Editorial Cite This: ACS Chem. Neurosci. 2019, 10, 1−4
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Editors’ Favorites: Best of 2018
ACS Chem. Neurosci. 2019.10:1-4. Downloaded from pubs.acs.org by 91.243.90.254 on 01/20/19. For personal use only.
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lead compounds for drug development.2 The identification of two compounds that act as anticonvulsants in multiple species and the demonstration that targeting GSK-3 can reduce seizures will be important for the epilepsy field going forward. The study further demonstrated the power of collaboration with plant biologists and the joining of forces associated with traditional medicine approaches and synthetic methods of drug development. This multicontinent study involved authors from Vrije Universiteit Brussel, Belgium, the University of Leuven, Belgium, the Salama Neuroscience Center, Democratic Republic of the Congo, the University of Strathclyde, Scottland, and Muhimbili University of Health & Allied Sciences, Tanzania! Associate Editor Prof. Anne Andrews (University of California, Los Angeles) highlighted two ACS Chemical Neuroscience publications on “caged” opioids. More than a hundred people die each day in the United States from opioid overdose. Misuse and addiction involving prescription drugs to treat pain or illicit opioids, such as heroin, have resulted in the current U.S. public-health crisis. Improved tools to investigate brain opioid systems are needed to improve fundamental understanding of the neurobiology of these systems and to develop new treatments for substance use disorder.
he year 2018 was the best to-date for ACS Chemical Neuroscience. The journal broke records for numbers of citations and manuscript submissions, while setting new records at American Chemical Society Publications for growth in numbers of papers downloaded. As Editors of ACS Chemical Neuroscience, we are thrilled to see the quality and impact of papers published in the journal continue to rise. Similar to 2017,1 we selected our favorite papers of 2018 to highlight here. As in years past, this proved a challenging task as there were many exciting papers to choose from. Prof. Catherine Abbott of the University of Edinburgh, one of two new Associate Editors, was intrigued by a paper identifying GSK-3 as a target for epilepsy.2 Epilepsy is often perceived as a condition characterized by one-time or occasional seizures. At one extreme, this is the case. However, at the other, epilepsy is a devastating disorder, particularly early onset epilepsy, which can have detrimental effects on brain development. There is a large, unmet need for novel therapies. Researchers are developing new high-throughput systems to screen antiepileptic drug candidates. A promising new system is the zebrafish larval model. Zebrafish larvae exhibit seizurelike behavior in response to pentylenetetrazol (PTZ), which is commonly used to produce experimental seizures in other vertebrates. Zebrafish larvae PTX-induced seizures respond well to conventional antiepileptic drugs, validating this model for screens of new therapeutic entities.
The zebrafish larvae system was used to vet extracts from traditional medicinal plants found near the Congo River for anticonvulsant activity.2 Having identified antiseizure properties in crude extracts from Indigofera arrecta, the authors used the larval screening system further as an in vivo bioassay to identify anticonvulsant activity following extract fractionation. Indirubin, an inhibitor of glycogen synthase kinase (GSK-3), was identified as the bioactive component in I. arrecta. The authors showed that indirubin and another GSK-3 inhibitor, BIO-acetoxime, reduced seizure behaviors and epileptiform discharges, identified by electroencephalography, in zebrafish larvae. Importantly, both drugs show anticonvulsant activity in rat and mouse epilepsy models. Valproate, one of the most commonly prescribed antiepileptic drugs, has been shown to inhibit GSK-3 nonselectively. The work by Aourz et al. firmly identified GSK-3 as a specific therapeutic target for treating epilepsy. This paper by Najat Aourz. was significant in a number of aspects. Fractionation was used to advantage to demonstrate that identifying bioactive components in traditional plant extracts is an effective and viable route for ascertaining new © 2019 American Chemical Society
Caging, as the name implies, protects and thereby inactivates a ligand. When activated, by light (photolysis), for example, the caging group is cleaved to produce active drug or endogenous neurotransmitter, which binds to receptors with high spatial and temporal precision. A letter from Bernardo Sabatini and coauthors at the Howard Hughes Medical Institute at Harvard Medical School and the University of California, San Diego reported the synthesis and testing of an optimized caged opioid peptide.3 The endogenous peptide leu-enkephalin interacts with two subtypes of opiod receptorsmu and delta receptors. An optimized caged leu-enkephalin was activated by inexpensive UV-LED light. The uncaged peptide activated both receptor subtypes in mouse hippocampal slices. Importantly, the caged compound showed greatly reduced Published: January 16, 2019 1
DOI: 10.1021/acschemneuro.8b00717 ACS Chem. Neurosci. 2019, 10, 1−4
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affinity for delta opioid receptors compared to previously reported caged leu-enkephalins.
