Synthesis of Triaminopyrimidine Derivatives for Inhibition of Inflammatory Caspases

Caspases are cysteine-dependent aspartic proteases whose functions are connected to different mechanisms of cell death and inflammation. As caspase-1 plays a significant role in the immune response, its activity has been of interest as a target for inhibitor development as its inhibition will reduce the levels of pro-inflammatory cytokines in inflammatory diseases, thus minimizing the symptoms that arise and serving as a possible therapeutic approach. Prior work discovered a family of potent inhibitors of caspase-1 with a common triaminopyrimidine scaffold. To further explore structure-activity relationship profiles of potential inhibitors of caspase-1, two different syntheses were attempted to create two new series of analogs for future activity studies. The syntheses presented here were conducted to investigate whether the variation of the amino groups on the pyrimidine scaffold effect the inhibition of caspase-1. The successful synthesis of the desired compounds has not yet been accomplished, but the optimizations of the reactions for further studies are reported

MDGs 2.0 : what goals, targets and timeframe?

The Millennium Development Goals (MDGs) are widely cited as the primary yardstick against which advances in international development efforts are to be judged. At the same time, the Goals will be met or missed by 2015. It is not too early to start asking what's next? This paper builds on a discussion that has already begun to address potential approaches, goals, and target indicators to help inform the process of developing a second generation of MDGs or ‘MDGs 2.0.’ The paper outlines potential goal areas based on the original Millennium Declaration, the timeframe for any MDGs 2.0 and attempts to calculate some reasonable targets associated with those goal areas

Synthesis of a Small Molecule Nitrosocysteine Inhibitor to Reduce the Activity of Caspase-1

Caspase-1 is an enzyme that is overactive in autoimmune and autoinflammatory diseases cleaving pro-interleukin-1β to the cytokine interleukin-1β (IL-1β), which leads to inflammatory symptoms. The inhibition of caspase-1 will cause a decrease in the concentration of interleukin-1β (IL-1β), resulting in the reduction of inflammatory symptoms. Recent research has revealed that the appending of a nitric oxide (NO) or nitroxyl (HNO) donating group to non-steroidal anti-inflammatory drugs (NSAIDs) reduced, or avoided, the side effects caused by currently available treatments. A small molecule based on a known caspase-1 inhibitor with a nitrosocysteine appended on was synthesized to look at the effect of NO donation on caspase-1

Exploring the context and role of quality of care on HIV outcomes among female sex workers in the Dominican Republic

Female sex workers (FSWs) experience a substantially disproportionate burden of HIV. In the Dominican Republic (DR), FSWs have nearly five times greater odds to be living with HIV compared to other adults. Despite interventions focusing on facilitating FSWs’ engagement in the HIV care continuum, ART adherence and viral suppression remain sub-optimal. It is thus important to assess the contributing role of quality of HIV care on HIV outcomes and explore the mechanisms for improving this care as a means to address FSWs’ pathway to viral suppression. Thematic analysis was used to explore the dynamics contributing to the quality of HIV care among FSWs living in the DR using two rounds of in-depth interviews (IDIs) (n=20 per round) and clinic assessments (n=11). Next, drawing from survey data (n=211), multivariable logistic regressions were used to explore the associations between select individual, provider and clinic level factors, and ART adherence and viral suppression. Lastly, the role of peer navigation in enhancing the quality of HIV care was explored via IDIs and survey data. Results highlighted the influence of treatment literacy, relational aspects of the HIV care experience, availability of resources, and the cost of care on the quality of HIV care experienced by FSWs. Significant associations were found between treatment literacy and ART adherence and viral suppression, while positive patient-provider communication and respectful treatment were significantly associated with being virally suppressed. Cost of care was negatively associated with ART adherence and viral suppression. Peer navigation and support was found to positively enhance the quality of HIV services by promoting linkage and retention in care, respectful treatment, greater access to comprehensive care, and contributing to increasing FSWs’ agency in the clinic environment. Ultimately, peer navigation was linked to increased satisfaction with HIV services and was recommended by FSWs as a mechanism to improve HIV care among FSWs. Findings from this study enhance the understanding of the context and association between HIV care and positive HIV outcomes, including ART adherence and viral suppression, among FSWs. Results highlight areas for programmatic investments to promote effective HIV treatment and care programs targeting key populations disproportionately affected by HIV

A meta-analysis of the relation between therapeutic alliance and treatment outcome in eating disorders.

