A Genetically Selected Cyclic Peptide Inhibitor of BCL6 Homodimerization

Publication date: Available online 9 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Eliot L. Osher, Francisco Castillo, Nagarajan Elumalai, Michael J. Waring, Garry Pairaudeau, Ali Tavassoli
We report an inhibitor of the homodimeric protein-protein interaction of the BCL6 oncoprotein, identified from a genetically encoded SICLOPPS library of 3.2 million cyclic hexpeptides in combination with a bacterial reverse two-hybrid system. This cyclic peptide is shown to bind the BTB domain of BCL6, disrupts its homodimerization, and subsequent binding of the SMRT2 corepressor peptide.

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Design, synthesis and biological evaluation of novel spiro-pentacylamides as acetyl-CoA carboxylase inhibitors

Publication date: Available online 9 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Qiangqiang Wei, Liankuo Mei, Yifei Yang, Hui Ma, Hongyi Chen, Huibin Zhang, Jinpei Zhou
Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays an important role in the regulation of fatty acid oxidation. Therefore, ACC inhibition offers a promising option for intervention in nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2DM) and cancer. In this paper, a series of spiro-pentacylamide derivatives were synthesized and evaluated for their ACC1/2 inhibitory activities and anti-proliferation effects on A549, H1975, HCT116, SW620 and Caco-2 cell lines in vitro. Compound 6o displayed potent ACC1/2 inhibitory activity (ACC1 IC50 = 0.527 μM, ACC2 IC50 = 0.397 μM) and the most potent anti-proliferation activities against A549, H1975, HCT116, SW620 and Caco-2 cell lines, with IC50 values of 1.92 μM, 0.38 μM, 1.22 μM, 2.05 μM and 5.42 μM respectively. Further molecular docking studies revealed that compound 6o maintained hydrogen bonds between the two carbonyls and protein backbone NHs (Glu-B2026 and Gly-B1958). These results indicate that compound 6o is a promising ACC1/2 inhibitor for the potent treatment of cancer.

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Development of a microbioreactor for glycoconjugate synthesis

Publication date: Available online 9 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Katsuji Haneda, Takefumi Oishi, Hiroshi Kimura, Toshiyuki Inazu
A microbioreactor immobilized with a synthase-type mutant enzyme, Endo-M-N175Q (glycosynthase) of endo-β-N-acetylglucosaminidase derived from Mucor hiemalis (Endo-M), was constructed and used for glycoconjugate synthesis. The transglycosylation was performed with a reaction mixture containing an oxazoline derivative of sialo complex-type glycoside (SG), which was prepared from a sialo complex-type glycopeptide SGP derived from hen egg yolk, as a glycosyl donor and N-Fmoc-N-acetylglucosaminyl-L-asparagine [Fmoc-Asn(GlcNAc)-OH] as an acceptor. The reaction mixture was injected into a glycosynthase microbioreactor at a constant flow rate. Highly efficient and nearly stoichiometric transglycosylation occurred in the microbioreactor, and the transglycosylation product was eluted from the other end of the reactor. The glycosynthase microbioreactor was stable and could be used repeatedly for a long time.

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Synthesis and fungicidal activity of novel imidazole-based ketene dithioacetals

Publication date: Available online 9 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Stephane Jeanmart, Julien Gagnepain, Pulakesh Maity, Clemens Lamberth, Fredrik Cederbaum, Ramya Rajan, Olivier Jacob, Mathias Blum, Stephane Bieri
Novel imidazole-based ketene dithioacetals show impressive in planta activity against the economically important plant pathogens Alternaria solani, Botryotinia fuckeliana, Erysiphe necator and Zymoseptoria tritici. Especially derivatives of the topical antifungal lanoconazole, which bear an alkynyloxy or a heteroaryl group in the para-position of the phenyl ring, exhibit excellent control of the mentioned phytopathogens. These compounds inhibit 14α -demethylase in the sterol biosynthesis pathway of the fungi. Synthesis routes starting from either benzaldehydes or acetophenones as well as structure-activity relationships are discussed in detail.