Sabatini and coauthors had previously reported on the synthesis and characterization of caged naloxone.4 Naloxone is a drug that blocks opioid receptors, and when administered shortly after overdose naloxone can be life-saving. Since naloxone is an antagonist, it has advantages over agonists for investigating the kinetics of inhibiting/deactivating opioid receptors. In an article published in ACS Chemical Neuroscience, Anita Lewin, Ivy Carroll, and colleagues at the Research Triangle Institute reported an approach for producing caged naloxone (CNV-NLX) at laboratory scale and using common starting materials.5 Naloxone is a diastereomer with four chiral centers; the addition of the caging group adds a fifth stereocenter. Lewin et al. characterized nuclear magnetic resonance spectra assigning all proton and carbon resonances associated with both CNV-NLX diastereomers. They found that CNV-NLX was stable for at least 1 week when dissolved in a number of different common solvents and was resistant to uncaging when exposed to fluorescent overhead lighting or low-intensity blue light. Moreover, they characterized the uncaged products produced by UV light. Their findings indicate some caution in the use of CNV-NLX for biological studies associated with potential toxicity of the released caging groups and uncertainty surrounding the proportion of biologically active diastereomer following synthesis of CNVNLX. Associate Editor Prof. Jacob Hooker of Massachusetts General Hospital and Harvard Medical School found interesting a pair of papers focused on neurodegeneration, which is the brain-health challenge of our generation. Due to complexity of the human brain, simultaneous hypothesis testing will be needed to identify the origins of neurodegenerative processes. We have learned from top-down approaches about genetic variation in brain-cell populations, for example, through recent discoveries of somatic gene recombination6 and new technologies including single-cell sequencing.7 We must, however, improve understanding of the molecular processes that define brain diseases from the bottom up. Two papers published in ACS Chemical Neuroscience in 2018 are exemplary in the latter regard. In the first, Kundel et al.8 used single-molecule spectroscopy to study how the protein tau aggregates and amplifies filament fragmentation. Since tauopathies9 and related diseases begin in vulnerable brain regions and spread as diseases progress, understanding the fundamental biophysical behavior of key disease-associated molecules will lead to new treatment concepts. Techniques such as single-molecule spectroscopy may also prove valuable as assays for the development of intervention strategies that alter tau aggregation or amplification processes.
In the second paper, a battery of assays and computational analyses were used, in combination, to identify potential smallmolecule binding sites on α-synuclein fibrils.10 Synuclein aggregates are a hallmark of Parkinson’s disease (PD), yet little is known about how to design small molecules that recognize α-synuclein for use in positron emission tomography (PET) imaging or for therapeutic discovery. In fact, small-molecule discovery for PET imaging of α-synuclein has been so refractory that the Michael J. Fox (MJF) Foundation recently offered a $2 million prize to the first team to develop a viable, selective α-synuclein PET tracer and agreed to make that tracer broadly available to academic and industry researchers. The work by Hsieh et al. is an important step toward helping the field to achieve the critical goal of discovering an α-synuclein PET tracer and will aid whoever ultimately wins the MJF prize!
