Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science

It is well documented that the majority of adults, children and families in need of evidence-based behavioral health interventionsi do not receive them [1, 2] and that few robust empirically supported methods for implementing evidence-based practices (EBPs) exist. The Society for Implementation Research Collaboration (SIRC) represents a burgeoning effort to advance the innovation and rigor of implementation research and is uniquely focused on bringing together researchers and stakeholders committed to evaluating the implementation of complex evidence-based behavioral health interventions. Through its diverse activities and membership, SIRC aims to foster the promise of implementation research to better serve the behavioral health needs of the population by identifying rigorous, relevant, and efficient strategies that successfully transfer scientific evidence to clinical knowledge for use in real world settings [3]. SIRC began as a National Institute of Mental Health (NIMH)-funded conference series in 2010 (previously titled the “Seattle Implementation Research Conference”; $150,000 USD for 3 conferences in 2011, 2013, and 2015) with the recognition that there were multiple researchers and stakeholdersi working in parallel on innovative implementation science projects in behavioral health, but that formal channels for communicating and collaborating with one another were relatively unavailable. There was a significant need for a forum within which implementation researchers and stakeholders could learn from one another, refine approaches to science and practice, and develop an implementation research agenda using common measures, methods, and research principles to improve both the frequency and quality with which behavioral health treatment implementation is evaluated. SIRC’s membership growth is a testament to this identified need with more than 1000 members from 2011 to the present.ii SIRC’s primary objectives are to: (1) foster communication and collaboration across diverse groups, including implementation researchers, intermediariesi, as well as community stakeholders (SIRC uses the term “EBP champions” for these groups) – and to do so across multiple career levels (e.g., students, early career faculty, established investigators); and (2) enhance and disseminate rigorous measures and methodologies for implementing EBPs and evaluating EBP implementation efforts. These objectives are well aligned with Glasgow and colleagues’ [4] five core tenets deemed critical for advancing implementation science: collaboration, efficiency and speed, rigor and relevance, improved capacity, and cumulative knowledge. SIRC advances these objectives and tenets through in-person conferences, which bring together multidisciplinary implementation researchers and those implementing evidence-based behavioral health interventions in the community to share their work and create professional connections and collaborations

Binding mode and potency of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors targeting Trypanosoma cruzi CYP51.

Chagas disease is a chronic infection in humans caused by Trypanosoma cruzi and manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8 million people infected with T. cruzi worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component in eukaryotes, is a promising drug target in T. cruzi. We report the structure-activity relationships (SAR) of an N-arylpiperazine series of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors designed to probe the impact of substituents in the terminal N-phenyl ring on binding mode, selectivity and potency. Depending on the substituents at C-4, two distinct ring binding modes, buried and solvent-exposed, have been observed by X-ray structure analysis (resolution of 1.95-2.48 Å). The 5-chloro-substituted analogs 9 and 10 with no substituent at C-4 demonstrated improved selectivity and potency, suppressing ≥ 99.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days

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 Î-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

Erratum: Lead identification to clinical candidate selection: drugs for Chagas disease (Journal of Biomolecular Screening (2015) 20 (101-111)

R. Jeffrey Neitz, Steven Chen, Frantisek Supek, Vince Yeh, Danielle Kellar, Jiri Gut, Clifford Bryant, Alejandra Gallardo-Godoy, Valentina Molteni, Steven L. Roach, Arnab K. Chatterjee, Stephanie Robertson, Adam R. Renslo, Michelle Arkin, Richard Glynne, James McKerrow, and Jair L. Siqueira-Neto. Lead Identification to Clinical Candidate Selection: Drugs for Chagas Disease J. Biomol. Screen. 2015, 20, 101-111. (Original doi:10.1177/1087057114553103) In the January 2015 issue of the Journal of Biomolecular Screening, the names of two authors were not published with this article, Shilpi Khare and Monique Stinson. Their names should have appeared after Steven L. Roach, and the affiliation for both of the missing authors is the Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA, USA

Machine Learning Models and Pathway Genome Data Base for <i>Trypanosoma cruzi</i> Drug Discovery