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Fine-tuning the physicochemical properties of peptide-based blood-brain barrier shuttles

Publication date: Available online 9 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Somaye Ghasemy, Júlia García-Pindado, Fatemeh Aboutalebi, Kianoush Dormiani, Meritxell Teixidó, Morteza Malakoutikhah
N-methylation is a powerful method to modify the physicochemical properties of peptides. We previously found that a fully N-methylated tetrapeptide, Ac-(N-MePhe)4-CONH2, was more lipophilic than its non-methylated analog Ac-(Phe)4-CONH2. In addition, the former crossed artificial and cell membranes while the latter did not. Here we sought to optimize the physicochemical properties of peptides and address how the number and position of N-methylated amino acids affect these properties. To this end, 15 analogs of Ac-(Phe)4-CONH2 were designed and synthesized in solid-phase. The solubility of the peptides in water and their lipophilicity, as measured by ultra performance liquid chromatography (UPLC) retention times, were determined. To study the permeability of the peptides, the Parallel Artificial Membrane Permeability Assay (PAMPA) was used as an in vitro model of the blood-brain barrier (BBB). Contrary to the parent peptide, the 15 analogs crossed the artificial membrane, thereby showing that N-methylation improved permeability. We also found that N-methylation enhanced lipophilicity but decreased the water solubility of peptides. Our results showed that both the number and position of N-methylated residues are important factors governing the physicochemical properties of peptides. There was no correlation between the number of N-methylated amide bonds and any of the properties measured. However, for the peptides consecutively N-methylated from the N-terminus to the C-terminus (p1, p5, p11, p12 and p16), lipophilicity correlated well with the number of N-methylated amide bonds and the permeability of the peptides. Moreover, the peptides were non-toxic to HEK293T cells, as determined by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay.

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Selective binding and controlled release of anticancer drugs by polyanionic cyclodextrins

Publication date: Available online 10 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Jian-Guang Cheng, Hua-Jiang Yu, Yong Chen, Yu Liu
The binding stoichiometry, binding constants, and inclusion mode of some water-soluble negatively charged cyclodextrin derivatives, i.e. heptakis-[6-deoxy-6-(3-sulfanylpropanoic acid)]-β-cyclodextrin(H1), heptakis-[6-deoxy-6-(2-sulfanylacetic acid)]-β-cyclodextrin(H2), mono-[6-deoxy-6-(2-sulfanylacetic acid)]-β-cyclodextrin (H3) and mono-[6-deoxy-6-(3-sulfanylpropanoic acid)]-β-cyclodextrin (H4), with three anticancer drugs, i.e. irinotecan hydrochloride; topotecan hydrochloride; doxorubicin hydrochloride, were investigated by means of ¹H NMR, UV-Vis spectroscopy, mass spectra and 2D NMR. Polyanionic cyclodextrins H1-H2 showed the significantly high binding abilities of up to 2.6 × 10⁴∼2.0 × 10⁵ M^-1 towards the selected anticancer drugs, which were nearly 50-1000 times higher than the corresponding Ks values of native β-cyclodextrin. In addition, these polyanionic cyclodextrins also showed the pH-controlled release behaviors. That is, the anticancer drugs could be efficiently encapsulated in the cyclodextrin cavity at a pH value similar to that of serum but sufficiently released at an endosomal pH value of a cancer cell, which would make these cyclodextrin derivatives the potential carriers for anticancer drugs.

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Structure–activity relationships of succinimidyl-Cys-C(O)-Glu derivatives with different near-infrared fluorophores as optical imaging probes for prostate-specific membrane antigen

Publication date: Available online 10 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Daiko Matsuoka, Hiroyuki Watanabe, Yoichi Shimizu, Hiroyuki Kimura, Yusuke Yagi, Ryoko Kawai, Masahiro Ono, Hideo Saji
Prostate-specific membrane antigen (PSMA), which is overexpressed in malignant prostate cancer (PCa), is an ideal target for imaging and therapy of PCa. We previously reported a PSMA imaging probe, 800CW-SCE, based on succinimidyl-Cys-C(O)-Glu (SCE) for optical imaging of PCa. In this study, we investigated the structure–activity relationships of novel SCE derivatives with five different near-infrared (NIR) fluorophores (IRDye 680LT, IRDye 750, Indocyanine Green, Cyanine 5.5, and Cyanine 7) as optical imaging probes targeting PSMA. An in vitro binding assay revealed that 800CW-SCE, 680LT-SCE, and 750-SCE exhibited higher binding affinity than 2-PMPA, which is known as a PSMA inhibitor. These three SCE derivatives were internalized into PSMA-positive cells (LNCaP cells) but not into PSMA-negative cells (PC-3 cells). In the in vivo imaging study, 800CW-SCE and 750-SCE were highly accumulated in LNCaP tumors but not in PC-3 tumors, and the ratio of LNCaP/PC-3 accumulation of 800CW-SCE was higher than that of 750-SCE. The present study may provide valuable molecular design information for the future development of new PSMA imaging probes based on the SCE scaffold.