Parkinson’s disease is a common movement disorder characterized by progressive loss of dopamine neurons in the midbrain. The diagnosis of PD relies primarily on clinical evaluation. However, it is not easy to diagnose early PD or to distinguish PD from other disorders with predominant movement impairment, such as essential tremor, progressive supranuclear palsy, or multiple system atrophy. An objective measure is needed to diagnose PD accurately and early in its progression to improve treatment. Prof. Jiawei Zhou of the 2
DOI: 10.1021/acschemneuro.8b00717 ACS Chem. Neurosci. 2019, 10, 1−4
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Institute on Neuroscience, Chinese Academy of Sciences, Shanghai, China, another new Associate Editor, selected a paper by John Finberg, Hossam Haick, and coauthors at the Technion in Haifa, Isreal as his favorite paper published ACS Chemical Neuroscience in 2018. The authors developed an electronic “nose” screening and diagnostic technology to detect volatile organic compounds in exhaled breath that de novo identified PD subjects.11 The sensitivity, specificity, and accuracy of the sensor array to identify PD vs control subjects were similar to commonly used clinical approaches for PD diagnosis, such as midbrain ultrasonography. The authors showed that increased levels of benzaldehyde in PD patients, together with acetophenone, are a molecular signature differentiating PD and control individuals. This study, along with the authors’ previous work in animal models,12 demonstrates the potential of sensor arrays to detect PD. Rare individuals with highly discriminatory olfaction have also recently been found to identify PD patients, even prior to clinical diagnosis (McFadden, J., The Telegraph, December 19, 2017). Nonetheless, sensor technologies would be more easily translated to the clinic. The identification of metabolites in exhaled breath suggests that these compounds may serve as biomarkers for PD diagnosis. These findings also support the notion that while PD is largely considered a central nervous system disorder, it may also involve peripheral tissues and organs. Whether alterations in exhaled breath composition in PD patients merely reflect dysregulated metabolism or are a result of dysfunction of the respiratory system during the disease course, needs to be investigated in the future.
tactics for psychoactive drug production. In this seminal piece, the authors encyclopedically describe all known routes to synthesize morphine, codeine, hydrocodone, oxycodone, buprenorphine, naloxone, opium, krokodil demerol, fentanyl, methodone, valium, xanax, cocaine, crack, amphetamine, MDMA, LSD, ketamine, PCP, and mescaline. Not only does this review cover pharmaceutical and professional chemistry approaches, but also those of clandestine chemists and crude, “bucket approaches” for street preparation.14 Intertwined with the syntheses are historical anecdotes, discussions of pharmacology, and mechanistic insights. The review by Chamber et al. represents a compendium of synthetic chemistry and a unique teaching tool. There is no other review like it, and rereading yielded new information and insights each time. Clearly, Prof. Lindsley is not alone as the review by Townsend and coauthors has been downloaded >2000 times as of this writing, placing it in the top 5% of all research outputs by Altmetric. Overall, 2018 was a highly impactful year at ACS Chemical Neuroscience. Looking forward, next year will be our 10th year of publishing ACS Chemical Neuroscience. We wish all of our authors, reviewers, readers, and staff a Happy New Year and look forward to your submissions and to sharing your science with the neuroscience and chemistry communities and beyond in 2019.
Editor-in-Chief Craig Lindsley (Vanderbilt University) examines all manuscripts submitted to ACS Chemical Neuroscience. In doing so, he witnesses firsthand the ways in which authors broaden, shape, and creatively impact the scope of the journal and the field of neuroscience. Selecting favorites out of many truly impactful papers was more difficult this year than in all previous years. Nonetheless, the following two reviews emerged as his favorites for 2018. The first is a review that discussed the importance of drug-target kinetics in drug discovery.13 Here, Peter Tonge opines on the value of considering time-dependent target occupancy, the benefits of drug-target kinetics (including kinetic and thermodynamic selectivity), and time-dependent drug activity (e.g., resonance time). By assessing and understanding these parameters, an additional dimension of information will be realized for selecting and optimizing drug leads. In particular, prolonging target occupancy has the potential to extend pharmacological activity at low drug concentrations. The latter provides improved therapeutic windows and the potential for reduced side effects. Another favorite review was by Townsend and colleagues of Vanderbilt University that detailed the “DARK” side of total synthesis.14 This review described detailed strategies and
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Craig W. Lindsley, Editor-in-Chief Catherine Abbott, Associate Editor Anne M. Andrews, Associate Editor Jacob M. Hooker, Associate Editor Jiawei Zhou, Associate Editor AUTHOR INFORMATION
ORCID
Craig W. Lindsley: 0000-0003-0168-1445 Anne M. Andrews: 0000-0002-1961-4833 Jacob M. Hooker: 0000-0002-9394-7708 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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REFERENCES
(1) Lindsley, C. W., Cunningham, K. A., Hooker, J. M., and Andrews, A. M. (2018) Editors’ favorites of 2017. ACS Chem. Neurosci. 9, 1−4.