The therapeutic alliance has demonstrated an association with favorable psychotherapeutic outcomes in the treatment of eating disorders (EDs). However, questions remain about the inter-relationships between early alliance, early symptom improvement, and treatment outcome. We conducted a meta-analysis on the relations among these constructs, and possible moderators of these relations, in psychosocial treatments for EDs. Twenty studies met inclusion criteria and supplied sufficient supplementary data. Results revealed small-to-moderate effect sizes, βs = 0.13 to 0.22 (p < .05), indicating that early symptom improvement was related to subsequent alliance quality and that alliance ratings also were related to subsequent symptom reduction. The relationship between early alliance and treatment outcome was partially accounted for by early symptom improvement. With regard to moderators, early alliance showed weaker associations with outcome in therapies with a strong behavioral component relative to nonbehavioral therapies. However, alliance showed stronger relations to outcome for younger (vs. older) patients, over and above the variance shared with early symptom improvement. In sum, early symptom reduction enhances therapeutic alliance and treatment outcome in EDs, but early alliance may require specific attention for younger patients and for those receiving nonbehaviorally oriented treatments

Vinyl Ether/Tetrazine Pair for the Traceless Release of Alcohols in Cells

The cleavage of a protecting group from a protein or drug under bioorthogonal conditions enables accurate spatiotemporal control over protein or drug activity. Disclosed herein is that vinyl ethers serve as protecting groups for alcohol-containing molecules and as reagents for bioorthogonal bond-cleavage reactions. A vinyl ether moiety was installed in a range of molecules, including amino acids, a monosaccharide, a fluorophore, and an analogue of the cytotoxic drug duocarmycin. Tetrazine-mediated decaging proceeded under biocompatible conditions with good yields and reasonable kinetics. Importantly, the nontoxic, vinyl ether duocarmycin double prodrug was successfully decaged in live cells to reinstate cytotoxicity. This bioorthogonal reaction presents broad applicability and may be suitable for in vivo applications.European Commission; China Scholarship Council; FCT Portugal; MINECO (CTQ2015-70524-R and RYC-2013-14706); EPSRC; Royal Society; European Research Council (TagIt

Approach Matters: The Kinetics of Interfacial Inverse‐Electron Demand Diels-Alder Reactions

Rapid and quantitative click functionalization of surfaces remains an interesting challenge in surface chemistry. In this regard, inverse electron demand Diels-Alder (IEDDA) reactions represent a promising metal‐free candidate. Herein, we reveal quantitative surface functionalization within 15 min. Furthermore, we report the comprehensive effects of substrate stereochemistry, surrounding microenvironment and substrate order on the reaction kinetics as obtained by surface‐bound mass spectrometry (DART‐HRMS)

Tailoring Chimeric Ligands for Studying and Biasing ErbB Receptor Family Interactions

Described is the development and application of a versatile semisynthetic strategy, based on a combination of sortase-mediated coupling and tetrazine ligation chemistry, which can be exploited for the efficient incorporation of tunable functionality into chimeric recombinant proteins. To demonstrate the scope of the method, the assembly of a set of bivalent ligands, which integrate members of the epidermal growth factor (EGF) ligand family, is described. By using a series of bivalent EGFs with variable intraligand spacing, the differences in structure were correlated with the ability to bias signaling in the ErbB receptor family in a cell motility assay. Biasing away from EGFR-HER2 dimerization with a bivalent EGF was observed to reduce cell motility in an intraligand distance-dependent fashion, thus demonstrating the utility of the approach for acutely perturbing receptor-mediated cell signaling pathways.National Cancer Institute (U.S.). Integrative Cancer Biology Program (Grant U54-CA112967)National Institutes of Health (U.S.) (R01DE019523-13)Massachusetts Institute of Technology. Computational and Systems Biology Program. MIT-Merck Postdoctoral FellowshipSwiss National Science Foundation (Postdoctoral Fellowship)National Institute of Environmental Health Sciences (Training Grant in Environmental Toxicology 5-T32-ES007020