Graphical abstract

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Synthesis, structure-activity relationships and preliminary mechanism study of N-benzylideneaniline derivatives as potential TLR2 inhibitors

Publication date: Available online 10 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Shaoyi Cai, Gengzheng Zhu, Xiaohong Cen, Jingjie Bi, Jingru Zhang, Xiaoshan Tang, Kun Chen, Kui Cheng
Toll-like receptor 2 (TLR2) can recognize pathogen-associated molecular patterns to defense against invading organisms and has been represents an attractive therapeutic target. Until today, none TLR2 small molecule antagonist have been developed in clinical trial. Herein, we designed and synthesized 50 N-benzylideneaniline compounds with the help of CADD. And subsequent in vitro studies leading to the optimized compound SMU-A0B13 with most potent inhibitory activity to TLR2 (IC50=18.21 ± 0.87 μM). Preliminary mechanism studies indicated that this TLR2 inhibitor can work through the NF-κB signaling pathway with high specificity and low toxicity, and can also efficiently downregulate inflammatory cytokines, such as SEAP, TNF-α and NO in HEK-Blue hTLR2, human PBMC and Raw 264.7 cell lines. Additionally, the docking situation also indicate SMU-A0B13 can well bind to the TLR2-TIR (PDB: 1FYW) active domain, which probably explains the bioactivity.

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Neuronal autophagy and intercellular regulation of homeostasis in the brain

Publication date: August 2018
Source:Current Opinion in Neurobiology, Volume 51
Author(s): Aditi Kulkarni, Jessica Chen, Sandra Maday
Neurons are particularly dependent on robust quality control pathways to maintain cellular homeostasis and functionality throughout their extended lifetime. Failure to regulate protein and organelle integrity is linked to devastating neurodegenerative diseases. Autophagy is a lysosomal degradation pathway that maintains homeostasis by recycling damaged or aged cellular components. Autophagy has important functions in development of the nervous system, as well as in neuronal function and survival. In fact, defects in autophagy underlie neurodegeneration in mice and humans. Here, we review the compartment-specific dynamics and functions for autophagy in neurons. Emerging evidence suggests novel pathways for the intercellular coordination of quality control pathways between neurons and glia to maintain homeostasis in the brain.



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Axonal transport and maturation of lysosomes

Publication date: August 2018
Source:Current Opinion in Neurobiology, Volume 51
Author(s): Shawn M Ferguson
Lysosomes perform degradative functions that are important for all cells. However, neurons are particularly dependent on optimal lysosome function due to their extremes of longevity, size and polarity. Axons in particular exemplify the major spatial challenges faced by neurons in the maintenance of lysosome biogenesis and function. What impact does this have on the regulation and functions of lysosomes in axons? This review focuses on the mechanisms whereby axonal lysosome biogenesis, transport and function are adapted to meet neuronal demand. Important features include the dynamic relationship between endosomes, autophagosomes and lysosomes as well as the transport mechanisms that support the movement of lysosome precursors in axons. A picture is emerging wherein intermediates in the lysosome maturation processes that would only exist transiently within the crowded confines of a neuronal cell body are spatially and temporally separated over the extreme distances encountered in axons. Axons may thus offer significant opportunities for the analysis of the mechanisms that control lysosome biogenesis. Insights from the genetics and pathology of human neurodegenerative diseases furthermore emphasize the importance of efficient axonal transport of lysosomes and their precursors.



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The electrical significance of axon location diversity

Publication date: August 2018
Source:Current Opinion in Neurobiology, Volume 51
Author(s): Maarten HP Kole, Romain Brette
The axon initial segment (AIS) is a unique domain of the proximal axon serving critical electrical and structural roles including the initiation of action potentials and maintenance of cellular polarity. Recent experimental and theoretical advances demonstrate that the anatomical site for initiation is remarkably diverse. The AIS location varies not only axially, along the axon, but axons also emerge variably from either the soma or proximal dendrites. Here, we review the evidence that the diversity of AIS and axon location has a substantial impact on the electrical properties and speculate that the anatomical heterogeneity of axon locations expands synaptic integration within cell types and improves information processing in neural circuits.