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(2) Aourz, N., Serruys, A-S.K., Chabwine, J. N., Balegamire, P. B., Afrikanova, T., Edrada-Ebel, R., Grey, A. I., Kamuhabwa, A. R., Walrave, L., Esguerra, C. V., van Leuven, F., de Witte, P. A. M., Smolders, I., and Crawford, A. D. (2018) Identification of GSK-3 as a potential therapeutic entry point for epilepsy. ACS Chem. Neurosci., DOI: 10.1021/acschemneuro.8b00281. (3) Banghart, M. R., He, X. J., and Sabatini, B. L. (2018) A caged enkephalin optimized for simultaneously probing mu and delta opioid receptors. ACS Chem. Neurosci. 9, 684−690. (4) Banghart, M. R., Williams, J. T., Shah, R. C., Lavis, L. D., and Sabatini, B. L. (2013) Caged naloxone reveals opioid signaling deactivation kinetics. Mol. Pharmacol. 84, 687−695. (5) Lewin, A. H., Fix, S. E., Zhong, D., Mayer, L. D., Burgess, J. P., Mascarella, S. W., Reddy, P. A., Seltzman, H. H., and Carroll, F. I. (2018) Caged naloxone: Synthesis, characterization, and stability of 3O-(4,5-dimethoxy-2-nitrophenyl)carboxymethyl naloxone (CNVNLX). ACS Chem. Neurosci. 9, 563−567. (6) Lee, M. H., Siddoway, B., Kaeser, G. E., Segota, I., Rivera, R., Romanow, W. J., Liu, C. S., Park, C., Kennedy, G., Long, T., and Chun, J. (2018) Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature 563, 639−645. (7) Macosko, E. Z., Basu, A., Satija, R., Nemesh, J., Shekhar, K., Goldman, M., Tirosh, I., Bialas, A. R., Kamitaki, N., Martersteck, E. M., Trombetta, J. J., Weitz, D. A., Sanes, J. R., Shalek, A. K., Regev, A., and McCarroll, S. A. (2015) Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161, 1202− 1214. (8) Kundel, F., Hong, L., Falcon, B., McEwan, W. A., Michaels, T. C. T., Meisl, G., Esteras, N., Abramov, A. Y., Knowles, T. J. P., Goedert, M., and Klenerman, D. (2018) Measurement of tau filament fragmentation provides insights into prion-like spreading. ACS Chem. Neurosci. 9, 1276−1282. (9) Lindsley, C. W., and Hooker, J. M. (2018) Beyond the amyloid hypothesis of Alzheimer’s disease. ACS Chem. Neurosci. 9, 2519. (10) Hsieh, C. J., Ferrie, J. J., Xu, K., Lee, I., Graham, T. J. A., Tu, Z., Yu, J., Dhavale, D., Kotzbauer, P., Petersson, E. J., and Mach, R. H. (2018) Alpha synuclein fibrils contain multiple binding sites for small molecules. ACS Chem. Neurosci. 9, 2521−2527. (11) Finberg, J. P. M., Schwartz, M., Jeries, R., Badarny, S., Nakhleh, M. K., Abu Daoud, E., Ayubkhanov, Y., Aboud-Hawa, M., Broza, Y. Y., and Haick, H. (2018) Sensor array for detection of early stage Parkinson’s disease before medication. ACS Chem. Neurosci. 9, 2548− 2553. (12) Finberg, J. P. M., Aluf, Y., Loboda, Y., Nakhleh, M. K., Jeries, R., Abud-Hawa, M., Zubedat, S., Avital, A., Khatib, S., Vaya, J., and Haick, H. (2018) Altered volatile organic compound profile in transgenic rats bearing A53T mutation of human α-synuclein: Comparison with dopaminergic and derotonergic denervation. ACS Chem. Neurosci. 9, 291−297. (13) Tonge, P. J. (2018) Drug-target kinetics in drug discovery. ACS Chem. Neurosci. 9, 29−39. (14) Chambers, S. A., DeSousa, J. M., Huseman, E. D., and Townsend, S. D. (2018) The DARK side of total synthesis: Strategies and tactics for psychoactive drug production. ACS Chem. Neurosci. 9, 2307−2330.
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DOI: 10.1021/acschemneuro.8b00717 ACS Chem. Neurosci. 2019, 10, 1−4
