß-galactosidase and an image-based, high-content screening (HCS) assay using the CA-I/72 strain of T. cruzi. Comparing molecules tested in both assays, we found that ergosterol biosynthesis inhibitors had greater potency in the colorimetric assay than in the HCS assay. Both assays were used to inform structure-activity relationships for antiparasitic efficacy and pharmacokinetics. A new anti-T. cruzi scaffold derived from xanthine was identified, and we describe its development as lead series.

The role of mindfulness skills in terms of distress tolerance: a pilot test among adult daily smokers.

BACKGROUND AND OBJECTIVES: Low distress tolerance is associated with difficulties quitting smoking. Mindfulness is associated with improved cessation outcomes and may be one method by which to increase distress tolerance. The purpose of the current study was to examine the relationship between mindfulness skills and distress tolerance among regular smokers. METHODS: Daily smokers (n=125; Mage=37.5, 70% male) completed self-report measures assessing smoking and emotions. RESULTS: After controlling for age, gender, and nicotine dependence, and education the mindfulness skills of acting with awareness and accepting without judgment significantly predicted distress tolerance. DISCUSSION AND CONCLUSIONS: For smokers, being able to pay attention to present moment vents and accept negative events without judgment is associated with a greater ability to withstand such events. SCIENTIFIC SIGNIFICANCE: These findings suggest that mindfulness-based approaches to smoking cessation may be effective because of improvements in distress tolerance. However, future prospective and laboratory-based studies are needed to better understand the mindfulness-distress tolerance link among smokers.

Drug discovery for neglected tropical diseases at the Sandler Center.

The Sandler Center's approach to target-based drug discovery for neglected tropical diseases is to focus on parasite targets that are homologous to human targets being actively investigated in the pharmaceutical industry. In this way we attempt to use both the know-how and actual chemical matter from other drug-development efforts to jump start the discovery process for neglected tropical diseases. Our approach is akin to drug repurposing, except that we seek to repurpose leads rather than drugs. Medicinal chemistry can then be applied to optimize the leads specifically for the desired antiparasitic indication.