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Advances in understanding neural mechanisms of social dominance

Publication date: April 2018
Source:Current Opinion in Neurobiology, Volume 49
Author(s): Tingting Zhou, Carmen Sandi, Hailan Hu
Dominance hierarchy profoundly impacts social animals' survival, physical and mental health and reproductive success. As the measurements of dominance hierarchy in rodents become established, it is now possible to understand the neural mechanism mediating the intrinsic and extrinsic factors determining social hierarchy. This review summarizes the latest advances in assay development for measuring dominance hierarchy in laboratory mice. It also reviews our current understandings on how activity and plasticity of specific neural circuits shape the dominance trait and mediate the 'winner effect'.



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Effect of language experience on selective auditory attention: An event-related potential study

Publication date: Available online 9 March 2018
Source:International Journal of Psychophysiology
Author(s): Pia Rämä, Alina Leminen, Satu Koskenoja-Vainikka, Miika Leminen, Kimmo Alho, Teija Kujala
Dual language experience has typically been shown to improve various executive control functions. We investigated with event-related brain potentials (ERPs) recorded from early (natively) bilingual speakers and control participants whether it also affects auditory selective attention. We delivered to our participants two tone streams, one to the left and one to the right ear. Both streams consisted of standard tones and two types of infrequent deviant tones which had either an enhanced duration or intensity. The participants were instructed to attend either to the right or left stream and to detect longer-duration deviants in the attended stream. The results showed that the early bilinguals did not outperform the controls in target detection accuracy or speed. However, the late portion of the attention-related ERP modulation (the negative difference, Nd) was larger over the left hemisphere in the early bilinguals than in the controls, suggesting that the maintenance of selective attention or further processing of selectively attended sounds is enhanced in the bilinguals. Moreover, the late reorienting negativity (RON) in response to intensity-deviant tones was larger in the bilinguals, suggesting more efficient disengagement of attention from distracting auditory events. Hence, our results demonstrate that brain responses associated with certain aspects of auditory attention are enhanced in the bilingual adults, indicating that early dual language exposure modulates the neuronal responsiveness of auditory modality.



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Rationnel biologique de l’immunothérapie des cancers

Publication date: Available online 7 February 2018
Source:Revue des Maladies Respiratoires
Author(s): J. Benzaquen, C.-H. Marquette, N. Glaichenhaus, S. Leroy, P. Hofman, M. Ilié
IntroductionL'immunothérapie vise à promouvoir la réponse immunitaire anticancéreuse via une réponse immune contre certains antigènes tumoraux.État des connaissancesL'immunosurveillance module l'immunogénicité des tumeurs. Pour être efficace, elle doit comporter l'activation de lymphocytes T CD4⁺ et CD8⁺ et de l'immunité innée. Des molécules de costimulation activatrices et inhibitrices régulent l'activation lymphocytaire T au niveau de checkpoints de l'immunité notamment PD-1/PD-L1 et CTLA-4. La résistance immunitaire adaptative est un mode de résistance des tumeurs à l'immunosurveillance par le biais de ces checkpoints.PerspectivesLa combinaison de plusieurs immunothérapies entre elles ou avec la chimiothérapie et la radiothérapie et des anticorps contre d'autres molécules de costimulation sont en développement. Le développement de biomarqueurs capables de sélectionner une population cible et de prédire cette réponse thérapeutique représente un défi majeur. Le séquençage haut débit des tumeurs pourrait permettre d'affiner « l'immunoscore ». Le TCR intratumoral semble représenter un biomarqueur prometteur.ConclusionsLe développement de l'immunothérapie pose de nombreux défis et nécessitera de s'appuyer sur des données de recherche préclinique et translationnelle.IntroductionImmunotherapy aims to promote the immune system's activity against malignant cells by stimulating the response to several tumor antigens.State of the artImmunosurveillance may adjust the immunogenicity of tumors. To be effective, immunity must induce the specific activation of CD4+ and CD8+ T lymphocytes, as well as activation of innate immunity. Activator and inhibitory costimulatory molecules regulate T lymphocyte activation at immunity checkpoints such as PD-1/PD-L1 and CTLA-4. Adaptive immune resistance confers tumour resistance to immunosurveillance through these immune checkpoints.PerspectivesApproaches involving the combination of several immunotherapies with each other or with chemotherapy and radiotherapy and antibodies against other molecules of costimulation are under development. The development of biomarkers, which can select a targeted population and predict therapeutic response, represents a major challenge. Tumour high-throughput sequencing could refine "immunoscore". Intratumoral T cell receptor seems to represent a promising biomarker.ConclusionsNumerous challenges still remain in developing research approaches for the development of immunotherapies.