<div><p>Background</p><p>Chagas disease is a neglected tropical disease (NTD) caused by the eukaryotic parasite <i>Trypanosoma cruzi</i>. The current clinical and preclinical pipeline for <i>T</i>. <i>cruzi</i> is extremely sparse and lacks drug target diversity.</p><p>Methodology/Principal Findings</p><p>In the present study we developed a computational approach that utilized data from several public whole-cell, phenotypic high throughput screens that have been completed for <i>T</i>. <i>cruzi</i> by the Broad Institute, including a single screen of over 300,000 molecules in the search for chemical probes as part of the NIH Molecular Libraries program. We have also compiled and curated relevant biological and chemical compound screening data including (i) compounds and biological activity data from the literature, (ii) high throughput screening datasets, and (iii) predicted metabolites of <i>T</i>. <i>cruzi</i> metabolic pathways. This information was used to help us identify compounds and their potential targets. We have constructed a Pathway Genome Data Base for <i>T</i>. <i>cruzi</i>. In addition, we have developed Bayesian machine learning models that were used to virtually screen libraries of compounds. Ninety-seven compounds were selected for <i>in vitro</i> testing, and 11 of these were found to have EC₅₀ < 10μM. We progressed five compounds to an <i>in vivo</i> mouse efficacy model of Chagas disease and validated that the machine learning model could identify <i>in vitro</i> active compounds not in the training set, as well as known positive controls. The antimalarial pyronaridine possessed 85.2% efficacy in the acute Chagas mouse model. We have also proposed potential targets (for future verification) for this compound based on structural similarity to known compounds with targets in <i>T</i>. <i>cruzi</i>.</p><p>Conclusions/ Significance</p><p>We have demonstrated how combining chemoinformatics and bioinformatics for <i>T</i>. <i>cruzi</i> drug discovery can bring interesting <i>in vivo</i> active molecules to light that may have been overlooked. The approach we have taken is broadly applicable to other NTDs.</p></div

Targeting Ergosterol Biosynthesis in <i>Leishmania donovani</i>: Essentiality of Sterol 14alpha-demethylase

<div><p><i>Leishmania</i> protozoan parasites (Trypanosomatidae family) are the causative agents of cutaneous, mucocutaneous and visceral leishmaniasis worldwide. While these diseases are associated with significant morbidity and mortality, there are few adequate treatments available. Sterol 14alpha-demethylase (CYP51) in the parasite sterol biosynthesis pathway has been the focus of considerable interest as a novel drug target in <i>Leishmania</i>. However, its essentiality in <i>Leishmania donovani</i> has yet to be determined. Here, we use a dual biological and pharmacological approach to demonstrate that CYP51 is indispensable in <i>L</i>. <i>donovani</i>. We show via a facilitated knockout approach that chromosomal <i>CYP51</i> genes can only be knocked out in the presence of episomal complementation and that this episome cannot be lost from the parasite even under negative selection. In addition, we treated wild-type <i>L</i>. <i>donovani</i> and CYP51-deficient strains with 4-aminopyridyl-based inhibitors designed specifically for <i>Trypanosoma cruzi</i> CYP51. While potency was lower than in <i>T</i>. <i>cruzi</i>, these inhibitors had increased efficacy in parasites lacking a <i>CYP51</i> allele compared to complemented parasites, indicating inhibition of parasite growth via a CYP51-specific mechanism and confirming essentiality of CYP51 in <i>L</i>. <i>donovani</i>. Overall, these results provide support for further development of CYP51 inhibitors for the treatment of visceral leishmaniasis.</p></div

4‑Aminopyridyl-Based CYP51 Inhibitors as Anti-Trypanosoma cruzi Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency

CYP51 is a P450 enzyme involved in the biosynthesis of the sterol components of eukaryotic cell membranes. CYP51 inhibitors have been developed to treat infections caused by fungi, and more recently the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize drug candidates for T. cruzi CYP51 (<i>Tc</i>CYP51), we explored the structure–activity relationship (SAR) of a <i>N</i>-indolyl-oxopyridinyl-4-aminopropanyl-based scaffold originally identified in a target-based screen. This scaffold evolved via medicinal chemistry to yield orally bioavailable leads with potent anti-T. cruzi activity in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase, we prioritized the biaryl and <i>N</i>-arylpiperazine analogues by oral bioavailability and potency. The drug–target complexes for both scaffold variants were characterized by X-ray structure analysis. Optimization of both binding mode and pharmacokinetic properties of these compounds led to potent inhibitors against experimental T. cruzi infection

Binding Mode and Potency of <i>N</i>‑Indolyloxopyridinyl-4-aminopropanyl-Based Inhibitors Targeting <i>Trypanosoma cruzi</i> CYP51

Chagas disease is a chronic infection in humans caused by <i>Trypanosoma cruzi</i> and manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8 million people infected with <i>T. cruzi</i> worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component in eukaryotes, is a promising drug target in <i>T. cruzi</i>. We report the structure–activity relationships (SAR) of an <i>N</i>-arylpiperazine series of <i>N</i>-indolyloxopyridinyl-4-aminopropanyl-based inhibitors designed to probe the impact of substituents in the terminal N-phenyl ring on binding mode, selectivity and potency. Depending on the substituents at C-4, two distinct ring binding modes, buried and solvent-exposed, have been observed by X-ray structure analysis (resolution of 1.95–2.48 Å). The 5-chloro-substituted analogs <b>9</b> and <b>10</b> with no substituent at C-4 demonstrated improved selectivity and potency, suppressing ≥99.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days

The Manatee [2013]

The Manatee is a literary journal run by the students of Southern New Hampshire Universit