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Zika virus: From an obscurity to a priority

Publication date: Available online 9 March 2018
Source:Microbes and Infection
Author(s): Cheryl Yi-Pin Lee, Lisa F.P. Ng
Despite being discovered approximately 70 years ago, Zika virus (ZIKV) has received little attention, until the occurrence of alarming epidemics in the Pacific Islands and Latin America between 2013 and 2016. These series of outbreaks resulted in crippling neurological complications in adults, and congenital deformities in new-borns. The dire outcomes marked ZIKV as a re-emerging pathogen of public health concern. Over a period of two years, extensive studies have been conducted to understand different aspects of ZIKV from pathogen biology to infection, including the immune response during virus-host interplay in established animal models, as well as potential therapeutics against ZIKV infection. The vast diversity of novel findings has added value to ZIKV research, and a strategic consolidation is crucial to encompass the latest advances and developments, as well as missing pieces of the puzzle. This review thus aims to provide a concise yet extensive update on current ZIKV studies.



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Editorial board

Publication date: February 2018
Source:Microbes and Infection, Volume 20, Issue 2





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Regional-level exchange in Postclassic Central Mexico

Publication date: June 2018
Source:Journal of Anthropological Archaeology, Volume 50
Author(s): Angela C. Huster
This article uses evidence of regional-scale ceramic exchange to evaluate three proposed causal factors (Aztec imperial expansion, bottom-up demand, and elite competition) for the development of the market-based economy of Postclassic Central Mexico. The factors used to evaluate these models may be applied more widely to other cases of market development. Using previously published datasets, I compare the quantities and diversities of non-local ceramics from sites in the Basin of Mexico, Morelos, and the Toluca Valley regions of central highland Mexico across the Middle (CE 1150–1350) and Late (CE 1350–1521) Postclassic periods. The results show that the highest proportion of trade occurs under Aztec rule, and is dominated by ceramics exported out of the Basin of Mexico. However, areas outside the Basin of Mexico have higher numbers of trading partners, and these ties are well developed during the Middle Postclassic. These results provide partial support for both bottom-up demand and elite competition as causal factors for market development. This article also demonstrates the continued utility of legacy data and emphasizes the need to make basic data sets available for new analyses.



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Autopsy Neuropathology Findings in a Child with Chronic Infantile Krabbe Leukoencephalopathy

Publication date: Available online 9 March 2018
Source:Pediatric Neurology
Author(s): Marc R. Del Bigio




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Passing the Newborn Hearing Screen Does Not Always Exclude Infectious Congenital Acquired Hearing Loss

Publication date: Available online 8 February 2018
Source:Pediatric Neurology
Author(s): Elizabeth Sabroske, Melissa D. Svoboda, Yu-Tze Ng




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Abobotulinumtoxina Efficacy and Safety in Children with Equinus Foot Previously Treated with Botulinum Toxin

Publication date: Available online 7 February 2018
Source:Pediatric Neurology
Author(s): Edward Dabrowski, Marcin Bonikowski, Mark Gormley, Magali Volteau, Philippe Picaut, Mauricio R. Delgado
BackgroundThe effects of botulinum toxin are transient, and repeat injections are required in children with lower-limb spasticity. However, the efficacy of botulinum toxin in patients who have received previous injections has remained largely unexplored.MethodsWe present subgroup analyses of a Phase III study conducted in ambulatory children (aged 2–17) with spastic equinus foot. Patients were randomized to single doses of abobotulinumtoxinA 10U/kg/leg, 15U/kg/leg or placebo injected into the gastrocnemius-soleus complex (one/both legs). The first analysis was pre-specified to review the effect of abobotulinumtoxinA in children previously treated with botulinum toxin versus those new to the treatment; a second post-hoc analysis evaluated the effect of abobotulinumtoxinA in children who changed botulinum toxin formulation.ResultsOf the 241 randomized patients, 113 had previously received botulinum toxin, including 86 who had been treated with another formulation. In both analyses, muscle tone (modified Ashworth Scale) and the Physicians Global Assessment at week- 4 improved with abobotulinumtoxinA treatment versus placebo, regardless of baseline botulinum toxin status. Placebo responses in patients new to treatment were consistently higher than in the previously treated group.ConclusionsThese results demonstrate similar abobotulinumtoxinA efficacy and safety profiles in children with spasticity who are new to botulinum toxin treatment and those previously treated. The efficacy and safety of abobotulinumtoxinA treatment in these previously-treated patients were comparable with the overall trial population, indicating that doses of 10U/kg/leg and 15 U/kg/leg are suitable starting doses for children with spasticity regardless of the previous botulinum toxin preparation used.



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